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1.
Longitudinal Panretinal Leakage and Ischemic Indices in Retinal Vascular Disease after Aflibercept Therapy: The PERMEATE Study.
Figueiredo, N, Srivastava, SK, Singh, RP, Babiuch, A, Sharma, S, Rachitskaya, A, Talcott, K, Reese, J, Hu, M, Ehlers, JP
Ophthalmology. Retina. 2020;(2):154-163
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Abstract
PURPOSE To characterize the longitudinal panretinal retinal vascular dynamics in diabetic macular edema (DME) and retinal vein occlusion (RVO) over a 12-month period while being treated with intravitreal aflibercept injections (IAIs). DESIGN Prospective open-label study (clinicaltrials.gov identifier, NCT02503540). PARTICIPANTS Thirty-one treatment-naive eyes with foveal-involving retinal edema secondary to DME and RVO. METHODS Participants received 2 mg IAI every 4 weeks for the first 6 months, followed by 2 mg every 8 weeks. Ultra-widefield fluorescein angiography (UWFA; California Optos [Optos, Dunfermline, United Kingdom]) and spectral-domain OCT (Cirrus; Zeiss, Oberkochen, Germany) scans were obtained and analyzed using a novel quantitative assessment platform. Visual acuity, central subfield thickness, and adverse events also were collected. MAIN OUTCOME MEASURES The primary end point was the mean change in panretinal leakage index at month 12 from baseline as measured by UWFA. RESULTS Mean age was 67.1 years. At month 12, visual acuity significantly improved by a mean of 18.4±21.4 letters (P < 0.0001), and central subfield thickness also improved significantly, with a mean reduction of 301.3±250.3 μm (P < 0.0001). Mean panretinal leakage index improved significantly, decreasing from 3.4% at baseline to 0.5% at month 6 (P <0.0001) and 0.4% at month 12 (P < 0.0001). Panretinal ischemic index did not demonstrate any significant change but showed a nonsignificant increase from 5.5% at baseline to 6.1% at month 6 (P = 0.315) and 8.7% at month 12 (P = 0.193). Eyes with DME showed a decrease in leakage index from 3.5±2.7% at baseline to 1.6±0.8% at month 12 (P = 0.018) and overall stability in ischemic index from 5.0±4.1% at baseline to 4.7±3.5% at month 12 (P = 0.689). Participants with RVO showed a decrease in leakage index from 3.3±1.1% at baseline to 0.02±0.03% at 12 months (P < 0.0001) and a nonsignificant increase in ischemic index from 5.9±4.5% at baseline to 12.6±9.8% at month 12 (P = 0.172). CONCLUSIONS Intravitreal aflibercept injections resulted in a dramatic reduction in panretinal leakage index. Panretinal ischemic index did not improve and trended toward worsening.
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Optical Coherence Tomography (Angiography) Biomarkers in the Assessment and Monitoring of Diabetic Macular Edema.
Suciu, CI, Suciu, VI, Nicoara, SD
Journal of diabetes research. 2020;:6655021
Abstract
Retinopathy is one of the most severe diabetes-related complications, and macular edema is the major cause of central vision loss in patients with diabetes mellitus. Significant progress has been made in recent years in optical coherence tomography and angiography technology. At the same time, various parameters have been attributed the role of biomarkers creating the frame for new monitoring and treatment strategies and offering new insights into the pathogenesis of diabetic retinopathy and diabetic macular edema. In this review, we gathered the results of studies that investigated various specific OCT (angiography) parameters in diabetic macular edema, such as central subfoveal thickness (CST), cube average thickness (CAT), cube volume (CV), choroidal thickness (CT), retinal nerve fiber layer (RNFL), retinal thickness at the fovea (RTF), subfoveal choroidal thickness (SFCT), central macular thickness (CMT), choroidal vascularity index (CVI), total macular volume (TMV), central choroid thickness (CCT), photoreceptor outer segment (PROS), perfused capillary density (PCD), foveal avascular zone (FAZ), subfoveal neuroretinal detachment (SND), hyperreflective foci (HF), disorganization of the inner retinal layers (DRIL), ellipsoid zone (EZ), inner segment/outer segment (IS/OS) junctions, vascular density (VD), deep capillary plexus (DCP), and superficial capillary plexus (SCP), in order to provide a synthesis of biomarkers that are currently used for the early diagnosis, assessment, monitoring, and outlining of prognosis.
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Risk factors for progression of age-related macular degeneration.
Heesterbeek, TJ, Lorés-Motta, L, Hoyng, CB, Lechanteur, YTE, den Hollander, AI
Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians (Optometrists). 2020;(2):140-170
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Abstract
PURPOSE Age-related macular degeneration (AMD) is a degenerative disease of the macula, often leading to progressive vision loss. The rate of disease progression can vary among individuals and has been associated with multiple risk factors. In this review, we provide an overview of the current literature investigating phenotypic, demographic, environmental, genetic, and molecular risk factors, and propose the most consistently identified risk factors for disease progression in AMD based on these studies. Finally, we describe the potential use of these risk factors for personalised healthcare. RECENT FINDINGS While phenotypic risk factors such as drusen and pigment abnormalities become more important to predict disease progression during the course of the disease, demographic, environmental, genetic and molecular risk factors are more valuable at earlier disease stages. Demographic and environmental risk factors such as age and smoking are consistently reported to be related to disease progression, while other factors such as sex, body mass index (BMI) and education are less often associated. Of all known AMD variants, variants that are most consistently reported with disease progression are rs10922109 and rs570618 in CFH, rs116503776 in C2/CFB/SKIV2L, rs3750846 in ARMS2/HTRA1 and rs2230199 in C3. However, it seems likely that other AMD variants also contribute to disease progression but to a lesser extent. Rare variants have probably a large effect on disease progression in highly affected families. Furthermore, current prediction models do not include molecular risk factors, while these factors can be measured accurately in the blood. Possible promising molecular risk factors are High-Density Lipoprotein Cholesterol (HDL-C), Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), zeaxanthin and lutein. SUMMARY Phenotypic, demographic, environmental, genetic and molecular risk factors can be combined in prediction models to predict disease progression, but the selection of the proper risk factors for personalised risk prediction will differ among individuals and is dependent on their current disease stage. Future prediction models should include a wider set of genetic variants to determine the genetic risk more accurately, and rare variants should be taken into account in highly affected families. In addition, adding molecular factors in prediction models may lead to preventive strategies and personalised advice.
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Efficacy and Safety of Abicipar in Neovascular Age-Related Macular Degeneration: 52-Week Results of Phase 3 Randomized Controlled Study.
Kunimoto, D, Yoon, YH, Wykoff, CC, Chang, A, Khurana, RN, Maturi, RK, Agostini, H, Souied, E, Chow, DR, Lotery, AJ, et al
Ophthalmology. 2020;(10):1331-1344
Abstract
PURPOSE To compare the efficacy and safety of abicipar every 8 weeks and quarterly (after initial doses) versus ranibizumab every 4 weeks in treatment-naïve patients with neovascular age-related macular degeneration (AMD). DESIGN Two randomized, multicenter, double-masked, parallel-group, active-controlled, phase 3 clinical trials (CEDAR, SEQUOIA) with identical protocols were conducted. Data from both trials were pooled for analysis. PARTICIPANTS Patients with active choroidal neovascularization secondary to AMD and best-corrected visual acuity (BCVA) of 24-73 Early Treatment Diabetic Retinopathy Study letters in the study eye were enrolled. METHODS Patients (n = 1888) were randomized in a 1:1:1 ratio to study eye treatment with abicipar 2 mg every 8 weeks after 3 initial doses at baseline and weeks 4 and 8 (Q8), abicipar 2 mg every 12 weeks after 3 initial doses at baseline and weeks 4 and 12 (Q12), or ranibizumab 0.5 mg every 4 weeks (Q4). MAIN OUTCOME MEASURES The primary efficacy end point was proportion of patients with stable vision (defined as <15-letter loss in BCVA from baseline) in the study eye at week 52. Secondary end points included change from baseline in BCVA and central retinal thickness (CRT) at week 52. Safety measures included adverse events (AEs). RESULTS The proportion of patients with stable vision at week 52 was 93.2%, 91.3%, and 95.8% in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively, with both abicipar Q8 and Q12 noninferior to ranibizumab Q4. Week 52 mean change from baseline in BCVA was 7.5, 6.4, and 8.4 letters and in CRT was -144, -145, and -144 μm in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively. Incidence of intraocular inflammation (IOI) AEs was 15.4%, 15.3%, and 0.3%, respectively. The IOI AEs were typically mild or moderate in severity and treated with topical corticosteroids; 62 of 192 patients (32.3%) received oral and/or injectable corticosteroids. CONCLUSIONS Abicipar Q8 and Q12 were both noninferior to ranibizumab Q4 in the primary end point of stable vision at week 52. Intraocular inflammation was more frequent with abicipar. Quarterly and Q8 abicipar reduce nAMD disease and treatment burden compared with monthly treatment.
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Use of optical coherence tomography angiography for assessment of microvascular changes in the macula and optic nerve head in hypertensive patients without hypertensive retinopathy.
Hua, D, Xu, Y, Zeng, X, Yang, N, Jiang, M, Zhang, X, Yang, J, He, T, Xing, Y
Microvascular research. 2020;:103969
Abstract
PURPOSE To compare optical coherence tomography angiography (OCTA) screening parameters of the macula and optic nerve head (ONH) between healthy volunteers and chronic hypertensive patients without hypertensive retinopathy. METHODS This was an observational, cross-sectional study. Fifty-seven chronic hypertensive patients without hypertensive retinopathy (22 men and 35 women) and 40 healthy volunteers (17 men and 23 women), ranging in age from 60 to 70 years, were included in this study. Patients and volunteers were divided into three groups and one eye was selected randomly from each participant. Group A comprised patients who had a history of hypertension for >10 years (n = 35); Group B comprised patients who had a history of hypertension for 5-10 years (n = 22); and Group C comprised 40 healthy volunteers who had no history of hypertension. A 3 × 3-mm macula scan and a 4.5 × 4.5-mm ONH scan were performed in each group by OCTA using prototype AngioVue software within the AngioVue device. Vessel density (VD), foveal avascular zone (FAZ) area, choriocapillaris flow area, ONH capillary density, retinal nerve fiber layer (RNFL) thickness, and demographic information were compared among the groups. RESULTS Macula scans showed that superficial plexus VD was significantly lower in groups A and B than in group C (P < 0.05). In addition, FAZ area was significantly larger in group A than in group C (P < 0.05). Inner retinal layer thickness was significantly thinner in groups A and B than in group C (P < 0.05). In ONH scans, RNFL thickness was significantly thinner in group A than in groups B and C (P < 0.05); it was significantly thinner in group B than in group C (P < 0.05). Inside disc capillary density and peripapillary capillary density were significantly lower (P < 0.05) and greater (P < 0.05), respectively, in groups A and B than in group C. CONCLUSIONS Superficial plexus VD, FAZ area, capillary density, and inner retinal thickness changed significantly in hypertensive patients without hypertensive retinopathy. However, only RNFL thickness was significantly thinner in patients who had >10 years of hypertension, compared to patients who had 5-10 years of hypertension. In addition, OCTA provided a method to prospectively assess changes in retinal microvasculature and thickness, thereby avoiding further long-term retinal damage in hypertensive patients.
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Aflibercept plus micropulse laser versus aflibercept monotherapy for diabetic macular edema: 1-year results of a randomized clinical trial.
Abouhussein, MA, Gomaa, AR
International ophthalmology. 2020;(5):1147-1154
Abstract
PURPOSE To evaluate the role of adjuvant micropulse laser with aflibercept injections in the management of treatment naive center involving DME, looking at decreased treatment burden and increased efficacy as outcomes after 1 year. METHODS This was a prospective, single center, randomized trial that included 40 eyes (40 patients) with previously untreated center involved DME. Patients were randomly assigned to receive either aflibercept plus micropulse laser (group A) or aflibercept monotherapy (group B). RESULTS Overall, 40 patients were included in the study; they were randomized into either group A (aflibercept + micropulse; 20 patients) or group B (aflibercept monotherapy; 20 patients). The mean number of injections after the loading dose was 4.5 ± 1.4 in group A and was 5.4 ± 1.7 in group B, and the difference between both groups was statistically significant (P = 0.029). CONCLUSION Adding 577-nm micropulse laser to aflibercept is effective for treatment naïve DME and is associated with decreased number of injections.
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Comparison of Retinal Layer Thickness in Eyes with Resolved Diabetic Macular Edema Receiving Ranibizumab with Normal Eyes.
Rentiya, ZS, Kherani, S, Usmani, B, Qazi, MA, Sadiq, MA, Iftikhar, M, Nguyen, QD, Shah, SM, Sepah, YJ, ,
Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde. 2020;(1):27-36
Abstract
PURPOSE To evaluate the thickness of individual retinal layers in eyes with resolved diabetic macular edema (DME) after treatment with ranibizumab (RBZ). METHODS Spectral-domain optical coherence tomography (OCT) scans of 25 eyes (25 patients) with DME that had been treated with RBZ (and shown resolution of edema as evident by the absence of fluid in a high-resolution grid placed on the fovea) were acquired using Spectralis HRA + OCTTM. Thickness measurements of individual layers were calculated using papillomacular bundle (PMB), central subfield, and inner- and outer-ring Early Treatment Diabetic Retinopathy Study (ETDRS) grids. Measurements were compared to 45 normal eyes with no known retinal disease. A post-hoc analysis was done correlating visual acuity (VA) with individual retinal layer thickness. RESULTS Full retinal thickness (FRT) was thinner than normal individuals across all 4 grids. There were similarities and differences among the 4 grids; however, PMB and inner-ring ETDRS grids displayed the most resemblance. The VA significantly correlated with the FRT measured in PMB (p = 0.004), central subfield (p = 0.02), and inner-ring (p = 0.006) ETDRS. CONCLUSIONS Segmentation of OCT scans revealed significant differences in the overall thickness of the retina and of individual retinal layers in patients with resolved DME. PMB grid showed a stronger correlation between affected retinal layers and VA compared to ETDRS. PMB also showed significance with VA in layers that were shown to be not significant in ETDRS grid.
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Systematic ultrastructural comparison of swept-source and full-depth spectral domain optical coherence tomography imaging of diabetic macular oedema.
Mitsch, C, Lammer, J, Karst, S, Scholda, C, Pablik, E, Schmidt-Erfurth, UM
The British journal of ophthalmology. 2020;(6):868-873
Abstract
BACKGROUND/AIMS: Optical coherence tomography (OCT) is commonly used to diagnose and assess diabetic macular oedema (DME). Swept-source OCT (SS-OCT) promises improved imaging depth and more independence from media opacities. Heidelberg Spectralis full-depth imaging (FDI) combines details at different depths to one representation. The aim of this study was to determine the comparability of the imaging methods concerning DME ultrastructure. METHODS Two graders assessed the presence of typical DME phenomena in eyes with centre-involving DME on Topcon Atlantis SS-OCT and Heidelberg Spectralis FDI spectral-domain OCT (SD-OCT) B-scans. Retinal layer segmentation was corrected and choroidal layers were manually segmented. Graders measured cyst and subretinal fluid (SRF) diameters and counted hyper-reflective foci (HRF). Findings were recorded and statistically analysed. RESULTS Statistically significant systematic biases (Spectralis-Atlantis) were found for the HRF count (outside the central mm, -6.39, p=0.0338), chorioretinal thickness (central mm: -35.45 µm, p=0.00034), choroidal thickness (central mm: -60.97 µm, p=0.00004) and Sattler's layer thickness (-42.69 µm, p=0.0001). Intergrader agreement was excellent or very good for posterior vitreous detachment, vitreomacular attachment (central mm) and SRF presence in both devices. Manually delineated Sattler's layer thickness showed an intraclass correlation of 0.85 with FDI SD-OCT but 0.26 with SS-OCT (p=0.003). CONCLUSION Prominent aspects such as cysts in the outer nuclear layer and SRF can be identified with comparable confidence, while a significant systematic bias underlies chorioretinal, choroidal and Sattler's layer thickness and HRF count. Specialists should use the same device at every examination during longitudinal clinical consideration or cross-sectional evaluation of these ultrastructural biomarkers.
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Are Dilated Fundus Examinations Needed for OCT-Guided Retreatment of Exudative Age-Related Macular Degeneration?
Patel, Y, Miller, DM, Fung, AE, Hill, LF, Rosenfeld, PJ
Ophthalmology. Retina. 2020;(2):141-147
Abstract
PURPOSE To determine whether presence of macular hemorrhage on dilated fundus examination (DFE) or fundus photography influences vision outcomes with OCT-guided pro re nata (PRN) ranibizumab retreatment in patients with neovascular age-related macular degeneration (nAMD), we investigated whether hemorrhage without OCT-detectable fluid impacted vision outcomes. DESIGN Post hoc analysis of prospectively collected data from the 24-month pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvascular age-related macular degeneration (HARBOR) trial (ClinicalTrials.gov identifier, NCT00891735). PARTICIPANTS This post hoc analysis examined 1097 patients from the intention-to-treat population of HARBOR. METHODS Dilated fundus examination and fundus photography were evaluated for hemorrhage, and spectral-domain (SD) OCT images from HARBOR participants were analyzed for macular fluid secondary to macular neovascularization. Agreement between methods was determined for each time point. Visual outcomes were evaluated for 82 patients with evidence of hemorrhage on DFE or fundus photography at 3 months and no evidence of SD-exudative activity requiring retreatment at month 3. MAIN OUTCOME MEASURES Pooled data from the intention-to-treat population of HARBOR were analyzed for hemorrhage on DFE or fundus photography and exudative activity on SD OCT. A subgroup of PRN patients were analyzed for best-corrected visual acuity gains at 24 months. RESULTS Most study eyes (89% [973/1095]) showed macular hemorrhages at baseline, declining to 31% (319/1042) at month 3 and stabilizing at 11% (111/989) by month 6 of follow-up. After baseline, exudative activity was detected on SD-OCT in more than 89% of eyes when hemorrhage was present on DFE or fundus photography. Patients not requiring a month 3 PRN ranibizumab injection achieved similar visual gains over 24 months, regardless of month 3 hemorrhage presence versus absence: 9.4 and 8.7 Early Treatment Diabetic Retinopathy Study letter scores, respectively (P = 0.74). CONCLUSIONS After 3 initial ranibizumab injections, SD-OCT detected nAMD activity in 89% of eyes when hemorrhage was present on fundus photography. Ranibizumab retreatment guided by monthly SD-OCT achieved similar vision gains with or without injection when hemorrhage was present without OCT-detectable fluid. This suggests that macular hemorrhages without OCT-detectable macular fluid may not require treatment and DFE may not be needed at every visit. These conclusions should be confirmed in a prospective randomized trial before firm recommendations regarding clinical practice can be made.
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PRAGMATISM OF RANDOMIZED CLINICAL TRIALS ON RANIBIZUMAB FOR THE TREATMENT OF DIABETIC MACULAR EDEMA: Impact on Clinical Outcomes.
Stewart, S, Yeong, JL, Virgili, G, Azuara-Blanco, A, Lois, N
Retina (Philadelphia, Pa.). 2020;(5):919-927
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Abstract
PURPOSE To evaluate the pragmatism and generalizability of randomized clinical trials (RCTs) on ranibizumab for diabetic macular edema and determine whether clinical outcomes would differ based on whether or not patients fulfill the eligibility criteria of these RCTs. METHODS Pragmatism and generalizability of three RCTs on ranibizumab for diabetic macular edema (DRCRnet Protocols I and T, and RESTORE) were rated using the PRECIS-2 tool. A cohort of consecutive patients with diabetic macular edema was assessed to determine whether clinical outcomes differed based on whether or not patients met the RCT eligibility criteria. Univariable and multivariable regression analyses, adjusted for baseline best-corrected visual acuity, central retinal thickness and number of injections received, were used. RESULTS All RCTs were rated as being more pragmatic than explanatory, with DRCRnet trials being the most pragmatic. Of the 216 eyes (176 patients) included in the cohort, 63% would have met eligibility criteria for Protocol T, 61% for Protocol I, and 56% for RESTORE. When adjusted for best-corrected visual acuity, central retinal thickness, and number of ranibizumab injections received, there were no statistically significant differences in best-corrected visual acuity or central retinal thickness found between "eligible" and "ineligible" patients. CONCLUSION Randomized clinical trials evaluating ranibizumab for diabetic macular edema were more pragmatic than explanatory. "Ineligible" patients still benefited from ranibizumab therapy.