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:

• Systemic Health and Medication Use’s Impact on GA Rate in AMD
• Treatment of nAMD: An Economic Cost-Risk Analysis of Anti-VEGF agents
• OCT Features of Polypoidal Lesion Closure in PCV Treated with Aflibercept
• Anti-VEGF Therapy in Treatment-naïve nAMD Diagnosed on OCTA: The REVEAL study
• Genetic Associations of Anti-VEGF Therapy Response in AMD
• Localized Choriocapillaris Perfusion & Macular Function in GA
• Inhibition of Complement C3 in GA with NGM621
• GA Characteristics Using Fluorescence Lifetime Imaging Ophthalmoscopy
• Clinical Features and Treatment Outcomes of Inflammatory CNV
• Dexamethasone Intravitreal Implant in Treatment-naïve DME
  
• Intravitreal Pharmacotherapies for DME: A Report by the American Academy of Ophthalmology
• Contrast Sensitivity & QOL Following Intravitreal Ranibizumab Injection for CRVO
  
• Noteworthy

 

Systemic Health and Medication Use’s Impact on GA Rate in AMD

The associations of geographic atrophy progression with systemic health status and medication use are unclear. In this study, investigators manually delineated GA in 318 eyes in the Age-Related Eye Disease Study. They calculated GA perimeter-adjusted growth rate as the ratio between GA area growth rate and mean GA perimeter between the first and last visit for each eye (mean follow-up=5.3 years). Patients' history of systemic health and medications was collected through questionnaires administered at study enrollment. Investigators evaluated the associations between GA perimeter-adjusted growth rate and 27 systemic health factors, using univariable and multivariable linear mixed-effects regression models.

Here are some of the findings:
• In the univariable model, GA perimeter-adjusted growth rate was associated with:
   o GA in the fellow eye at any visit (p=0.002);
   o hypertension history (p=0.03);
   o cholesterol-lowering medication use (p<0.001);
   o beta-blocker use (p=0.02);
   o diuretic use (p<0.001); and
   o thyroid hormone use (p=0.03).
• Among the six factors, GA in the fellow eye at any visit (p=0.008), cholesterol-lowering medication use (p=0.002) and diuretic use (p<0.001) were independently associated with higher GA perimeter-adjusted growth rate in the multivariable model.
• GA perimeter-adjusted growth rate was 51.1 percent higher in patients with vs. without cholesterol-lowering medication use history, and was 37.8 percent higher in patients with a history of diuretic use vs. those without.

Investigators reported that the GA growth rate may be associated with the fellow eye status, cholesterol-lowering medication use and diuretic use. However, they added that these possible associations don’t imply causal relationships, and future prospective studies are required to investigate the relationships further.

SOURCE: Shen LL, Xie Y, Sun M, et al. Associations of systemic health and medication use with the enlargement rate of geographic atrophy in age-related macular degeneration. Br J Ophthalmol 2021; Sep 6. [Epub ahead of print].

 

Treatment of nAMD: An Economic Cost-Risk Analysis of Anti-VEGF agents  

Investigators aimed to find the best cost-effective NVAMD treatment to improve vision while avoiding complications, using a model based on a cost-risk tradeoff analysis from policymakers' perspectives.

A simulation model was created using two years of treatment with the four commonly used anti-VEGF drugs (bevacizumab, ranibizumab, aflibercept and brolucizumab) across three injection protocols, building on prior findings that these drugs are non-inferior. The model incorporated blinding complications, their management and associated cost to society. Each option and several "what-if" scenarios were simulated 1,000 times with 100,000 hypothetical patients.

Participants included 100,000 simulated patients using data from published clinical trials in the Case- and eye-specific cost-risk economic analysis.

Main outcome measures included costs of NVAMD treatment per patient and number of eyes that become blind due to treatment over two years.

Here are some of the findings:
• Using published prices and fees on injection protocols following in clinical studies, results showed that the mean cost per patient was $16,859 ±3.65 for bevacizumab, $32,949 ±3.27 for brolucizumab, $39,831 ±3.80 for aflibercept and $53,056 ±2.99 for ranibizumab.
• The numbers of treated eyes that became blind were 108 ±10.18, 694 ±26.66, 168 ±12.83 and 108 ±10.52, respectively.
• Researchers further provided a lower bound (when all patients were maximally extended) and upper bound (when no patient was extended) to these numbers. For brolucizumab the upper bound was the two-month interval injection protocol.

Investigators wrote that taking a policymaking perspective, this study suggested that bevacizumab was the preferred first-line therapy. They added that recommendation for second-line therapy depended on the extent of the policymaker's risk-aversion because of the tradeoff between cost and risk of blindness due to treatment. In risk-neutral settings, investigators wrote further, the least expensive option (brolucizumab) was preferred. But if risk-aversion was moderate to high, then aflibercept or ranibizumab was preferred.

Source: Moisseiev E, Tsai YL, Herzenstein M. Treatment of neovascular age-related macular degeneration: an economic cost-risk analysis of anti-VEGF agents. Ophthalmol Retina 2021; Aug 25. [Epub ahead of print].

OCT Features of Polypoidal Lesion Closure in PCV Treated with Aflibercept

Researchers evaluated whether optical coherence tomography can determine polypoidal lesion (PL) perfusion in polypoidal choroidal vasculopathy eyes following 12-months of aflibercept monotherapy. They wrote that PL perfusion status, assessed by indocyanine green angiography, is an important anatomical outcome in PCV management.

Researchers used post hoc data from a prospective, randomized, open-label, study in eyes with PCV undergoing monotherapy with aflibercept to evaluate PL perfusion status based on ICGA (gold standard) and OCT features from baseline to 12-months.

Here are some of the findings:
• Individual PLs (110 in total) from 48 eyes (48 patients) showed at 12-months; 57/110 PLs (51.8 percent) were closed on ICGA.
• At 12-months, eyes with closed PLs were more likely to have the following OCT features:
   o no SRF (67.1 vs. 32.9 percent);
   o smaller PED height (67.2 [±43.8] vs. 189.2 [±104.9] μm);
   o densely hyper-reflective PED contents (84 vs. 16 percent);
   o an absence of a hyper-reflective ring (64 vs. 36 percent); and
   o an indistinct overlying RPE (71.4 vs. 28.6 percent)(all p<0.05).
• The three OCT features that most reliably differentiated perfused from closed PLs were: no SRF; densely hyper-reflective PED contents; and an absence of hyper-reflective ring (area under the ROC curve, respectively: 0.85, 0.73 and 0.70). A combination of these three features achieved an AUC-ROC of 0.90.

Researchers wrote that PL closure, an important anatomical treatment outcome in PCV typically defined by ICGA, can be accurately detected by specific OCT features.

SOURCE: Tan ACS, Jordan-Yu JM, Vyas CH. Optical coherence tomography features of polypoidal lesion closure in polypoidal choroidal vasculopathy treated with aflibercept. Retina 2021; Aug 16. [Epub ahead of print].

Anti-VEGF Therapy in Treatment-naïve nAMD Diagnosed on OCTA: The REVEAL study

Investigators compared 12-month visual and anatomical outcomes of treatment-naïve neovascular age-related macular degeneration patients diagnosed by optical coherence tomography angiography compared with fluorescein angiography (FA)/indocyanine green angiography (ICGA) after anti-VEGF treatment in a real-world setting.

In a monocentric, observational, parallel-group study of nAMD patients diagnosed with either FA/ICGA or noninvasive OCTA methods, patients were treated with a fixed dosing regimen of intravitreal ranibizumab or aflibercept and followed up for 12 months. Primary outcomes were the 12 months functional (BCVA) and anatomical (CST reduction) gains between the two groups. The stratification of BCVA and CST gains by type of neovascular lesion and by anti-VEGF treatment was also assessed.

Here are some of the findings:
• Seventy-two patients received FA/ICGA for the initial diagnosis of nAMD while 73 received OCTA.
• Overall, the mean BCVA gain at 12 months was 11.5 ±9.6 letters.
• No statistically significant differences were found between the invasive and noninvasive imaging groups in BCVA gain (p=0.87) or CST reduction (p=0.76).
• No statistically significant outcome differences between different lesion types and the two drugs were observed.

Investigators reported, in a real-world setting, nAMD patients diagnosed with OCTA showed meaningful improvements in visual and anatomical parameters during 12 months of treatment, without significant differences from those diagnosed by invasive modalities.

SOURCE: Lupidi M, Schiavon S, Cerquaglia A, et al. Real-world outcomes of anti-VEGF therapy in treatment-naïve neovascular age-related macular degeneration diagnosed on OCT angiography: The REVEAL study. Acta Ophthalmol 2021; Aug 18. [Epub ahead of print].

Genetic Associations of Anti-VEGF Therapy Response in AMD

Researchers assessed the association of all reported common polymorphisms in anti-vascular endothelial growth factor therapy response and identified potential clinically useful biomarkers for anti-VEGF therapy response in patients with age-related macular degeneration.

They searched the Embase, PubMed and Web of Science databases in English, and the China National Knowledge Infrastructure, WanFang and VIP databases in Chinese for pharmacogenetics studies on anti-VEGF therapy response in AMD. Odds ratios with 95 percent confidence intervals were calculated using the random effects model.

Among the 10,468 records yielded by the literature search, 33 articles that met the eligibility criteria were included in the meta-analysis. Nine single-nucleotide polymorphisms (SNP) in four genes were observed to be associated with the anti-VEGF therapy response in AMD patients.

• The following SNPs were associated with good anti-VEGF therapy responses:
   o rs1120063 in the HTRA1 gene;
   o rs10490924 in the age-related maculopathy susceptibility (ARMS2) gene;
   o rs1061170 in the complement factor H (CFH) gene; and
   o rs323085 in the OR52B4 gene.
• The following SNPs were associated with poor anti-VEGF therapy response in the AMD patients:
   o rs800292, rs1410996 and rs1329428 in the CFH gene; and
   o rs4910623 and rs10158937 in the OR52B4 gene.

Researchers wrote that nine SNPs of four genes were indicated to be significantly associated with the anti-VEGF therapy response in the samples. They added that further studies based on various ethnicities and large sample sizes are warranted to strengthen the evidence found in the present study.

 

SOURCE: Wang Z, Zou M, Chen A, et al. Genetic associations of anti-vascular endothelial growth factor therapy response in age-related macular degeneration: A systematic review and meta-analysis. Acta Ophthalmol 2021; Aug 17. [Epub ahead of print].

 

Localized Choriocapillaris Perfusion & Macular Function in GA

Investigators tested the hypothesis that choriocapillaris perfusion correlates with visual function in geographic atrophy, as part of a cross-sectional, single-center study.

Investigators imaged choriocapillaris flow using 6 mm x 6 mm swept-source optical coherence tomography angiography scans and measured retinal sensitivity using fundus-guided microperimetry in the central 20 degrees in 18 eyes of 12 subjects with GA, and seven eyes of four normal subjects. OCTA scans were divided into a grid, and microperimetry results were superimposed using retinal vascular landmarks. The main outcome measure correlated choriocapillaris flow deficit with retinal sensitivity at each localized region. Robust linear mixed effects regression compared flow deficit or sensitivity with distance from the fovea. The Pearson ρ correlation described the relationship between flow deficit or retinal sensitivity and distance from the GA border.

Here are some of the findings:
• Choriocapillaris flow deficit was significantly greater in GA than normal (mean ± standard deviation 24.2 ±7.9 percent vs. 7.9 ±2.3 percent, p=0.0015), while retinal sensitivity was significantly lower in GA than normal (mean difference -17.0 ±1.2 dB, p<0.001).
• In GA, choriocapillaris flow deficit decreased (ρ=-0.40; CI, -0.54 to -0.27), while retinal sensitivity increased (ρ=+0.63; CI, 0.30 to 0.81) with distance from the GA margin.
• Choriocapillaris flow deficits inversely correlated with retinal sensitivity (ρ=-0.61; CI, -0.75 to -0.42).

Investigators found that choriocapillaris flow and retinal sensitivity improved with distance from the GA margin. Furthermore, they wrote, choriocapillaris flow deficit was inversely correlated with sensitivity, supporting the hypothesis that choriocapillaris perfusion correlated with macular function.

SOURCE: Rinella NT, Zhou H, Wong J, et al. Correlation between localized choriocapillaris perfusion and macular function in eyes with geographic atrophy. Am J Ophthalmol 2021; Aug 23. [Epub ahead of print].

Inhibition of Complement C3 in GA with NGM621

Investigators evaluated the safety and tolerability of single and multiple intravitreal injections of NGM621 in patients with geographic atrophy and characterized the pharmacokinetics and immunogenic potential in a multicenter, open-label, single- and multiple-dose Phase I study.

Fifteen patients enrolled at four sites in the United States were included. Participants had GA secondary to age-related macular degeneration, lesion size ≥2.5 mm² and best-corrected visual acuity of four to 54 letters (20/80 to 20/800 Snellen equivalent) in the study eye and no history of choroidal neovascularization in either eye. Patients who met eligibility criteria were treated in a single ascending-dose phase (2 mg, 7.5 mg, 15 mg) or received two doses NGM621 15 mg four weeks apart in the multidose phase and were followed for 12 weeks (85 days). Assessments included adverse events, best-corrected visual acuity, low luminance visual acuity, vital signs, clinical laboratory evaluations, GA lesion area as measured by fundus autofluorescence, spectral-domain optical coherence tomography; and pharmacokinetic, immunogenicity and pharmacodynamic assessments.

All 15 participants completed the 12-week study. Here are some of the findings:
• There were no serious adverse events and no drug-related adverse events, and no choroidal neovascularization developed in either eye.
• Mean visual acuity and GA lesion area appeared stable through week 12 for all cohorts.
• Pharmacokinetic analyses indicated that NGM621 serum exposures appeared to be dose proportional, and no antidrug antibodies were identified at any of the evaluated time points.

Investigators wrote, in this small, open-label, 12-week Phase I study, NGM621 was safe and tolerable when administered intravitreally up to 15 mg.

SOURCE: Wykoff CC, Hershberger V, Eichenbaum D, et al. Inhibition of complement C3 in geographic atrophy with NGM621: Phase 1 dose-escalation study results. Am J Ophthalmol 2021; Sep 9. [Epub ahead of print].

GA Characteristics Using Fluorescence Lifetime Imaging Ophthalmoscopy

Researchers wrote that short foveal fluorescence lifetimes (fFLTs) in geographic atrophy are typically found in eyes with foveal sparing disease but may also occur in eyes without foveal sparing disease. They investigated whether short fFLTs could serve as a functional biomarker for disease progression in geographic atrophy.

Thirty-three eyes were followed over four to six years. Foveal sparing was assessed using fluorescence lifetime imaging ophthalmoscopy, optical coherence tomography, fundus autofluorescence and macular pigment optical density.

Here are some of the findings:
• Eyes with foveal sparing exhibited shorter fFLTs compared to eyes without foveal sparing.
• Short fFLTs (<600 ps) were measured in all eyes with foveal sparing and half of the eyes without foveal sparing.
• Eyes with foveal sparing showed a greater increase in fFLTs per year (+39/+30 ps [SSC/LSC]) in foveal sparing vs. +29/+22 ps [SSC/LSC] in non-foveal sparing).
• BCVA correlated significantly with fFLTs (p=0.018 and p=0.005 for SSC/LSC).
• MPOD measurements correlated significantly with fFLTs but not in all spectral channels (p=0.018 to 0.077).

Researchers determined that, in GA, shorter foveal fluorescence lifetimes were associated with foveal sparing and also were observed in eyes without foveal sparing. They added that longitudinal data suggested that shorter fFLT features in eyes with loss of foveal sparing represented an earlier stage of disease and may increase the risk of visual acuity loss.

SOURCE: Lincke JB, Dysli C, Jaggi D, et al. Longitudinal foveal fluorescence lifetime characteristics in geographic atrophy using fluorescence lifetime imaging ophthalmoscopy (FLIO). Retina 2021; Jul 17. [Epub ahead of print].

 

Clinical Features and Treatment Outcomes of Inflammatory CNV

Investigators considered the long-term clinical features and treatment outcomes of patients with inflammatory choroidal neovascularization treated with intravitreal anti-vascular endothelial growth factor, as part of a retrospective, interventional, consecutive case series.

They included 65 eyes of 65 patients with inflammatory CNV treated with anti-VEGF injections and followed up for at least 12 months. A retrospective chart review was conducted at a single tertiary referral center.

Study participants were followed for 60.6 ±42.8 (range: 16 to 160) months. Mean age was 33.4 ±10.8 years, and mean refractive error was -3.94 ±1.35 D in spherical equivalent. Final best-corrected visual acuity was 0.21 ±0.20 logMAR (around 20/32) after treatment. Patients were treated with bevacizumab (76.9 percent), ranibizumab (4.6 percent), aflibercept (3.1 percent) and drug combinations (15.4 percent). Here are some of the findings:
• Systemic corticosteroid or immunosuppressant use wasn’t correlated with visual outcome, required number of anti-VEGF injections or recurrence.
• Commonly occurring optical coherence tomography features included:
   o ellipsoid zone disruption;
   o choroidal hypertransmission;
   o retinal pigment epithelium atrophy (RPEA) or absence;
   o intraretinal hyperreflective foci (HRF);
   o choroidal vessel engorgement;
   o focal choroidal excavation; and
   o irregular vascular loops (on OCT angiography).
• RPEA after treatment (β=0.238, p=0.036) and BCVA (β=0.267, p=0.029) showed significant correlation with final BCVA.
• Twenty-eight patients (43.1 percent) experienced recurrence; intraretinal HRF after treatment was the single risk factor for recurrence (OR, 2.712; p=0.031).

Investigators found that inflammatory CNV recurrence showed higher rates over time after anti-VEGF treatment than previously reported, even though the overall visual outcome was good. They also reported that baseline BCVA and RPEA after treatment were significant predictors of visual outcome, and that intraretinal HRF after anti-VEGF treatment may indicate a heightened risk of recurrence.

SOURCE: Kim M, Lee J, Park YG, et al. Long-term analysis of clinical features and treatment outcomes of inflammatory choroidal neovascularization. Am J Ophthalmol 2021; Jul 20. [Epub ahead of print].