Ophthalmology. 2019 Oct 11. pii: S0161-6420(19)32137-2.
Treatment outcomes of ranibizumab versus aflibercept for neovascular age-related macular degeneration: data from the Fight Retinal Blindness! Registry.
Bhandari S, Nguyen V, Arnold J, Young S, Banerjee G, Gillies M, Barthelmes D.
Purpose: Ranibizumab and aflibercept are both approved for the treatment of neovascular age-related macular degeneration (nAMD). Herein, we compare the 3-year treatment outcomes of the 2 in routine clinical practice.
Design: Retrospective analysis of data from a prospectively designed observational outcomes registry, the Fight Retinal Blindness!
Participants: Treatment-naïive eyes starting nAMD treatment from December 1, 2013 through December 31, 2015, with either ranibizumab or aflibercept that were tracked in the registry.
Methods: Visual acuity (VA) was analyzed annually in completers (those who completed 3 years of treatment) and in all eyes (completers, noncompleters, and those who switched treatment ).
Main outcome measures: The primary outcome was mean change in VA (number of letters read on a logarithm of the minimum angle of resolution chart).
Results: A total of 965 eyes of 897 patients (ranibizumab, 499 eyes [469 patients]; aflibercept, 466 eyes [432 patients) were identified. The mean VA and the type of the choroidal neovascularization (CNV) at the start of treatment were similar between the 2 groups. The group receiving ranibizumab was older. The crude mean VA change of +1.5 letters (95% confidence interval [CI], 0-3.1 letters) in the ranibizumab group and of +1.6 letters (95% CI, -0.2 to 3.3 letters; P = 0.97) in the aflibercept group at 3 years in all eyes was similar, as was the adjusted mean VA change, +0.3 letters (95% CI, -1.5 to 2.0 letters) versus +1.0 letters (95% CI, -0.7 to 2.8 letters; P = 0.66). Both treatment groups received a median of 18 injections from a median of 21 clinical visits. The adjusted proportion of clinical visits when the CNV was graded active over 3 years was similar between ranibizumab (43%) and aflibercept (51%; P = 0.9). More switches from ranibizumab to aflibercept (P < 0.001) took place than vice versa. The proportion of eyes that did not complete 3 years of treatment in each of the group was similar (P = 0.21).
Conclusions: Neither ranibizumab nor aflibercept was superior to the other in terms of VA outcomes and treatment frequency at 3 years for nAMD.
PMID: 31757494 DOI: 10.1016/j.ophtha.2019.10.006
Retina. 2019 Nov 19.
Ranibizumab treatment in treatment-naive neovascular age-related macular degeneration: results from LUMINOUS, a global real-world study.
Holz FG, Figueroa MS, Bandello F, Yang Y, Ohji M, Dai H, Wykrota H, Sharma S, Dunger-Baldauf C, Lacey S, Macfadden W, Mitchell P.
Purpose: To evaluate the effectiveness, safety, and treatment patterns of ranibizumab 0.5 mg in treatment-naive patients with neovascular age-related macular degeneration enrolled in LUMINOUS study.
Methods: This 5-year, prospective, multicenter, observational study recruited 30,138 adult patients (treatment-naive or previously treated with ranibizumab or other ocular treatments) who were treated according to the local ranibizumab label.
Results: Six thousand two hundred and forty-one treatment-naive neovascular age-related macular degeneration patients were recruited. Baseline (BL) demographics were, mean (SD) age 75.0 (10.2) years, 54.9% females, and 66.5% Caucasian. The mean (SD) visual acuity (VA; letters) gain at 1 year was 3.1 (16.51) (n = 3,379; BLVA, 51.9 letters [Snellen: 20/92]) with a mean (SD) of 5.0 (2.7) injections and 8.8 (3.3) monitoring visits. Presented by injection frequencies <3 (n = 537), 3 to 6 (n = 1,924), and >6 (n = 918), visual acuity gains were 1.6 (14.93), 3.3 (16.57), and 3.7 (17.21) letters, respectively. Stratified by BLVA <23 (n = 382), 23 to <39 (n = 559), 39 to <60 (n = 929), 60 to <74 (n = 994), and ≥74 (n = 515), visual acuity change was 12.6 (20.63), 6.7 (17.88), 3.6 (16.41), 0.3 (13.83), and -3.0 (11.82) letters, respectively. The incidence of ocular/nonocular adverse events was 8.2%/12.8% and serious adverse events were 0.9%/7.4%, respectively.
Conclusion: These results demonstrate the effectiveness and safety of ranibizumab in treatment-naive neovascular age-related macular degeneration patients.
PMID: 31764612 DOI: 10.1097/IAE.0000000000002670
J Ophthalmol. 2019 Oct 21;2019:6274209.
Submacular injection of ranibizumab as a new surgical treatment for refractory diabetic macular edema.
El-Baha SM, Abdel Hadi AM, Abouhussein MA.
Purpose: In this study, we describe a new surgical technique for the treatment of refractory DME. The technique consists of vitrectomy with ILM peeling with a subretinal injection of ranibizumab.
Methods: This is a prospective interventional noncomparative study including patients with refractory DME. Included patients were subjected to the new surgical technique of pars plana vitrectomy with subretinal injection of ranibizumab.
Results: The study included 19 eyes with refractory macular edema, in which this novel technique was attempted. There were 10 males and 9 females. The age of the patients ranged from 17 to 67 years with a mean of 55.58 ± 13.242 years. The duration of diabetes before enrollment in the study ranged from 7 to 25 years with a mean of 16.3 years. Preoperatively, the mean CMT of the eyes ranged from 352 to 883 microns with mean ± SD of 498.58 ± 152.16 microns. Postoperatively, this improved significantly to 373.5 ± 100.3, 355.9 ± 89.8, and 365.74 ± 120.12 microns at 1, 3, and 6 months, respectively (p ≤ 0.001 for all).
Conclusion: This novel surgical procedure of vitrectomy with ILM peeling with a subretinal injection of ranibizumab is effective in cases of refractory DME. The study has been registered in Contact ClinicalTrials.gov PRS Identifier: NCT03975088.
PMID: 31772766 PMCID: PMC6854934 DOI: 10.1155/2019/6274209
Int J Part Ther. 2016 Mar;2(4):555-569.
Context for protons as adjunctive therapy in neovascular age-related macular degeneration: A review.
Rice SR, Katz MSJ, Mehta MP.
Abstract: In the last few years we have witnessed increasing availability of proton therapy in the United States and worldwide. As a result, proton therapy is considered as either a primary or adjunctive approach for numerous indications where conventional radiation therapy shows promise but is accompanied by toxicities. Age-related macular degeneration (AMD) remains the leading cause of adult blindness in industrialized nations, and third worldwide, following cataract and glaucoma. Current standard therapy is intravitreal injection of anti-vascular endothelial growth factor agents. While this treatment shows improvement and stabilization in visual acuity for 40% of patients, 60% still experience disease progression. These injections are costly, necessitate repeated office visits, and carry the risk of endophthalmitis. The pathophysiology underlying neovascular AMD (nAMD) underscores the need to simultaneously target multiple pathways to retain useful vision. Radiation can be antiangiogenic, anti-inflammatory, and antiproliferative. Early photon therapy clinical trials were heterogeneous, and a Cochrane review of data demonstrated usefulness in treatment of nAMD but recommended further studies. Advantages of proton therapy over photon therapy include the ability to deliver a focal dose to the target while minimizing dose to normal structures, which is enhanced by unique treatment planning software that uses fluorescein angiography to verify target location and allows conformation of dose to the irregular shape and thickness characteristic of choroidal neovascular membranes, the pathognomonic finding in nAMD. Preliminary data suggest a potential role for proton therapy in the treatment of nAMD. In this article we review previous treatments for AMD, including those with both photon and proton radiation, and recommend future directions for clinical investigations to evaluate the role of proton therapy as an adjunct to antiangiogenic therapy, the current standard of care in this challenging setting.
PMID: 31772967 PMCID: PMC6871634 DOI: 10.14338/IJPT-15-00019.1
Acta Ophthalmol. 2019 Nov 26.
Evaluation of a deep learning system for the joint automated detection of diabetic retinopathy and age-related macular degeneration.
González-Gonzalo C, Sánchez-Gutiérrez V, Hernández-Martínez P, Contreras I, Lechanteur YT, Domanian A, van Ginneken B, Sánchez CI.
Purpose: To validate the performance of a commercially available, CE-certified deep learning (DL) system, RetCAD v.1.3.0 (Thirona, Nijmegen, The Netherlands), for the joint automatic detection of diabetic retinopathy (DR) and age-related macular degeneration (AMD) in colour fundus (CF) images on a dataset with mixed presence of eye diseases.
Methods: Evaluation of joint detection of referable DR and AMD was performed on a DR-AMD dataset with 600 images acquired during routine clinical practice, containing referable and non-referable cases of both diseases. Each image was graded for DR and AMD by an experienced ophthalmologist to establish the reference standard (RS), and by four independent observers for comparison with human performance. Validation was furtherly assessed on Messidor (1200 images) for individual identification of referable DR, and the Age-Related Eye Disease Study (AREDS) dataset (133 821 images) for referable AMD, against the corresponding RS.
Results: Regarding joint validation on the DR-AMD dataset, the system achieved an area under the ROC curve (AUC) of 95.1% for detection of referable DR (SE = 90.1%, SP = 90.6%). For referable AMD, the AUC was 94.9% (SE = 91.8%, SP = 87.5%). Average human performance for DR was SE = 61.5% and SP = 97.8%; for AMD, SE = 76.5% and SP = 96.1%. Regarding detection of referable DR in Messidor, AUC was 97.5% (SE = 92.0%, SP = 92.1%); for referable AMD in AREDS, AUC was 92.7% (SE = 85.8%, SP = 86.0%).
Conclusion: The validated system performs comparably to human experts at simultaneous detection of DR and AMD. This shows that DL systems can facilitate access to joint screening of eye diseases and become a quick and reliable support for ophthalmological experts.
PMID: 31773912 DOI: 10.1111/aos.14306
Graefes Arch Clin Exp Ophthalmol. 2019 Nov 28.
The flicker response of venous oxygen saturation is significantly reduced in the early and late stages of age-related macular degeneration.
Donicova E, Ramm L, Augsten R, Hammer M.
Background: Retinal oxygen saturation (SO2) during flicker light stimulation was measured non-invasively in humans with age-related macular degeneration (AMD). Furthermore, the differences between early and late stages of AMD were evaluated.
Methods: In 60 eyes of 45 AMD patients (74 ± 8.3 years) and 23 eyes of 23 healthy controls (73.4 ± 7.4 years), the SO2 of arterioles and venules was measured with the oximetry module of the Retinal Vessel Analyzer. Arterial SO2, venous SO2 and arteriovenous SO2 difference at baseline and with the flicker were assessed and compared with controls. From the difference between the arteriovenous SO2 under flicker stimulation and at baseline, the parameter delta av. Diff was calculated. Subgroup analyses of non-exudative (dry) AMD, exudative (wet) AMD and their end stages, geographic atrophy (GA) and disciform scar (DS) were performed.
Results: In comparison with healthy subjects (mean - 4.90, CI [- 6.32, - 3.43]), the parameter delta av. Diff was significantly reduced in all AMD patients (mean - 2.20, CI - 3.15, -1.23, p = 0.003), dry AMD (mean - 1.97, CI - 3.31, -0.63, p = 0.013) and wet AMD (mean - 2.35, CI - 3.50, - 1.19, p = 0.025). The comparison between wet and dry AMD revealed no significant results (p = 1). The comparison between AMD subgroups and healthy controls (median (IQR) - 4.29 (- 8.32; - 2.42) %) showed significant differences in non-neovascular (early dry AMD) (median (IQR) - 2.43 (- 4.59; - 0.74) %, p = 0.038), GA (median (IQR) 0.10 (- 4.02; 3.15) %, p = 0.019) and DS (median (IQR) - 1.67 (- 3.52; - 0.12) %, p = 0.03). A nearly significant reduction was observed in exudative (early wet) AMD (median (IQR) - 2.71 (- 5.84; - 0.2) %, p = 0.055). Minimal, not statistically significant differences of delta av. Diff were found between AMD subgroups. None of the baseline parameters was significantly different between patients and healthy controls, even after flicker light stimulation.
Conclusions: Non-invasive retinal oximetry with flicker light stimulation seems to be a suitable method to study the pathogenetic mechanisms of AMD. The mathematically derived parameter delta av. Diff appears to be more sensitive than arteriovenous SO2 difference. Results suggest that the regulation of retinal oxygen supply, oxygen consumption or both is impaired in AMD.
PMID: 31781881 DOI: 10.1007/s00417-019-04533-6
J Ophthalmol. 2019 Oct 31;2019:1649156.
Association between metformin and a lower risk of age-related macular degeneration in patients with type 2 diabetes.
Chen YY, Shen YC, Lai YJ, Wang CY, Lin KH, Feng SC, Liang CY, Wei LC, Chou P.
Purpose: This population-based, retrospective cohort study was to investigate whether metformin is associated with a lower risk of subsequent age-related macular degeneration (AMD) in patients with type 2 diabetes.
Methods: Using the Taiwan National Health Insurance Research Database from 2001 to 2013, 68205 subjects with type 2 diabetes were enrolled in the study cohort. Among them, 45524 were metformin users and 22681 were nonusers. The metformin and nonmetformin groups were followed until the end of 2013. Cox regression analyses were used to estimate hazard ratios (HRs) for AMD development associated with metformin use. Confounders included for adjustment were age, sex, and comorbidities (hypertension, hyperlipidemia, coronary artery disease, obesity, diabetic retinopathy, chronic kidney disease, and insulin treatment). Furthermore, propensity score (PS) matching method was used to choose the matched sample, and PS-adjusted Cox regression was performed. Finally, how HRs changed according to metformin treatment duration and dose was also evaluated in the metformin group.
Results: After adjusting for confounders, the metformin group had a significantly lower risk of AMD (adjusted HR = 0.54; 95% confidence interval [CI], 0.50-0.58). In the PS-matched sample, the significance remained (adjusted HR = 0.57; 95% CI, 0.52-0.63). In the metformin group, the adjusted HRs for the second (1.5-4 years) and third (≥4 years) tertiles of metformin treatment duration were 0.52 and 0.14, respectively, compared with the first tertile (<1.5 years). We also found significant trends of lower HRs (all p-value for trend <0.05) with increasing total and average doses.
Conclusions: Among patients with type 2 diabetes, those who use metformin are at a significantly lower risk of developing AMD relative to individuals who do not use metformin. Also, the trend of a significantly lower AMD risk was found with a higher dose of metformin.
PMID: 31781371 PMCID: PMC6875398 DOI: 10.1155/2019/1649156
Invest Ophthalmol Vis Sci. 2019 Nov 1;60(14):4943-4950.
Low birth weight is linked to age-related macular degeneration: results from the population-based Gutenberg Health Study (GHS).
Fieß A, Elbaz H, Korb CA, Nickels S, Schulz A, Münzel T, Wild PS, Beutel ME, Schmidtmann I, Lackner KJ, Peto T, Pfeiffer N, Schuster AK.
Purpose: This study analyzed whether low birth weight is linked to prevalence and incidence of age-related maculopathy (AMD) in adulthood.
Methods: The Gutenberg Health Study (GHS) is a population-based, observational cohort study in Germany. GHS participants at an age from 35 to 74 years were included. An ophthalmologic examination with fundus photography was carried out. Fundus photographs were graded according to the Rotterdam Grading Scheme for AMD at baseline and at the 5-year follow-up examination. Participants were divided into three different birth weight groups (low: <2500 g; normal: 2500-4000 g; and high: >4000 g). Poisson regression analysis with adjustment for several confounders was used to assess associations between birth weight and AMD prevalence (overall, early, late AMD) and 5-year cumulative incidence.
Results: Overall, 6492 participants were included (3538 female, aged 50.7 ± 10.4 years). Prevalence of total AMD was highest in the low birth weight group (11.2%; 40/358) compared to the normal birth weight group (6.5%; 346/5328) and the high birth weight group (8.4%; 68/806). Low birth weight was associated with overall AMD prevalence (prevalence ratio [PR] = 1.54, P = 0.006), and in particular with early AMD prevalence (PR = 1.52; P = 0.01). No association was observed between low birth weight and cumulative 5-year incidence of AMD.
Conclusions: Our analyses indicate that low birth weight may lead to higher prevalence of retinal diseases in later life, as we observed for AMD. Our results are limited due to missing data and loss to follow-up, but may be a first hint that AMD has one of its origins in early life.
PMID: 31770434 DOI: 10.1167/iovs.19-27964
Curr Eye Res. 2019 Nov 28:1-11.
Treatment of age-related macular degeneration with pluripotent stem cell-derived retinal pigment epithelium.
Vitillo L, Tovell VE, Coffey P.
Abstract: Retinal pigment epithelium (RPE) degradation is central to the onset and progression of age-related macular degeneration (AMD), a growing and currently incurable form of blindness.Due to its key role in maintaining the retinal structure and homeostasis, cell replacement of the RPE monolayer has emerged as a promising therapy to rescue visual acuity in AMD patients.Thanks to the tremendous progress of pluripotent stem cell technologies over the last decade, a potentially unlimited new source for RPE transplantation has reached clinical trials. This review summarizes the methods by which pluripotent stem cell-based RPE cells are produced for transplantation, the delivery methods currently being adopted and the latest clinical outcomes with regard to the treatment of AMD.
PMID: 31777296 DOI: 10.1080/02713683.2019.1691237