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:

• Outcomes of Eyes with Intraocular Inflammation after Brolucizumab: Post Hoc Analysis of HAWK and HARRIER
• Efficacy & Safety of Biosimilar FYB201 Compared with Ranibizumab in nAMD
• Anti-VEGF-resistant Subretinal Fluid Associated with Better Vision and Reduced Risk of Macular Atrophy
• Early Predictive Factors of Visual Loss in nAMD Under Anti-VEGF: The GEFAL Study
• NIH Study Affirms AREDS2 Results
• Prevalence of Visual Acuity Loss or Blindness in the US: A Bayesian Meta-analysis
• Dilated Choroidal Veins & Myopic Macular Neovascularization Recurrence
• Intravitreal Conbercept for DME
• OCTA-measured Area of Retinal Neovascularization Predictive of Treatment Response and PDR Progression
• Using OCTA to Compare Central Macular Fluid Volume & Central Subfield Thickness in DME
• T&E Regimen with Aflibercept for BRVO: 1-Year Results of PLATON
• Noteworthy

 

Outcomes of Eyes with Intraocular Inflammation after Brolucizumab: Post Hoc Analysis of HAWK and HARRIER

This analysis of the Phase III HAWK and HARRIER trials sought to provide insights on the timing of presentation, management and outcomes of intraocular inflammation (IOI)-related adverse events (AEs), as reported by investigators in these trials.

The post hoc analysis of investigator-reported IOI-related AEs in HAWK and HARRIER included 49 eyes of 1,088 brolucizumab-treated eyes (3 mg or 6 mg) that experienced at least one IOI-related AE.

Researchers analyzed reports of IOI-related AEs and provided statistics for outcome measures. The main outcome measures included incidence and description of eyes with IOI-related AEs, timing of presentation, management, clinical outcomes and brolucizumab treatment after the first IOI-related AE.

Here are some of the findings:
• A total of 70 IOI-related AEs were reported in 49 eyes.
• Prior to the onset of first IOI-related AE, eyes received a mean of 3.9 ±2.2 brolucizumab injections.
• Median (25th to 75th percentile) time to first IOI-related AE from the last administered brolucizumab injection was 18 (four to 29) days.
• Of the 70 AEs, 61 (87.1 percent) were treated, the majority with topical corticosteroids; systemic and intraocular corticosteroids were used for three AEs each.
• Overall, inflammation resolved completely in 39 eyes (79.6 percent), resolved with sequelae in five eyes (10.2 percent), and it didn’t resolve in five eyes (10.2 percent) by the end of the study.
• Overall, mean best-corrected visual acuity change was:
   o from baseline to the end of the study: -0.84 ±20.6 ETDRS letters;
   o before AE to the lowest BCVA in three months after AE: -16.31 ±17.6 letters; and
   o from before AE to the end of the study was -0.22 ±18.9 letters.
• Of the 36 eyes (73.5 percent) that continued on brolucizumab after the first IOI-related AE, 24 completed the trials and 12 discontinued them; the mean BCVA change in the eyes was 2.6 ±17.6, 7.8 ±13.2 and -7.7 ±21.3 letters, respectively, from baseline to the end of the study.
• The remaining 13 eyes (26.5 percent) weren’t treated with brolucizumab after the first IOI-related AE and had a mean BCVA change of -10.4 ±25.5 letters from baseline to the end of the study.

Researchers wrote that their findings highlighted the need for continued vigilance and monitoring for any signs of IOI-related events in patients receiving brolucizumab.

SOURCE: Singer M, Albini TA, Seres A, et al. Clinical characteristics and outcomes of eyes with intraocular inflammation after brolucizumab: Post hoc analysis of HAWK and HARRIER. Ophthalmol Retina 2021; May 7. [Epub ahead of print].

 

Efficacy & Safety of Biosimilar FYB201 Compared with Ranibizumab in nAMD  

Investigators assessed the clinical equivalence of the proposed biosimilar FYB201 and reference ranibizumab in individuals with treatment-naive, subfoveal choroidal neovascularization caused by neovascular age-related macular degeneration.

This prospective, multicenter, evaluation-masked, parallel-group, 48-week, Phase III randomized study included 477 patients randomly assigned to receive FYB201 (n=238) or reference ranibizumab (n=239).

Patients received FYB201 or ranibizumab 0.5 mg by intravitreal injection in the study eye every four weeks.

The primary endpoint was change from baseline in best-corrected visual acuity by Early Treatment Diabetic Retinopathy Study letters at eight weeks prior to the third monthly intravitreal injection. Biosimilarity of FYB201 to its originator was assessed via a two-sided equivalence test, with an equivalence margin in BCVA of three ETDRS letters.

Here are some of the findings:
• BCVA improved in both groups, with a mean improvement of +5.1 (FYB201) and +5.6 (reference ranibizumab) ETDRS letters at week eight.
• The analysis of covariance (ANCOVA) least squares mean difference for the change from baseline between FYB201 and reference ranibizumab was -0.4 ETDRS letters; CI, -1.6 to 0.9.
• The primary endpoint was met, as the CI was within the predefined equivalence margin.
• Adverse events were comparable between treatment groups.

Investigators found that the FYB201 biosimilar referenced ranibizumab in terms of clinical efficacy, and ocular and systemic safety in the treatment of patients with nAMD.

SOURCE: Holz FG, Oleksy P, Ricci F, et al.; COLUMBUS-AMD Study Group. Efficacy and safety of biosimilar FYB201 compared with ranibizumab in neovascular age-related macular degeneration. Ophthalmology 2021; May 3. [Epub ahead of print].

Anti-VEGF-resistant Subretinal Fluid Associated with Better Vision and Reduced Risk of Macular Atrophy

Scientists evaluated relationships between subretinal fluid (SRF), macular atrophy (MA) and visual outcomes in ranibizumab-treated neovascular age-related macular degeneration.

The post hoc HARBOR trial (NCT00891735) analysis included ranibizumab-treated (0.5 or 2.0 mg monthly or as needed, all treatment arms pooled) eyes with nAMD and baseline (screening, baseline and week 1) SRF. SRF presence, SRF thickness (0, >0 to 50, >50 to 100 and >100 µm) and subretinal fluid volume (SRFV) were determined by spectral domain optical coherence tomography. Best-corrected visual acuity was assessed. MA was identified using fluorescein angiograms and color fundus photographs, as well as SD-OCT.

Seven hundred eighty-five of 1,097 eyes met analysis criteria. Here are some of the findings:

• In eyes without baseline MA, residual vs. no SRF at month (M) 3 was associated with lower MA rates at M12 (5.1 vs. 22.1 percent) and M24 (13.3 vs. 31.2 percent) (both p<0.0001); MA percentages at M12/M24 were similar among patients with residual SRF at M6.
• Higher baseline SRFV was associated with a lower MA rate.
• Greater mean BCVA was observed with residual SRF of any thickness (>0-50 µm, 71.2 letters; >50-100 µm, 71.3 letters; >100 µm, 69.2 letters) vs. no SRF (63.6 letters), but the change in BCVA from baseline to M12 or M24 was the same for eyes with or without treatment-resistant subretinal fluid (TR-SRF) at M3 or M6.

Scientists wrote that TR-SRF wasn’t detrimental to vision outcomes over two years, regardless of thickness. They added that MA rates were significantly higher without TR-SRF.

SOURCE: Zarbin MA, Hill L, Maunz A, et al. Anti-VEGF-resistant subretinal fluid is associated with better vision and reduced risk of macular atrophy. Br J Ophthalmol 2021; May 26. [Epub ahead of print.]

Early Predictive Factors of Visual Loss in nAMD Under Anti-VEGF: The GEFAL Study

Investigators evaluated early predictive factors of visual loss in individuals treated with anti-vascular endothelial growth factor injections under an as-needed regimen for neovascular age-related macular degeneration.

The post-hoc analysis of the randomized controlled trial GEFAL comparing ranibizumab and bevacizumab for neovascular AMD in 393 patients age 50 and older with neovascular AMD was based on one-year data from individuals included in the study.

Patients were put into one of three categories according to the BCVA change at three months (M3) and one year:
   1) patients with no vision loss ≥5 letters at M3 and at one year (absence of loss ≥5-letters);
   2) patients with no vision loss ≥5-letters at M3 but loss ≥5 letters at one year (secondary loss ≥5 letters); and
   3) patients with vision loss ≥5 letters at M3 and one year (initial loss ≥5 letters). The threshold of at least five letters lost indicated clinical significance.

The following factors were evaluated at baseline and at M3: age; sex; BCVA; presence of fluid; central macular thickness; angiographic choroidal neovascularization subtype; CNV area measured in disk area on fluorescein angiography; and the number of intravitreal injections.

Here are some of the findings:
• 225 patients (57.3 percent) didn’t lose ≥5 letters; a secondary loss of ≥5 letters after M3 was found in 109 patients (27.7 percent); and an initial loss of ≥5 letters of BCVA was found in 59 patients (15 percent).
• Baseline characteristics were comparable between the three groups except for the total CNV area, which was larger in the initial and the secondary loss groups (p=0.0412).
• At M3 a significant association was found between presence of subretinal fluid (p=0.0318) and vision loss of ≥5 letters, with an even stronger significant association between the presence of intraretinal fluid (p=0.0066) and vision loss of ≥5 letters.

Investigators found that a large CNV area at baseline was significantly associated with initial or secondary loss of visual acuity ≥5 letters despite anti-VEGF injections. They added that the presence of fluid, both subretinal and intraretinal at M3, was found in patients with poorer trajectories.

SOURCE: Kodjikian L, Rezkallah A, Decullier E, et al; GEFAL Study Group. Early predictive factors of visual loss at 1-year in neovascular age-related macular degeneration under anti-VEGF in the GEFAL study. Ophthalmol Retina 2021; May 12. [Epub ahead of print].

NIH Study Affirms AREDS2 Results

Researchers from the National Eye Institute performed a 10-year follow-on study of the Age-Related Eye Disease Study 2, and found that the results confirm those of the original, five-year study. They shared their results at the recent meeting of the Association for Research in Vision and Ophthalmology.

The AREDS2 clinical trial randomly assigned participants with bilateral intermediate AMD or late AMD in one eye to lutein/zeaxanthin and/or omega-3 fatty acids or placebo. Secondary randomization also evaluated varying doses of beta-carotene (0 vs. 15 mg) and zinc (25 vs. 80 mg). At the end of the clinical trial, a follow-up study was conducted with telephone calls every six months to the surviving AREDS2 participants from the central coordinating center to collect outcome data and adverse events for safety monitoring for an additional five years.

In the study, 6,360 eyes (3,887 patients) were analyzed and 3,047 (48 percent) progressed to late AMD. The main effects of lutein/zeaxanthin vs. no lutein-zeaxanthin and of omega-3 fatty acids vs. no omega-3 fatty acids resulted in hazard ratios of 0.91 (95% CI: 0.89-0.99) (p=0.03) and 1.00 (0.92-1.09) (p=0.91), respectively. When the lutein/zeaxanthin main effect analysis was restricted to those randomized secondarily to beta-carotene, the HR was 0.80 (0.69-92) (p=0.003).

On direct analysis of lutein/zeaxanthin vs. beta-carotene, the HR was 0.85 (0.74-0.98) (p=0.026). For the comparisons of low vs. high zinc and no beta-carotene vs. beta-carotene, the HRs were 1.04 (p=0.48) and 1.04 (p=0.50), respectively. For those randomized to beta-carotene, the odds ratio (OR) of developing lung cancer was 1.92 (1.11-3.31)(p=0.02) while the OR for those randomized to lutein/zeaxanthin was 1.19 (0.82-1.73) (p=0.35).

The researchers say that, again, they showed that lutein/zeaxanthin was safer than using beta-carotene, as the latter was found to double the chance of lung cancer. They say the use of lutein/zeaxanthin showed a more favorable response when compared with beta-carotene.

SOURCE: Chew EY, Clemons TE, Keenan TD, et al. The results of the 10 year follow-on study of the age-related eye disease study 2 (AREDS2). Presented at the 2021 ARVO Annual Meeting.

Prevalence of Visual Acuity Loss or Blindness in the US: A Bayesian Meta-analysis

Investigators wrote that globally, more than 250 million people live with visual acuity loss or blindness, and people in the United States fear losing vision more than memory, hearing or speech. But they added, it appeared there were no recent empirical estimates of visual acuity loss or blindness for the United States.

As such, the investigators produced estimates of visual acuity loss and blindness by age, sex, race/ethnicity and U.S. state. They obtained data from the American Community Survey (2017), National Health and Nutrition Examination Survey (1999 to 2008), and National Survey of Children's Health (2017), as well as population-based studies (2000 to 2013).

All relevant data from the US Centers for Disease Control and Prevention's Vision and Eye Health Surveillance System were included. The prevalence of visual acuity loss or blindness was estimated, stratified when possible by factors including U.S. state, age group, sex, race/ethnicity and community-dwelling or group-quarters status. Data analysis occurred from March 2018 to March 2020.

Main outcomes or measures included the prevalence of visual acuity loss (defined as a best-corrected visual acuity greater than or equal to 0.3 logMAR) and blindness (defined as a logMAR of 1.0 or greater) in the better-seeing eye.

For 2017, this meta-analysis generated an estimated U.S. prevalence of 7.08 (95% uncertainty interval, 6.32 to 7.89) million people living with visual acuity loss, of whom 1.08 (95% uncertainty interval, 0.82 to 1.30) million people were living with blindness. Of this, 1.62 (95% uncertainty interval, 1.32 to 1.92) million persons with visual acuity loss were younger than 40 years, and 141,000 (95% uncertainty interval, 95,000 to 187,000) persons with blindness were younger than 40 years.

Investigators reported that this analysis of all available data with modern methods produced estimates substantially higher than those previously published.

Dilated Choroidal Veins & Myopic Macular Neovascularization Recurrence

Researchers looked at a possible correlation between the presence of macular dilated choroidal vein (DCV) and the recurrence of myopic macular neovascularization (MNV) after anti-vascular endothelial growth factor treatment.

The medical records of 168 eyes of 163 patients with myopic MNV were reviewed for the presence of macular DCV and episodes of recurrences. A macular DCV was defined as a choroidal vein whose diameter was two times larger than the adjacent veins coursing in the macular area of 5.5 mm diameter.

• Macular DCV existed in 47 eyes (28 percent) with myopic MNV.
• Seventy eyes (41.7 percent) had recurrence during a mean follow-up period of 52.5 ±23 months.
• Recurrence was found in 28 of 47 eyes (59.6 percent) with DCV, which was significantly more frequent than in the 42 of the 121 eyes (34.7 percent) without DCV (p=0.003).
• Cox model analysis showed that macular DCV was an independent risk factor (HR, 2; CI, 1.1 to 3.5) for recurrence.
• The recurrence rate was significantly higher in eyes with DCV within the first two years after the onset than in eyes without DCV.

Researchers concluded that macular DCVs may be indicators of a more aggressive phenotype of eyes with myopic MNV. They suggested that these eyes need careful monitoring after anti-VEGF therapies.

SOURCE: Xie S, Du R, Fang Y, et al. Dilated choroidal veins and their role in recurrences of myopic macular neovascularisations. Br J Ophthalmol 2021; Apr 28. [Epub ahead of print].

Intravitreal Conbercept for DME

Researchers evaluated the efficacy and safety of intravitreal injections of conbercept vs. laser photocoagulation in the treatment of diabetic macular edema.

A 12-month multicenter, randomized, double-masked, double-sham, parallel controlled, Phase III trial (Sailing Study) was followed by a 12-month open-label extension study. Patients with center-involved DME were randomly assigned to receive either laser photocoagulation followed by pro re nata sham intravitreal injections (laser/sham) or sham laser photocoagulation followed by PRN 0.5 mg conbercept intravitreal injections (sham/conbercept). Individuals who entered the extension study received PRN conbercept treatment. The primary endpoint was the change in best-corrected visual acuity from baseline.

A total of 248 eyes were included in the full analysis set, and 157 eyes continued in the extension study. Here are some of the findings:
• Significant improvement in mean change in BCVA from baseline to month 12 was observed in the sham/conbercept group (8.2 ±9.5 letters), whereas no improvement was observed in the laser/sham group (0.3 ±12 letters).
• Individuals in the laser/sham group showed a marked improvement in BCVA after the switch to conbercept in the extension study, and there was no difference in BCVA between the two groups at the end of the extension study.

Researchers reported that the use of a conbercept PRN intravitreal injection regimen improved the BCVA of DME patients, and its efficacy was better than that of laser photocoagulation, which was also observed when eyes treated with laser alone were switched to conbercept.

SOURCE: Liu K, Wang H, He W, et al. Intravitreal conbercept for diabetic macular oedema: 2-year results from a randomised controlled trial and open-label extension study. Br J Ophthalmol 2021 ; May 17. [Epub ahead of print].

 

OCTA-measured Area of Retinal Neovascularization Predictive of Treatment Response and PDR Progression

The purpose of this study was to evaluate the area of retinal neovascularization in patients with treatment-naïve proliferative diabetic retinopathy, as measured by optical coherence tomography angiography as a marker of subsequent treatment response after panretinal photocoagulation, and to determine if this area correlated with area of retinal neovascularization as measured by fluorescein angiography.

En face OCTA scans (4.5 × 4.5 mm) of neovascularizations were obtained at baseline before PRP and at month three and six (M3 and M6) after treatment. Progression of PDR was defined as lesion growth (assessed by ophthalmoscopy and widefield fundus photo) or increasing leakage by Optos ultra-widefield FA. Patients were divided into two groups: progression or non-progression. Mann-Whitney U test and Wilcoxon signed-rank test were used to analyze differences between groups and between time points. Areas of retinal neovascularizations (OCTA and FA) were calculated by algorithms developed in Python (version 3.6.8, the Python Software Foundation).

 

Here are some of the findings:

• Of 21 eyes included, 14 had disease progression.
• Median OCTA area didn’t differ between the two groups (progression vs. non-progression) at baseline (76.40 ±162.03 vs. 72.62 ±94.15, p=0.43) but were statistically significantly larger in the progression group at M6 (276.69 ±168.78 vs. 61.30 ±70.90, p=0.025).
• Median FA area didn’t differ in the progression vs. the non-progression group at BL (111.42 ±143.08 vs. 60.80 ±54.83, p=0.05) or at M6 (200.12 ±91.81 vs. 123.86 ±162.16, p=0.62).
• Intraclass correlation between area by OCTA and FA was -5.99 (CI, -35.28 to 0.993), p=0.71.

In this study of patients with treatment-naïve PDR, researchers showed that increasing area of retinal neovascularization measured by OCTA at M6 indicated progression of disease after PRP. The results suggest that area by OCTA reflects disease activity and that it can be used as an indicator to monitor the progression of PDR over time, and to evaluate treatment response six months after PRP.

SOURCE: Vergmann AS, Sørensen KT, Torp TL, et al. Optical coherence tomography angiography measured area of retinal neovascularization is predictive of treatment response and progression of disease in patients with proliferative diabetic retinopathy. Int J Retina Vitreous 2020; Nov 4;6(1):49.