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:

• Safety Outcomes of Brolucizumab in nAMD
• Delayed Intravitreal Anti-VEGF Therapy for Treating Retinal Pathology
• Impact of Intra- and Subretinal Fluid on Vision Based on Volume Quantification in the HARBOR Trial
• Correlation Between CST and VA Changes in nAMD
• Association of Flow Signals Within Polyps on OCTA with Treatment Responses After Combination Therapy for PCV
• Statin Use and Incidence of AMD: A Meta-Analysis
• Intravitreal Anti-VEGF in DME: Review of Clinical Practice Guidelines
• New UWF Angiography Biomarker for Anti-VEGF Therapy in PDR
• RNFL Thickness as a Measure of Diabetic Retinal Neurodegeneration
• Deep Learning to Detect OCT-Derived DME from Retinal Photographs
  
• Use of Intravitreal Triamcinolone Acetonide After PVD
• Noteworthy

Safety Outcomes of Brolucizumab in nAMD

Researchers wrote that limited data exist on the real-world safety outcomes of patients with neovascular age-related macular degeneration treated with brolucizumab (Beovu, Novartis).

They evaluated the real-world incidence of intraocular inflammation (IOI), including retinal vasculitis (RV) and/or retinal vascular occlusion (RO) for patients with neovascular age-related macular degeneration who underwent brolucizumab treatment, along with risk factors associated with these adverse events. Several of the researchers are employees of Beovu’s maker, Novartis, and others consult for the company.

This cohort study included patients with nAMD in the Intelligent Research in Sight (IRIS) Registry and Komodo Healthcare Map. Patients initiating and receiving one or more brolucizumab injections from October 8, 2019, to June 5, 2020, with up to six months of follow-up were included.

Main outcomes and measures included incidence of IOI, (including RV) and/or RO and RV and/or RO, and risk stratification for the identified risk factors.

A total of 11,161 included eyes (from the IRIS Registry and Komodo Health database) with median follow-up times of 97 and 95 days were included. Here are some of the findings, respectively:
• Most eyes switched from another anti-vascular endothelial growth factor agent (9,686 of 10,654 [90.9 percent] and 10,487 of 11,161 [94 percent]).
   o The most common switch was to aflibercept (7,160 of 9,686 [73.9 percent] and 7,156 of 10,487 [68.2 percent]);
   o Most patients who switched were women (6,105 of 10,654 [57.3 percent] and 6,452 of 11,161 [57.8 percent]).
• The overall incidence of IOI and/or RO was 2.4 percent (255 of 10,654 eyes) and 2.4 percent (268 of 11,161 eyes) for the IRIS and Komodo groups, respectively, and the overall incidence of RV and/or RO was 0.6 percent (59 of 10,654 eyes and 63 of 11,161 eyes), respectively.
• Patients with a history of IOI and/or RO in the 12 months before brolucizumab initiation had an increased observed risk rate (8.7 percent [CI, 6.0 to 11.4 percent] and 10.6 percent [CI, 7.5 to 13.7 percent]) for an IOI and/or RO event in the six months following the first brolucizumab treatment compared with patients without prior IOI and/or RO (2 percent in both data sets).
• An increased estimated incidence rate was observed in women (2.9 percent [CI, 2.5 to 3.3 percent] and 3 percent [CI, 2.6 to 3.4 percent]) compared with men (1.3 percent [CI, 1 to 1.7 percent] and 1.4 percent [CI, 1 to 1.7 percent]), but this risk wasn’t as large as that of a prior IOI and/or RO. Similar findings were observed for patients with RV and/or RO events.

Researchers determined that the incidence rate of IOI and/or RO was approximately 2.4 percent. Patient eyes with IOI and/or RO in the 12 months prior to first brolucizumab injection had the highest observed risk rate for IOI and/or RO in the early months after the first brolucizumab treatment. However, researchers added, given study limitations, the identified risk factors couldn’t be used as predictors of IOI and/or RO events, nor could causality with brolucizumab be determined.

SOURCE: Khanani AM, Zarbin MA, Barakat MR, et al. Safety outcomes of brolucizumab in neovascular age-related macular degeneration: Results from the IRIS registry and Komodo healthcare map. JAMA Ophthalmol 2021; Nov 24. [Epub ahead of print].

Delayed Intravitreal Anti-VEGF Therapy for Treating Retinal Pathology

Researchers determined the anatomical consequences of delaying intravitreal injection (IVI) therapy with anti-vascular endothelial growth factor in patients using a treat-and-extend protocol.

The retrospective medical record review included consecutive patients receiving intravitreal anti-VEGF therapy using a T&E protocol prior to and during the COVID-19 pandemic.

The study included 923 eyes of 691 patients: 58.8 percent (543 eyes) had nvAMD; 25 percent (231 eyes) had DME; and 16.2 percent (149 eyes) had RVO. Mean patient age was 74.5 ±11.7 years.

Here are some of the findings:
• Overall, 56.3 percent of cases had a delay in therapy of ≥7 days:
   o 56.2 percent of nvAMD cases;
   o 61.5 percent of DME cases; and
   o 49 percent of RVO cases.
• The median delay in days among cases ≥7 days late was 21 (IQR 7 to 42) days, with:
   o 21 (IQR 7 to 45) days of delay among patients with nvAMD;
   o 22.5 (IQR 8 to 42) days of delay among patients with DME; and
   o 14 (IQR 7 to 33.5) days of delay among patients with RVO.
• Delaying therapy by ≥7 days resulted in increased central subfield thickness in:
   o 47.5 percent of of nvAMD cases;
   o 58.5 percent of DME cases; and
   o 58.9 percent of RVO cases, with a significant correlation between the length of treatment delay and the increase in CST (Spearman's rho: 0.196; p<0.001).

Researchers wrote that delayed IVI treatment in eyes treated with a T&E protocol was associated with increased macular thickness and potential consequences for visual outcomes.

SOURCE: Navarrete A, Vofo B, Matos K, et al. The detrimental effects of delayed intravitreal anti-VEGF therapy for treating retinal pathology: Lessons from a forced test-case. Graefes Arch Clin Exp Ophthalmol 2022; Jan 7. [Epub ahead of print].

Impact of Intra- and Subretinal Fluid on Vision Based on Volume Quantification in the HARBOR Trial

Investigators assessed functional associations of intra- and subretinal fluid volumes at baseline and after the loading dose, in addition to fluid changes after the first injection in patients with neovascular AMD who received an anti-VEGF treatment over 24 months.

This was a post-hoc analysis of a Phase III, randomized, multicenter trial, in which ranibizumab was administered monthly or in a PRN regimen (HARBOR).

Participants included study eyes of 1,094 treatment-naïve nAMD patients. Intraretinal (IRF) and subretinal (SRF) fluid volumes were segmented automatically on monthly SD-OCT images. Fluid volumes and changes were included as covariates into longitudinal mixed effects models, modeling BCVA trajectories.

Main outcome measures included: BCVA estimates corresponding to baseline; follow-up and persistent IRF/SRF volumes following the loading dose; BCVA estimates of change in fluid volumes following the first injection; and marginal and conditional R².

Here are some of the findings:
• Analysis of 22,494 volumetric scans revealed that foveal IRF consistently showed a negative correlation with BCVA at baseline and subsequent visits (-3.23 and -4.32 letters/100 nl, respectively).
• After the first injection, BCVA increased by +2.13 letters/100 nl decrease of foveal IRF.
• Persistent IRF was associated with lower baseline BCVA and less improvement.
• Foveal SRF correlated with better BCVA at baseline and subsequent visits (+6.52 and +1.42 letters/100 nl, respectively).
• After the first injection, SRF decrease was associated with significant vision gain (+5.88 letters/100 nl).
• Foveal fluid correlated more with BCVA than parafoveal IRF/SRF.

Investigators found that, while IRF consistently correlated with decreased function and recovery throughout therapy, SRF was associated with a more pronounced functional improvement. Investigators suggested that fluid-function correlation represented an essential basis for the development of personalized treatment regimens.

SOURCE: Riedl S, Vogl W-D, Waldstein SM, et al. Impact of intra- and subretinal fluid on vision based on volume quantification in the HARBOR trial. Ophthalmol Retina 2021; Dec 15. [Epub ahead of print].

Correlation Between CST and VA Changes in nAMD

Investigators aimed to determine a correlation between changes in central subfield thickness and best-corrected visual acuity in neovascular age-related macular degeneration receiving anti-VEGF agents, as part of a post hoc analysis of VIEW 1 and 2 randomized clinical trials.

This analysis included participants randomized: to ranibizumab 0.5 mg q4 weeks (Rq4); intravitreal aflibercept injection (IAI) 2 mg q4 weeks (2q4); and IAI q8 weeks after three monthly doses (2q8) to week 52, followed by capped pro re nata (at least q12 weeks) dosing to week 96. The relationship between changes in CST and BCVA was determined using Pearson correlation coefficient.

Here are some of the findings:
• Of 1,815 eyes, 595 were assigned to Rq4, 613 to 2q4, and 607 to 2q8 arms.
• Correlations (CI at weeks 12, 52 and 96 were):
   o -0.08 (-0.17, 0.00), -0.05 (-0.14, 0.04) and -0.15 (-0.24, -0.06) for Rq4;
   o -0.13 (-0.21, -0.04), -0.06 (-0.14, 0.03) and -0.04 (-0.13, 0.05) for 2q4; and
   o -0.04 (-0.12, 0.05), -0.01 (-0.09, 0.08) and -0.01 (-0.10, 0.09) for 2q8.
• Linear regression analysis adjusted for relevant baseline factors showed CST changes accounted for 11 percent of BCVA changes.
• Every 100-µm decrease in CST was associated with a 0.3-letter decrease (p=0.25) at week 52 and a 0.14-letter decrease (p=0.69) at week 96.

Investigators found weak or no correlation between changes in CST and BCVA with either agent or regimen, suggesting changes in CST shouldn’t be used as a surrogate for visual acuity outcomes in nAMD.

SOURCE: Nanegrungsunk O, Gu SZ, Bressler SB, et al. Correlation of change in central subfield thickness and change in visual acuity in neovascular AMD: Post hoc analysis of VIEW 1 and 2. Am J Ophthalmol 2021; Nov 27. [Epub ahead of print].

Association of Flow Signals Within Polyps on OCTA with Treatment Responses After Combination Therapy for PCV

Researchers evaluated the changes of blood circulation within the polypoidal lesions by OCT angiography in eyes with polypoidal choroidal vasculopathy after combination therapy with aflibercept and photodynamic therapy.

A total of 46 eyes from 46 patients who underwent the combination therapy for PCV were followed for more than six months. OCT angiography covering an area of 6 × 6 mm² including the macula were performed at baseline, two weeks, and three and six months post-treatment.

Here are some of the findings:

• The subretinal fluid resolved within three months after treatment in 44 eyes (95.7 percent), and 27 eyes (58.7 percent) showed no recurrence, with no additional treatment.
• Seventeen eyes (37 percent) showed recurrence, and two eyes (4.3 percent) showed poor response.
• On OCTA at two weeks after treatment, flow signals were detected in three of 27 eyes (11.1 percent) without recurrence and in eight of 19 eyes (42.1 percent) with recurrence or poor responses.
• A detectable flow signals at two weeks was significantly associated with recurrence or poor response (p=0.032).

Researchers wrote that persistent flow signals within polyps on OCTA at two weeks after combination therapy suggested less effectiveness of the initial treatment.

SOURCE: Fukuyama H, Komuku Y, Araki T, et al. Association of flow signals within polyps on optical coherence tomography angiography with treatment responses after combination therapy for polypoidal choroidal vasculopathy. Retina 2021; Dec 22. [Epub ahead of print].

Statin Use and Incidence of AMD: A Meta-Analysis

Age-related macular degeneration shares many of the same risk factors with atherosclerosis, and some researchers have postulated that lipid-lowering agents may help in preventing AMD. This meta-analysis investigated the possible role of statins in the prevention of AMD onset and progression.

Scientists systematically searched MEDLINE, EMBASE, Cochrane CENTRAL and the reference lists of included studies from inception to September 2020. Studies were included if they measured the risk of AMD development or progression with statin use. The primary outcomes assessed were AMD incidence and progression. Secondary outcomes included the incidence of early AMD, late AMD, choroidal neovascularization and geographic atrophy.

Here are some of the findings:

• 21 articles (1 RCT, 20 observational studies) collectively reporting on 1,460,989 participants were included.
• The pooled risk ratios for statin use were:
• on any AMD incidence: 1.05 [CI, 0.85 to 1.29] (p=0.44);
• on early AMD incidence: 0.99 [CI, 0.88 to 1.11] (p=0.86); and
• on late AMD incidence: 1.15 [0.90,1.47] (p=0.27).
• In patients with existing AMD, the respective risk ratios for statin use were:
• on incidence of AMD progression: 1.04 [CI, 0.70,1.53] (p=0.85);
• on incidence of CNV: 0.99 [CI, 0.66 to1.48] (p=0.95); and
• on incidence of GA: 0.84 [CI, 0.58 to 1.22] (p=0.36).

Scientists found no significant difference in the incidence or progression of AMD based on statin use.

SOURCE: Eshtiaghi A, Popovic MM, Sothivannan A, et al. Statin use and the incidence of age-related macular degeneration: A meta-analysis. Retina 2021; Dec 30. [Epub ahead of print].

Intravitreal Anti-VEGF in DME: Review of Clinical Practice Guidelines

Researchers identified diabetic macular edema clinical practice guidelines that made anti-VEGF treatment recommendations, and assessed their reporting quality and their considerations when making recommendations.
Eligibility criteria included CPGs published between December 2009 and December 2019, that made explicit anti-VEGF recommendations in DME.

Sources of evidence included a sensitive search strategy in Embase, Google Scholar and hand-searching on 165 websites. Researchers extracted information from each CPG with a previously piloted sheet. Two independent authors applied the Appraisal of Guidelines, Research and Evaluation tool (AGREE-II) assessment for each CPG.

Here are some of the findings:
• Twenty-one sources including CPGs recommended anti-VEGF for DME, with wide variation among the clinical aspects included, such as location of DME, visual acuity required, and therapeutic alternatives or discontinuation.
• Most had a poor quality of reporting based on the AGREE-II tool assessment, especially those developed by ophthalmological societies, those that had exclusive content about DME, and those in which most authors disclosed conflict of interests with pharmaceutical industry or where the authors didn’t report COIs.
• Pharmaceutical-sponsored CPGs didn’t use systematic reviews to support their recommendations.
• Very few recommendations considered patient values and preferences, equity, acceptability and feasibility of the intervention.

Researchers determined that most of the clinical practice guidelines that made recommendations of anti-VEGF for DME had poor quality of reporting, didn’t use systematic reviews and didn’t consider patients' values and preferences.

SOURCE: Vargas-Peirano M, Verdejo C, Vergara-Merino L, et al. Intravitreal antivascular endothelial growth factor in diabetic macular oedema: scoping review of clinical practice guidelines recommendations. Br J Ophthalmol 2021; Dec 14. [Epub ahead of print].

New UWF Angiography Biomarker for Anti-VEGF Therapy in PDR

Researchers quantified changes of the retinal vascular bed area (RVBA) on stereographically projected ultra-widefield (UWF) fluorescein angiography (FA) images in eyes with proliferative diabetic retinopathy following anti-vascular endothelial growth factor injection.

The prospective, observational study included early-phase UWF FA images (Optos 200Tx) of 40 eyes with PDR and significant non-perfusion obtained at baseline and after six months. The images were stereographically projected by correcting peripheral distortion, and the global retinal vasculature on UWF FA was extracted for calculating RVBA by summing the real size (mm²) of all the pixels automatically.

Here are some of the findings:
• For the entire cohort, global RVBA for the entire retina decreased from 67.1 ±15.5 mm² to 43.6 ±18.8 mm² after anti-VEGF treatment at six months (p<0.001).
• In the sub-group receiving monthly anti-VEGF injections, global RVBA decreased from 68.7 ±16.2 mm² to 33.9 ±13.3 mm² (p<0.001).
• In the sub-group receiving anti-VEGF every three months, global RVBA decreased from 65.6 ±15.1 mm² to 50.8 ±19.3 mm² (p=0.004).

Researchers wrote that RVBA appeared to be a new biomarker indicating efficiency of retinal vascular changes after anti-VEGF injection. They added that eyes with PDR and significant non-perfusion demonstrated reduced RVBA following anti-VEGF treatment.

SOURCE: Fan W, Nittala MG, Wykoff CC, et al. A new biomarker quantifying the effect of anti-VEGF therapy in eyes with proliferative diabetic retinopathy on ultra-wide field fluorescein angiography: Recovery study. Retina 2021; Nov 19. [Epub ahead of print].

RNFL Thickness as a Measure of Diabetic Retinal Neurodegeneration

Markers for clinical evaluation of structural changes caused by diabetic retinal neurodegeneration (DRN) haven’t been established. To study the potential role of peripapillary retinal nerve fiber layer (pRNFL) thickness as a marker for DRN, investigators evaluated the relationship between diabetes and glycemic control, regardless of diabetes status and pRNFL thickness.

With data from a population-based cohort, they used general linear mixed models (GLMMs) with a random intercept for patients and eyes to assess the association between pRNFL thickness (via GDx) and demographics, and systemic and ocular parameters, adjusting for typical scan score. GLMMs were also used to determine the relationship between glycated hemoglobin/HbA1c (irrespective of diabetes diagnosis) and pRNFL thickness; diabetes and pRNFL thickness; and pRNFL quadrants affected in diabetics.

A total of 7,076 participants were included. Here are some of the findings:

• Per unit increase in HbA1c (after controlling for covariates):
• inferior pRNFL thickness was 0.94 µm lower (CI, -1.28 to -0.60 µm);
• superior pRNFL thickness was 0.83 µm lower (CI, -1.17 to -0.49 µm);
• and temporal pRNFL thickness was 1.33 µm higher (CI, 0.99 to 1.67 µm).
• Nasal pRNFL thickness wasn’t significantly associated with HbA1c (p=0.23).
• Similar trends were noted when diabetes was used as the predictor.

Investigators found that superior and inferior pRNFL was significantly thinner in those with higher HbA1c levels and/or diabetes, representing areas of the pRNFL that may be most affected by diabetes.

SOURCE: Zafar S, Staggers KA, Gao J, et al. Evaluation of retinal nerve fibre layer thickness as a possible measure of diabetic retinal neurodegeneration in the EPIC-Norfolk Eye Study. Br J Ophthalmol 2021; Dec 24. [Epub ahead of print].