Macular Disease Foundation Australia logo

    Research update: 510

    The latest research highlights for 13 September 2021

    Research update


    Effectiveness of anti-vascular endothelial growth factors in neovascular age-related macular degeneration and variables associated with visual acuity outcomes: Results from the EAGLE study.

    PLoS One. 2021 Sep 1;16(9):e0256461.

    Staurenghi G, Bandello F, Viola F, Varano M, Barbati G, Peruzzi E, Bassanini S, Biancotto C, Fenicia V, Furino C, Vadalà M, Reibaldi M, Vujosevic S, Ricci F; EAGLE study investigators.

    OBJECTIVE: To assess the overall effectiveness of anti-vascular endothelial growth factor (VEGF) therapy in treatment-naïve patients with neovascular age-related macular degeneration (nAMD) in a clinical practice setting.

    STUDY DESIGN: EAGLE was a retrospective, 2-year, cohort observational, multicenter study conducted in Italy that analyzed secondary data of treatment-naïve patients with nAMD. The primary endpoint evaluated the mean annualized number of anti-VEGF injections at Years 1 and 2. The main secondary endpoints analyzed the mean change in visual acuity (VA) from baseline and variables associated with visual outcomes at Years 1 and 2.

    RESULTS: Of the 752 patients enrolled, 745 (99.07%) received the first dose of anti-VEGF in 2016. Overall, 429 (57.05%) and 335 (44.5%) patients completed the 1- and 2-year follow-ups, respectively. At baseline, mean (standard deviation, SD) age was 75.6 (8.8) years and the mean (SD) VA was 53.43 (22.8) letters. The mean (SD) number of injections performed over the 2 years was 8.2 (4.1) resulting in a mean (SD) change in VA of 2.45 (19.36) (P = 0.0005) letters at Year 1 and -1.34 (20.85) (P = 0.3984) letters at Year 2. Linear regression models showed that age, baseline VA, number of injections, and early fluid resolution were the variables independently associated with visual outcomes at Years 1 and 2.

    CONCLUSIONS: The EAGLE study analyzed the routine clinical practice management of patients with nAMD in Italy. The study suggested that visual outcomes in clinical practice may be improved with earlier diagnosis, higher number of injections, and accurate fluid resolution targeting during treatment induction.

    DOI: 10.1371/journal.pone.0256461

    Treatment of Neovascular Age-Related Macular Degeneration: An Economic Cost-Risk Analysis of Anti-VEGF agents.

    Ophthalmol Retina. 2021 Aug 25:S2468-6530(21)00273-6.

    Moisseiev E, Tsai YL, Herzenstein M.

    OBJECTIVE: To find the best cost-effective NVAMD treatment to improve vision while avoiding complications. The model is based on a cost-risk tradeoff analysis from policymakers’ perspective. DESIGN: A powerful and flexible simulation models outcomes of 2 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 incorporates 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: 100,000 simulated patients using data from published clinical trials.

    METHOD: Case- and eye-specific cost-risk economic analysis.

    MAIN OUTCOME MEASURES: Costs of NVAMD treatment per patient and number of eyes that become blind due to treatment over 2 years.

    RESULTS: Using published prices and fees, the injection protocol that follows published clinical studies, results showed that the mean (SD) cost per patient were $16,859 (3.65), $32,949 (3.27), $39,831 (3.80), and $53,056 (2.99) for bevacizumab, brolucizumab, aflibercept, and ranibizumab. The numbers of treated eyes that became blind were 108 (10.18), 694 (26.66), 168 (12.83), and 108 (10.52) respectively. We further provide a lower bound (when all patients are maximally extended) and upper bound (when no patient is extended) to these numbers. For brolucizumab the upper bound is the 2-month interval injection protocol.

    CONCLUSIONS: Taking a policymaking perspective, this study suggests that bevacizumab is the preferred first-line therapy. Recommendation for second-line therapy depends on the extent of the policymaker’s risk-aversion because of the tradeoff between cost and risk of blindness due to treatment. If risk-neutral, the least expensive option (brolucizumab) is preferred. But if moderate to high, then aflibercept or ranibizumab are preferred. Since medical advances and different costs may change our findings, we provide a free application ( for readers who wish to use different cost structures. Simulating outcomes is an innovative approach, unique in ophthalmology, and presents significant opportunity as it can be easily adapted to different settings (using different costs, risks, and protocols), and to other diseases (e.g., DME), to ultimately improve wide-scale decision-making and use of funds.

    DOI: 10.1016/j.oret.2021.08.009

    Changes of retinal oxygen saturation during treatment of diabetic macular edema with a pre-defined regimen of aflibercept: a prospective study.

    Graefes Arch Clin Exp Ophthalmol. 2021 Sep 1.

    Hasan SM, Hammer M, Meller D.

    PURPOSE: To study the effect of anti-VEGF therapy for diabetic macular edema (DME) on retinal oxygen saturation (O2S) and its correlation with functional and anatomical changes of retinal tissue.

    METHODS: An interventional prospective single group study. Included were 10 eyes of 10 patients with visually significant DME which received a fixed regimen of intravitreal aflibercept every 4 weeks for 5 months, followed by 3 injections every 8 weeks, and were controlled monthly. Visual acuity (VA), central retinal thickness (CRT), arterial (aO2S), venous (vO2S) and arterio-venous difference (AVdO2S) retinal oxygen saturation were noted monthly. Changes after 5th (V6) injection and on last follow-up (V12) were studied. Correlations of different parameters were analyzed.

    RESULTS: The aO2S did not change whereas vO2S decreased (62.2 ± 9.4 pre-op to 57.2 ± 10.5 on V6, p = 0.03). This remained unchanged at 59.4 ± 13.2 on V12 (p = 0.2) and was accompanied by an increase of AVdO2S (40.8 ± 8.3 pre-op to 44.8 ± 10.6, p = 0.03 on V6) which was followed by a non-significant decrease to 41.8 ± 11.3 on V12 (p = 0.06). We found no correlation between BCVA and aO2S. However, mild correlation between BCVA and both vO2S and AVdO2S (r = -0.2 p = 0.035 and r = 0.185 p = 0.05 respectively) was found. No correlation was found between CRT and aO2S, vO2S, or AVdO2S.

    CONCLUSIONS: During DME treatment with fixed regimen of intravitreal aflibercept over 11 months, we observed a reduction of vO2S and increase of AVdO2S which correlated with BCVA but not CRT. This could be explained by increasing consumption of O2S in the central retina and, possibly, by re-perfusion process.

    DOI: 10.1007/s00417-021-05319-5

    Contrast sensitivity and quality of life following intravitreal ranibizumab injection for central retinal vein occlusion.

    Br J Ophthalmol. 2021 Aug 27:bjophthalmol-2021-319863.

    Murakami T, Okamoto F, Sugiura Y, Morikawa S, Okamoto Y, Hiraoka T, Oshika T.

    SYNOPSIS: We investigated the relationship between contrast sensitivity (CS) and vision-related quality of life (VR-QOL) in patients with central retinal vein occlusion following ranibizumab intravitreal injection; CS showed a stronger association with VR-QOL than visual acuity.

    BACKGROUND/AIMS: To investigate the relationship between CS, VR-QOL and optical coherence tomography (OCT) findings in patients with cystoid macular oedema secondary to central retinal vein occlusion (CRVO-CMO) following intravitreal injection of ranibizumab.

    METHODS: This was a multicentre, open-label, single-arm, prospective study. The study included 23 patients with CRVO-CMO who were followed up for 12 months after treatment. The best-corrected visual acuity (BCVA), letter contrast sensitivity (LCS) and OCT images were obtained every month. For VR-QOL assessment, the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25) was administered to the patients before treatment and at 3, 6 and 12 months following treatment.

    RESULTS: The LCS and VFQ-25 composite score improved significantly from baseline to 12 months following treatment. The multiple regression analysis revealed that the LCS of the affected eye and BCVA of the fellow eye were related to the VFQ-25 composite score following treatment. The LCS improvement showed a significant correlation with the improvement in the VFQ-25 composite score, whereas the BCVA improvement was not correlated with the improvement in the VFQ-25 composite score. Stepwise multiple regression analyses revealed that, at the time of macular oedema resolution, the distance between the external limiting membrane and retinal pigment epithelium (ELM-RPE) and average ganglion cell-inner plexiform layer (GCIPL) thickness were associated with LCS.

    CONCLUSION: CS had a stronger association with VR-QOL than with BCVA in patients with CRVO-CMO. With the resolution of macular oedema, CS was associated with ELM-RPE thickness and average GCIPL thickness.

    DOI: 10.1136/bjophthalmol-2021-319863

    Long-term effects of intravitreal bevacizumab and aflibercept on intraocular pressure in wet age-related macular degeneration.

    BMC Ophthalmol. 2021 Aug 28;21(1):312.

    Kähkönen M, Tuuminen R, Aaltonen V.

    BACKGROUND: To evaluate the incidence of sustained elevation of intraocular pressure (SE-IOP) associated with intravitreal injections of anti-vascular endothelial growth factors (anti-VEGF) bevacizumab and aflibercept in patients with wet age-related macular degeneration (wAMD).

    METHODS: A retrospective cohort study consisting of 120 eyes from 120 patients with anti-VEGF treatment for wAMD. Three different anti-VEGF groups were considered: i) 71 cases receiving bevacizumab only, ii) 49 cases receiving bevacizumab before switch to aflibercept, iii) 49 cases after switch to aflibercept. 120 uninjected fellow eyes served as controls. SE-IOP was defined as an increase from baseline ≥5 mmHg on 2 consecutive follow-up visits. The incidence of SE-IOP was analysed using exact Poisson tests and survival analysis. The time course of IOP was evaluated with linear mixed effect modelling.

    RESULTS: In total, 6 treated eyes (2.38% incidence per eye-year) and 9 fellow eyes (3.58% incidence per eye-year) developed SE-IOP, and survival analysis showed no statistically significant difference (p = 0.43). Furthermore, the incidence of SE-IOP did not differ between the three anti-VEGF groups. Comparing the injected eyes of patients under 70 years to those of patients over 70 years, there was a statistically significant difference in survival without SE-IOP (incidence of 16.7% vs 0.7%, respectively, p < 0.0001).

    CONCLUSION: Intravitreal anti-VEGF injections were not associated with sustained elevation of IOP. These results do not support the claim that repeated anti-VEGF injections could elevate IOP.

    DOI: 10.1186/s12886-021-02076-1


    High-addition segmented refractive bifocal intraocular lens in inactive age-related macular degeneration: A multicenter pilot study.

    PLoS One. 2021 Sep 2;16(9):e0256985.

    Auffarth GU, Reiter J, Leitritz M, Bartz-Schmidt KU, Höhn F, Breyer D, Kaymak H, Rohrschneider K, Khoramnia R, Yildirim TM.

    This multicenter, open-label study aimed to determine the safety and functional outcome of a high-addition segmented refractive bifocal intraocular lens (IOL) in late inactive age-related macular degeneration (AMD). Twenty eyes of 20 patients were enrolled and followed until 12 months after the intervention. Patients underwent cataract surgery with implantation of a LS-313 MF80 segmented refractive bifocal intraocular lens with a near addition of +8.0 D (Teleon Surgical Vertriebs GmbH, Berlin, Germany). The main outcome measures were distance corrected near visual acuity (DCNVA) and safety as determined by intra- and post-operative complications. Secondary outcomes included distance corrected visual acuity (CDVA), uncorrected distance visual acuity (UDVA), uncorrected near visual acuity (UNVA), the need for magnification to read newspaper, preferred reading distance, speed and performance (logRAD), as well as patient satisfaction. Mean DCNVA improved from 0.95 (±0.19) to 0.74 (±0.35) logMAR, until 6 months after surgery, P<0.05. CDVA improved from 0.70 (±0.23) to 0.59 (±0.30) logMAR, UDVA from 0.94 (±0.25) to 0.69 (±0.34) logMAR, UNVA from 1.08 (±0.19) to 0.87 (±0.43) logMAR. The mean need for magnification decreased from 2.9- to 2.3-fold, preferred reading distance from 23 to 20 cm. No intraoperative complications occurred during any of the surgeries. One patient lost > 2 lines of CDVA between 6 and 12 months, in another case, the study IOL was exchanged for a monofocal one due to dysphotopsia and decreased CDVA. Implantation of a segmented refractive bifocal IOL with +8.0 D addition improves near and distance vision in patients with late AMD and has a satisfactory safety profile.

    DOI: 10.1371/journal.pone.0256985


    Developing a normative database for retinal perfusion using optical coherence tomography angiography.

    Biomed Opt Express. 2021 Jun 14;12(7):4032-4045.

    Tan B, Sim YC, Chua J, Yusufi D, Wong D, Yow AP, Chin C, Tan ACS, Sng CCA, Agrawal R, Gopal L, Sim R, Tan G, Lamoureux E, Schmetterer L.

    Visualizing and characterizing microvascular abnormalities with optical coherence tomography angiography (OCTA) has deepened our understanding of ocular diseases, such as glaucoma, diabetic retinopathy, and age-related macular degeneration. Two types of microvascular defects can be detected by OCTA: focal decrease because of localized absence and collapse of retinal capillaries, which is referred to as the non-perfusion area in OCTA, and diffuse perfusion decrease usually detected by comparing with healthy case-control groups. Wider OCTA allows for insights into peripheral retinal vascularity, but the heterogeneous perfusion distribution from the macula, parapapillary area to periphery hurdles the quantitative assessment. A normative database for OCTA could estimate how much individual’s data deviate from the normal range, and where the deviations locate. Here, we acquired OCTA images using a swept-source OCT system and a 12×12 mm protocol in healthy subjects. We automatically segmented the large blood vessels with U-Net, corrected for anatomical factors such as the relative position of fovea and disc, and segmented the capillaries by a moving window scheme. A total of 195 eyes were included and divided into 4 age groups: < 30 (n=24) years old, 30-49 (n=28) years old, 50-69 (n=109) years old and >69 (n=34) years old. This provides an age-dependent normative database for characterizing retinal perfusion abnormalities in 12×12 mm OCTA images. The usefulness of the normative database was tested on two pathological groups: one with diabetic retinopathy; the other with glaucoma.

    DOI: 10.1364/BOE.423469

    Analysis of correlations between local geographic atrophy growth rates and local OCT angiography-measured choriocapillaris flow deficits.

    Biomed Opt Express. 2021 Jul 1;12(7):4573-4595.

    Moult EM, Shi Y, Zhang Q, Wang L, Mazumder R, Chen S, Chu Z, Feuer W, Waheed NK, Gregori G, Wang RK, Rosenfeld PJ, Fujimoto JG.

    The purpose of this study is to quantitatively assess correlations between local geographic atrophy (GA) growth rates and local optical coherence tomography angiography (OCTA)-measured choriocapillaris (CC) flow deficits. Thirty-eight eyes from 27 patients with GA secondary to age-related macular degeneration (AMD) were imaged with a commercial 1050 nm swept-source OCTA instrument at 3 visits, each separated by ∼6 months. Pearson correlations were computed between local GA growth rates, estimated using a biophysical GA growth model, and local OCTA CC flow deficit percentages measured along the GA margins of the baseline visits. The p-values associated with the null hypothesis of no Pearson correlation were estimated using a Monte Carlo permutation scheme that incorporates the effects of spatial autocorrelation. The null hypothesis (Pearson’s ρ = 0) was rejected at a Benjamini-Hochberg false discovery rate of 0.2 in 15 of the 114 visit pairs, 11 of which exhibited positive correlations; even amongst these 11 visit pairs, correlations were modest (r in [0.30, 0.53]). The presented framework appears well suited to evaluating other potential imaging biomarkers of local GA growth rates.

    DOI: 10.1364/BOE.427819


    Subretinal fibrosis in neovascular age-related macular degeneration: current concepts, therapeutic avenues, and future perspectives.

    Cell Tissue Res. 2021 Sep 3.

    Tenbrock L, Wolf J, Boneva S, Schlecht A, Agostini H, Wieghofer P, Schlunck G, Lange C.

    Age-related macular degeneration (AMD) is a progressive, degenerative disease of the human retina which in its most aggressive form is associated with the formation of macular neovascularization (MNV) and subretinal fibrosis leading to irreversible blindness. MNVs contain blood vessels as well as infiltrating immune cells, myofibroblasts, and excessive amounts of extracellular matrix proteins such as collagens, fibronectin, and laminin which disrupts retinal function and triggers neurodegeneration. In the mammalian retina, damaged neurons cannot be replaced by tissue regeneration, and subretinal MNV and fibrosis persist and thus fuel degeneration and visual loss. This review provides an overview of subretinal fibrosis in neovascular AMD, by summarizing its clinical manifestations, exploring the current understanding of the underlying cellular and molecular mechanisms and discussing potential therapeutic approaches to inhibit subretinal fibrosis in the future.

    DOI: 10.1007/s00441-021-03514-8


    A Case of Post-COVID-19-Associated Paracentral Acute Middle Maculopathy and Giant Cell Arteritis-Like Vasculitis.

    J Neuroophthalmol. 2021 Sep 1;41(3):351-355.

    Jonathan GL, Scott FM, Matthew KD.

    A 47-year-old man with a history of COVID-19 infection 2 months before presentation, presented with a scotoma of the paracentral visual field of the right eye. After thorough testing and evaluation, a diagnosis of paracentral acute middle maculopathy (PAMM) was established. Two months later, the patient developed temporal headache and jaw claudication. High-dose steroids were initiated, and workup for giant cell arteritis (GCA) was undertaken. The patient experienced resolution of the symptoms within 24 hours of steroid initiation. ESR, CRP, and temporal artery biopsy results were normal, although all were obtained more than 2 weeks after steroid initiation. To the best of our knowledge, our patient represents the first individual to date to potentially implicate COVID-19 in both small and large vessel vasculitis in the ophthalmic setting.

    DOI: 10.1097/WNO.0000000000001348


    Long-term exposure to ambient air pollutants and age-related macular degeneration in middle-aged and older adults.

    Environ Res. 2021 Aug 26;204(Pt A):111953.

    Ju MJ, Kim J, Park SK, Kim DH, Choi YH.

    In developed countries, age-related macular degeneration (AMD) is a leading cause of irreversible blindness in adults. The key pathways of AMD are suggested to be excessive oxidative stress and inflammation in the central retina. Because air pollution has been found capable of inducing oxidative stress and inflammation, it may play a role in development of AMD. This study investigated the association between ambient air pollution and AMD in 15,115 middle-aged and older adults (≥40 years) from Korean National Health and Nutrition Examination Survey 2008-2012. After controlling for important confounders, ambient NO2 and CO in current-to-5 prior years and PM10 in 2-to-5 prior years were significantly associated with higher prevalence of early AMD, while O3 in current-to-5 prior years was significantly associated with lower prevalence of early AMD. When modeled air pollution within administrative division units, its ORs with an IQR increase in NO2, CO, and O3 at current year were 1.24 (95% CI: 1.05-1.46), 1.22 (95% CI: 1.09-1.38), and 0.80 (95% CI: 0.70-0.92), respectively. Overall, results from air pollution at local/town units were consistent with those at administrative division units. Long-term exposures to ambient air pollution may play a role in the risk of AMD in middle-aged and older adults.

    DOI: 10.1016/j.envres.2021.111953

    Antioxidant supplements in age-related macular degeneration: are they actually beneficial?

    Ther Adv Ophthalmol. 2021 Aug 27;13:25158414211030418.

    Banerjee M, Chawla R, Kumar A.

    Age-related macular degeneration (ARMD) is one of the prominent causes of central visual loss in the older age group in the urbanized, industrialized world. In recent years, many epidemiological studies and clinical trials have evaluated the role of antioxidants and micronutrients to prevent the progression of ARMD. In this article, we review some of these major studies. In addition, we review the absorption and bioavailability and possible undesirable effects of these nutrients after ingestion. The role of genotypes and inappropriate use of these supplements are also discussed. From all the above evidence, we conclude that it may not be prudent to prescribe these formulations without a proper assessment of the individual’s health and dietary status. The effectiveness of all the components in antioxidant formulations is controversial. Thus, these supplements should not be prescribed just for the purpose of providing patients some kind of therapy, which may give a false sense of mental satisfaction.

    DOI: 10.1177/25158414211030418

    Intravitreal Anti-Vascular Endothelial Growth Factor Agents for the Treatment of Diabetic Retinopathy: A Review of the Literature.

    Pharmaceutics. 2021 Jul 26;13(8):1137.

    Chatziralli I, Loewenstein A.

    BACKGROUND: Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population. The purpose of this review is to gather the existing literature regarding the use of the approved anti-vascular endothelial growth (anti-VEGF) agents in the treatment of DR.

    METHODS: A comprehensive literature review in PubMed engine search was performed for articles written in English language up to 1 July 2021, using the keywords “diabetic retinopathy”, “ranibizumab”, “aflibercept”, and “anti-VEGF”. Emphasis was given on pivotal trials and recent robust studies.

    RESULTS: Intravitreal anti-VEGF agents have been found to significantly improve visual acuity and reduce retinal thickness in patients with diabetic macular edema (DME) in a long-term follow-up ranging from 1 to 5 years and are considered the standard-of-care in such patients. Regarding DR, intravitreal anti-VEGF agents provided ≥2-step improvement in DR severity on color fundus photography in about 30-35% of patients with NPDR at baseline, in the majority of clinical trials originally designed to evaluate the efficacy of intravitreal anti-VEGF agents in patients with DME. Protocol S and CLARITY study have firstly reported that intravitreal anti-VEGF agents are non-inferior to panretinal photocoagulation (PRP) in patients with proliferative DR (PDR). However, the use of new imaging modalities, such as optical coherence tomography-angiography and wide-field fluorescein angiography, reveals conflicting results about the impact of anti-VEGF agents on the regression of retinal non-perfusion in patients with DR. Furthermore, one should consider the high “loss to follow-up” rate and its devastating consequences especially in patients with PDR, when deciding to treat the latter with intravitreal anti-VEGF agents alone compared to PRP. In patients with PDR, combination of treatment of intravitreal anti-VEGF agents and PRP has been also supported. Moreover, in the specific case of vitreous hemorrhage or tractional retinal detachment as complications of PDR, intravitreal anti-VEGF agents have been found to be beneficial as an adjunct to pars plana vitrectomy (PPV), most commonly given 3-7 days before PPV, offering reduction in the recurrence of vitreous hemorrhage.

    CONCLUSIONS: There is no general consensus regarding the use of intravitreal anti-VEGF agents in patients with DR. Although anti-VEGF agents are the gold standard in the treatment of DME and seem to improve DR severity, challenges in their use exist and should be taken into account in the decision of treatment, based on an individualized approach.

    DOI: 10.3390/pharmaceutics13081137