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:

• Cost Analysis of a T&E Regimen with Anti-VEGFs in nAMD
• Long-term Outcomes of Bacillary Layer Detachment in nAMD
• Systemic Levels of VEGF After Intravitreal Injection of Aflibercept or Brolucizumab for nAMD
• Association of Smoking, Alcohol Consumption, BP, BMI and Glycemic Risk Factors with AMD
• MNV Cytokine Profiles Classified From Pachychoroid/Drusen Perspective
• Accuracy of Double-layer Sign in Detection of MNV Secondary to CSC
• Predicting Treatment Response in Center-involved DME Eyes Treated with Anti-VEGF Injections
• Lapses in Care Among Patients Assigned to Ranibizumab for PDR
• Age-related Changes in the Retinal Microvasculature, Cardiovascular Risk Factors and Smoking Behavior
• Collateral Vessel Development in CRVO and BRVO and Visual Outcomes
  
• Hyperreflective Foci in the Choroid of Normal Eyes
• Noteworthy

Cost Analysis of a T&E Regimen with Anti-VEGFs in nAMD

This study investigated the per-patient costs associated with neovascular age-related macular degeneration treatment, when using aflibercept, bevacizumab, or ranibizumab with a treat-and-extend regimen.

In this cost-minimization model, the per-patient costs in the Netherlands were modeled using a health-care payers' perspective over a three-year time horizon with the assumption that efficacy of treatments was similar. Additionally, the break-even price of the different anti-VEGFs was calculated relative to the cheapest option and injection frequency.

Here are some of the findings:
• The injection frequency varied from 14.2 for aflibercept to 27.4 for bevacizumab in three years; nonetheless, bevacizumab remained the cheapest treatment option (€14,215; $16,487.27), followed by aflibercept (€18,202; $21,111.59) and ranibizumab (€31,048; $36,011.02).
• The medication covered most of the per-patient costs for aflibercept and ranibizumab, while administration covered most of the per-patient costs for bevacizumab.
• The break-even prices of aflibercept and ranibizumab were, respectively, €507 / $588.03 and €60.58 / $70.26 per injection.
• Brolucizumab, which was included in the analysis, was more expensive than aflibercept (€20,446; $23,713.78).
• Brolucizumab would need to reduce to 13.8 injections over three years to be in line with aflibercept’s cost.

Researchers determined that bevacizumab was the cheapest anti-VEGF treatment, followed by aflibercept.

SOURCE: Quist SW, de Jong LA, van Asten F, et al. Cost-minimisation analysis of a treat-and-extend regimen with anti-VEGFs in patients with neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2021; Oct 13:1-13.

Long-term Outcomes of Bacillary Layer Detachment in nAMD  

Investigators evaluated the clinical characteristics, multimodal imaging features, and long-term treatment outcomes of eyes with neovascular age-related macular degeneration and bacillary layer detachment (BALAD) treated with intravitreal anti-vascular endothelial growth factor therapy.

The retrospective, longitudinal, case series included treatment-naive nAMD patients (n=30) showing BALAD on optical coherence tomography undergoing anti-VEGF therapy.

Clinical records and multimodal imaging were reviewed up to four years after diagnosis. Best-corrected visual acuity values were compared over time. The cumulative risk and risk factors of subretinal fibrosis were assessed with Cox regression analyses, and the adjusted hazard ratio (aHR) was computed.

Thirty eyes of 30 patients were included. Here are some of the findings:
• Macular neovascularization subtypes were distributed as follows:
     o type 1: 63 percent;
     o type 2: 27 percent;
     o mixed type 1 and type 2: 3 percent;
     o type 3: 3 percent; and
     o aneurysmal type 1: 3 percent.
• The BCVA significantly improved after anti-VEGF loading phase (Snellen equivalent, from 20/118 to 20/71, p=0.03), but it returned to baseline levels at four years (Snellen equivalent, 20/103, p=0.6).
• The cumulative risk of subretinal fibrosis was 77 percent at four years.
• Risk factors associated with subretinal fibrosis included hemorrhagic BALAD (aHR, 2.02; CI, 1.54 to 3.22; p<0.01) and the presence of subretinal hyperreflective material (aHR, 1.83; CI, 1.35 to 3.14; p<0.01).

Investigators found that BALAD was associated with all types of MNV in nAMD patients. They added that long-term observation revealed poor functional outcomes related to the high risk of subretinal fibrosis.

SOURCE: Ramtohul P, Malclès A, Gigon E, et al. Long-term outcomes of bacillary layer detachment in neovascular age-related macular degeneration. Ophthalmol Retina; 2021 Sep 26. [Epub ahead of print].

Systemic Levels of VEGF After Intravitreal Injection of Aflibercept or Brolucizumab for nAMD

Researchers analyzed and compared the effects of intravitreal brolucizumab vs. aflibercept on systemic vascular endothelial growth factor-A levels in patients with neovascular age-related macular degeneration. The researchers declared they have no financial interest in either drug.

In this prospective interventional case series study, the physicians injected brolucizumab (6.0 mg/50 µL) or aflibercept (2.0 mg/50 µL) intravitreally in 30 patients each. They drew blood samples at baseline, and seven and 28 days after the first injection. They measured systemic VEGF-A levels using enzyme-linked immunosorbent assay. Thirty healthy individuals served as controls.

Here are some of the findings:
• The median baseline systemic VEGF-A levels in the brolucizumab, aflibercept and control groups were 10.8 (8 to 13.2), 12 (8 to 18.5) and 10 (8 to 15.1) pg/ml, respectively (p=0.315).
• In the brolucizumab group, VEGF-A levels significantly decreased to 8 (8 to 11.5) pg/ml on day seven (p=0.0254), and to 8 (8 to 8) pg/ml on day 28 (p<0.001).
• In the aflibercept group, VEGF-A levels significantly decreased to 8 (8 to 8) pg/ml on day seven (p<0.001), but returned to baseline level— 12.5 (8.5 to 14.6) pg/ml—on day 28 (p=0.120).
• VEGF-A levels were significantly different between the treatment groups after 28 days (p<0.001).

Researchers reported that intravitreal brolucizumab resulted in a sustained reduction of systemic VEGF-A levels until 28 days post-treatment, which they said raises concerns about its safety and long-term effects.

SOURCE: Angermann R, Huber AL, Nowosielski Y, et al. Changes in systemic levels of vascular endothelial growth factor after intravitreal injection of aflibercept or brolucizumab for neovascular age-related macular degeneration. Retina 2021; Nov 1. [Epub ahead of print].

Association of Smoking, Alcohol Consumption, BP, BMI and Glycemic Risk Factors with AMD

Scientists assessed whether smoking, alcohol consumption, blood pressure, body mass index and glycemic traits were associated with increased risk of advanced age-related macular degeneration.

This study used two-sample mendelian randomization. Genetic instruments composed of variants associated with risk factors at genome-wide significance (p<5 × 10 to 8) were obtained from published genome-wide association studies. Summary-level statistics for these instruments were obtained for advanced AMD from the International AMD Genomics Consortium 2016 data set, which consisted of 16,144 individuals with AMD and 17,832 control individuals. Data were analyzed from July 2020 to September 2021.

Exposures included smoking and cessation, lifetime smoking, age at smoking initiation, alcoholic drinks per week, body mass index (BMI), systolic and diastolic blood pressure (BP), type 2 diabetes, glycated hemoglobin, fasting glucose and fasting insulin.

Main outcomes and measures included advanced AMD and its subtypes, geographic atrophy and neovascular AMD.

Here are some of the findings:

• A 1-SD increase in “logodds” of genetically predicted smoking initiation was associated with higher risk of advanced AMD (OR, 1.26; CI, 1.13 to 1.40; p<.001), while a 1-SD increase in logodds of genetically predicted smoking cessation (former vs. current smoking) was associated with lower risk of advanced AMD (OR, 0.66; CI, 0.50 to 0.87; p=0.003).
• Genetically predicted increased lifetime smoking was associated with increased risk of advanced AMD (OR per 1-SD increase in lifetime smoking behavior, 1.32; CI, 1.09 to 1.59; p=0.004).
• Genetically predicted alcohol consumption was associated with higher risk of GA (OR per 1-SD increase of log-transformed alcoholic drinks per week, 2.70; CI, 1.48 to 4.94; p=0.001).
• Scientists found insufficient evidence to suggest that genetically predicted blood pressure, BMI and glycemic traits were associated with advanced AMD.

Scientists determined that the findings provided genetic evidence that increased alcohol intake may be a causal risk factor for GA. They added, the results also supported previous observational studies associating smoking behavior with risk of advanced AMD, reinforcing existing public health messages regarding the risk of blindness associated with smoking.

SOURCE: Kuan V, Warwick A, Hingorani A, et al. Association of smoking, alcohol consumption, blood pressure, body mass index, and glycemic risk factors with age-related macular degeneration: A Mendelian randomization study. JAMA Ophthalmol 2021; Nov 4. [Epub ahead of print].

MNV Cytokine Profiles Classified From Pachychoroid/Drusen Perspective

Investigators classified macular neovascularization based on pachychoroid and drusen features, and examined the aqueous humor cytokine signatures of each group.

A total of 106 consecutive eyes with treatment-naïve MNV and 104 control eyes were examined. The aqueous humor concentrations of 15 cytokines were compared among the MNV groups classified based on the presence of drusen and/or pachychoroid features. Multidimensional scaling analysis was used to visualize the similarity level of the MNV subtypes according to their cytokine profiles.

Here are some of the findings:

• Classifications of eyes were in the following MNV groups:
• 31 pachychoroid-associated;
• 18 drusen-associated;
• 43 pachychoroid/drusen-associated; and
• 10 non-drusen/non-pachychoroid.
• Compared with the control group, cytokines were differently upregulated among the MNV groups.
• CRP and CXCL12 were significantly upregulated in all MNV groups, whereas CXCL13 and IL-8 were significantly upregulated in three MNV groups, excluding the non-pachychoroid/non-drusen-associated MNV group.
• Ang-2 was significantly upregulated in three MNV groups except the drusen-associated MNV group.
• PlGF was significantly upregulated in the pachychoroid-associated and drusen-associated MNV groups.
• CCL-2 was significantly upregulated in the pachychoroid-associated and pachychoroid/drusen-associated MNV groups.
• VEGF was downregulated in the pachychoroid-associated and drusen-associated MNV groups, respectively.
• Multidimensional scaling analysis showed a distinct cytokine profile for each MNV group.

Investigators concluded that all MNV groups showed distinct cytokine profiles. Specifically, they found that eyes with neovascular age-related macular degeneration with drusen and concomitant pachychoroid could share a similar etiology to those with pachychoroid neovasculopathy and choroidal neovascularization with drusen but had a distinct etiology to those without such characteristics. Investigators noted that the findings suggested the importance of evaluating drusen and the choroid during the diagnosis of nAMD.

SOURCE: Inoda S, Takahashi H, Inoue Y, et al. Cytokine profiles of macular neovascularization in the elderly based on a classification from a pachychoroid/drusen perspective. Graefes Arch Clin Exp Ophthalmol 2021; Oct 29. [Epub ahead of print].

Accuracy of Double-layer Sign in Detection of MNV Secondary to CSC

Investigators assessed the diagnostic value of elevated retinal pigment epithelium and double-layer sign (DLS) in identifying macular neovascularization secondary to central serous chorioretinopathy, as part of a retrospective, cross-sectional study.

Patients with CSCR underwent optical coherence tomography and OCT angiography at London’s Moorfields Eye Hospital. OCT scans were reviewed to identify the presence/absence of an RPE elevation. The maximum length/height of the elevated RPE were measured. A minimum length of 1,000 µm and a maximum height of 150 µm were used to define the “double-layer sign.” Other qualitative anatomical features were graded from OCT scans. OCTA was examined to confirm the presence/absence of MNV. Binary logistic regression analyses helped assess the association between OCT features and the detection of MNV on OCTA. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated to assess the diagnostic accuracy.

A total of 163 eyes from 132 patients were included. Here are some of the findings:
• Elevated RPE was detected in 148 eyes (91 percent).
• OCTA-confirmed MNV was detected in 54 eyes (33 percent).
• The sensitivity of RPE elevation was 100 percent, and specificity was 13.8 percent.
• DLS was identified in 95 eyes (58 percent).
• The sensitivity of DLS for detecting MNV was 87 percent, and specificity was 56 percent.
• Hyperreflectivity and non-homogeneity of the sub-RPE space were independently associated with MNV within the DLS (OR, 17.7 and 14.8, p<0.001 and p=0.02, respectively).
• None of the other demographic or anatomical features assessed were associated with MNV.
• The presence of non-homogeneous hyperreflective RPE elevation had a sensitivity of 98 percent and specificity of 67 percent, with PPV of 60 percent and NPV of 99 percent.

Investigators found that non-homogeneous and hyperreflective space under an elevated RPE of any length or height indicated an eye with higher risk of MNV than DLS. They suggested that OCTA should be performed for such eyes to confirm the presence of MNV and treat accordingly.

SOURCE: Hagag AM, Rasheed R, Chandra S, et al. The diagnostic accuracy of double-layer sign in detection of macular neovascularization secondary to central serous chorioretinopathy. Am J Ophthalmol 2021; Oct 23. [Epub ahead of print].

Predicting Treatment Response in Center-involved DME Eyes Treated with Anti-VEGF Injections

Researchers aimed to determine whether a combination of baseline and change in spectral domain-optical coherence tomography-based biomarkers can predict visual outcomes in eyes with diabetic macular edema treated with anti-vascular endothelial growth factors injections.

The retrospective cohort study conducted in Hong Kong included 196 eyes with center-involving DME who received anti-VEGF injections between January 1, 2011 and June 30, 2018. Medical records were retrieved retrospectively; and visual acuity at baseline, six, 12 and 24 months; and SD-OCT before initiation and after completion of anti-VEGF treatment were obtained. SD-OCT images were evaluated for:

• the morphology of DME;
• vitreomacular status;
• presence of disorganization of retinal inner layers (DRIL);
• sizes of intraretinal cysts;
• visibility of external limiting membrane (ELM), ellipsoid zone (EZ) and cone outer segment tip (COST); and
• presence of hyperreflective foci in retina or the choroid.

Here are some of the findings:

• The presence of baseline DRIL, hyperreflective foci in retina, and the disruption of ELM/EZ and COST were associated with worse baseline and subsequent VA up to 24 months after treatment.
• Improvement in DRIL (p=0.048), ELM/EZ (p=0.001) and COST (p=0.002) disruption after treatment was associated with greater improvement in VA at 12 months.
• Eyes with cystoid macular edema (p=0.003, OR=8.18) and serous retinal detachment (p=0.011, OR=4.84) morphology were more likely to achieve at least 20 percent reduction in central subfield thickness.

Researchers wrote that baseline SD-OCT biomarkers and their subsequent changes predicted VA and improvement in vision in DME eyes treated with anti-VEGF injections. They proposed an SD-OCT-based system that can be readily used in real-life eye clinics to improve decision making in the management of DME.

SOURCE: Szeto SK, Hui VWK, Tang FY, et al. OCT-based biomarkers for predicting treatment response in eyes with centre-involved diabetic macular oedema treated with anti-VEGF injections: A real-life retina clinic-based study. British Journal of Ophthalmology 2021; Nov 8. [Epub ahead of print].

Lapses in Care Among Patients Assigned to Ranibizumab for PDR

Researchers reported on the completion of scheduled exams among participants assigned to intravitreous injections of ranibizumab for PDR in a multicenter, randomized clinical trial.

The post hoc analysis evaluated data from a randomized clinical trial conducted at 55 U.S. sites of 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012. Both eyes were enrolled for 89 participants (one eye to each study group) for a total of 394 study eyes. The final two-year visit was completed in January 2015. Data were analyzed from April 2019 to July 2021.

Interventions included ranibizumab injections for PDR or macular edema, and main outcomes and measures included a lapse in care of eight or more weeks past a scheduled exam, dropout from follow-up and visual acuity at five years.

Among 170 participants, the median age was 51 years; 44.7 percent were female. Here are some of the findings:
• Through five years of follow-up, 94 of 170 participants (55.3 percent) had one or more long lapses in care.
• The median time to the first long lapse was 210 weeks, and 69 of 94 participants (73.4 percent) returned for an exam after the first long lapse.
• Fifty of 170 participants (29.4 percent) dropped out of follow-up by five years.
• Among 120 participants who completed the five-year exam, median change from baseline in visual acuity was -2 letters for participants who had one or more long lapses compared with +5 letters for those without a long lapse (p=0.02).
• After multivariable adjustment, the odds ratio for baseline associations with one or more long lapses was 1.21 (CI, 1.03 to 1.43) for each five-letter decrement in visual acuity score; 2.19 (CI, 1.09 to 4.38) for neovascularization of the disc and elsewhere; and 3.48 (CI, 1.38 to 8.78) for no prior laser treatment for diabetic macular edema.

Researchers found that, over five years, approximately half of participants assigned to ranibizumab for PDR had a long lapse in care despite substantial effort by the DRCR Retina Network to facilitate timely completion of exams. They recommended that the likelihood of a long lapse in care during long-term follow-up should be considered when choosing treatment for PDR.

SOURCE: Maguire MG, Liu D, Bressler SB, et al. Lapses in care among patients assigned to ranibizumab for proliferative diabetic retinopathy: A post hoc analysis of a randomized clinical trial. JAMA Ophthalmol 2021; Oct 21. [Epub ahead of print].

Age-related Changes in the Retinal Microvasculature, Cardiovascular Risk Factors and Smoking Behavior

This cross-sectional study investigated the association between retinal vessel complexity and age and studied the effects of cardiovascular health determinants.

Retinal vessel complexity was assessed by calculating the box-counting fractal dimension (Df) from digital fundus photographs of 850 subjects (three to 97 years). All photographs were labeled as “non-pathological” by the treating ophthalmologist.

Here are some of the findings:
• Statistical models showed a statistically significant decreasing relationship between age and Df (linear: R-squared=0.1897, p<0.0001; quadratic: R-squared=0.2343, p<0.0001; cubic: R-squared=0.2721, p< 0.0001), with the cubic regression model offering the best compromise between accuracy and model simplicity.
• Multivariate cubic regression showed that age, spherical equivalent and smoking behavior had an effect (p<0.0001) on Df.
• A significantly increasing effect of the number of pack-years on Df was observed (effect: 0.0004, p=0.0017), as well as a significantly decreasing effect of years since tobacco abstinence (effect: -0.0149, p<0.0001).

Investigators proposed using a cubic trend model with age, refractive error and smoking behavior to aid in interpreting retinal vessel complexity.

SOURCE: Lemmens S, Luyts M, Gerrits N, et al. Age-related changes in the fractal dimension of the retinal microvasculature, effects of cardiovascular risk factors and smoking behaviour. Acta Ophthalmol 2021; Nov 7. [Epub ahead of print].