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    Research update: 531

    The latest research highlights for 28 March 2022.


    Effect of anticoagulant/antiplatelet therapy on the development and progression of diabetic retinopathy.

    BMC Ophthalmology. 2022 Mar 17

    Jeng CJ, Hsieh YT, Lin CL, Wang IJ

    Background: We investigated whether antiplatelet/anticoagulant (APAC) therapy can protect patients with type 2 diabetes mellitus (T2DM) from the development or progression of diabetic retinopathy (DR).

    Methods: This is a retrospective cohort study using Longitudinal Health Insurance Database in Taiwan. A total of 73,964 type 2 diabetic patients older than 20 years old were included. Hazard ration (HR) of non-proliferative DR (NPDR), proliferative DR (PDR), and diabetic macular edema (DME) were analyzed with APAC usage as a time-dependent covariate. Age, sex, comorbidities, and medicines were further adjusted in a multi-variable model. Contributions of respective APAC was investigated with sensitivity analysis.

    Results: Compared with nonusers, APAC users had a lower cumulative incidence of NPDR (P < 0.001), overall incidence of NPDR (10.7 per 1000 person-years), and risk of developing NPDR (adjusted HR = 0.78, 95% CI = 0.73-0.83). However, no significant differences were observed between APAC users and nonusers in the risks of PDR or DME. Hypertension, diabetic nephropathy and diabetic neuropathy were risk factors for NDPR development, while heart disease, cardiovascular disease, peripheral arterial occlusive disease, and statin usage were covariates decreasing NPDR development. Aspirin and Dipyridamole showed significant protection against NPDR development. Clopidogrel, Ticlopidine, and warfarin showed enhanced protection in combination with aspirin usage.

    Conclusions: APAC medications have a protective effect against NPDR development. Diabetic patients benefit from single use of aspirin or dipyridamole on prevention of NPDR.

    DOI: 10.1186/s12886-022-02323-z


    KSI-301: an investigational anti-VEGF biopolymer conjugate for retinal diseases.

    Expert Opinion on Investigational Drugs. 2022 Mar 16

    Stern HD, Hussain RM.

    Introduction: KSI-301 is an intravitreal anti-vascular endothelial growth factor (VEGF) agent in clinical trials for the treatment of neovascular age-related macular degeneration (nAMD), diabetic retinopathy, diabetic macular edema (DME), and retinal vein occlusion (RVO). Its antibody-biopolymer conjugate structure is designed to decrease clearance from the eye and increase the duration of the effect.

    Areas covered: This article briefly discusses the impact and mechanisms of nAMD, DME, and RVO and evaluates currently approved anti-VEGF therapies. It progresses to examine a new agent, KSI-301 and the results from numerous clinical trials in these disease areas.

    Expert opinion: Despite varied results in the phase 2b/3 study for nAMD, there is potential for KSI-301 to serve as a durable therapy for VEGF-mediated retinal disorders. Ongoing phase 3 trials for nAMD, DME, and RVO will provide additional evidence on its efficacy, duration, and safety profiles.

    DOI: 10.1080/13543784.2022.2052042


    Association Between Visual Acuity and Fluid Compartments with Treat-and-Extend Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration: An ARIES Post Hoc Analysis.

    Ophthalmology and Therapy. 2022 Mar 18.

    Chaudhary V, Holz FG, Wolf S, Midena E, Souied EH, Allmeier H, Lambrou G, Machewitz T, Mitchell P; ARIES study investigators.

    Introduction: Recently, there has been growing interest in exploring the relationship between visual acuity and fluid localization in different retinal compartments. This post hoc analysis of the ARIES study explores the relationship between the presence of intraretinal fluid (IRF) and subretinal fluid (SRF), both at baseline and throughout treatment, and best-corrected visual acuity (BCVA) in patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal aflibercept (IVT-AFL) in a treat-and-extend regimen.

    Methods: ARIES (NCT02581891) was a multicenter, randomized, phase 3b/4 study comparing the efficacy of two IVT-AFL treat-and-extend regimens over 2 years in patients with treatment-naïve nAMD. This post hoc analysis explores the relationship between the presence of SRF/IRF and absolute BCVA (letter score) at baseline and fixed visits.

    Results: In 210 patients (treat-and-extend treatment arms combined), SRF presence at baseline was associated at every time point with a numerically higher mean BCVA than if absent, with 10 more letters at week 104. IRF presence at baseline was associated at all but one time point with a numerically lower mean BCVA than if absent (week 104, 8-letter difference). Baseline SRF+IRF was associated with lower BCVA (week 104, 7-letter difference) than if only SRF was present, but higher BCVA (week 104, 8-letter difference) than if only IRF was present. Absence of SRF+IRF was not associated with better BCVA at any time point during the study.

    Conclusion: In ARIES, in patients with nAMD treated with IVT-AFL, the presence of SRF was associated with better visual acuity, whereas IRF was associated with poorer visual acuity. The findings of this post hoc analysis suggest that differentiating IRF from SRF may offer better prognostic value in guiding treatment-extension decisions than the use of combined or “any” IRF and SRF. Prospective trials are needed to validate these results and determine their clinical relevance.

    DOI: 10.1007/s40123-022-00491-1

    A randomized, double-masked, multicenter trial of topical acrizanib (LHA510), a tyrosine kinase VEGF-receptor inhibitor, in treatment-experienced subjects with neovascular age-related macular degeneration.

    American Journal of Ophthalmology. 2022 Mar 2

    Poor SH, Weissgerber G, Adams CM, Harit Bhatt, Browning DJ, Chastain J, Ciulla TA, Ferriere M, Gedif K, Louis C Glazer, Joondeph BC, Normand G, Sheth V, Watters C, Grosskreutz CL.

    Purpose: To evaluate whether topical acrizanib (LHA510), a small molecule vascular endothelial growth factor receptor (VEGFR) inhibitor, could suppress the need for anti-VEGF therapy over a 12-week period in patients with neovascular age-related macular degeneration (nAMD)

    Design: A phase 2 multicenter randomized double masked, vehicle-controlled proof of concept study

    Methods: Trial includes n = 90 patients with active choroidal neovascularization due to nAMD and under anti-VEGF treatment. All patients received an intravitreal injection of ranibizumab at baseline and were re-treated when there was evidence of disease recurrence (rescue). Patients were randomized 1:1 to receive topical LHA510 or vehicle for 12 weeks. Drops were administered twice a day for 8 weeks and then three times a day for the last 4 weeks

    Main Outcome Measure: The primary outcome was the number of patients requiring rescue over 84 days of topical dosing. Key secondary outcome measures were time to first rescue, total number of ranibizumab injections, changes in central subfield thickness (CSFT) and changes of visual acuity from baseline to Day 84.

    Results: The extended per protocol set included seventy patients of whom 25 of 33 patients in the LHA510 group (75.8%) and 25 of 37 patients in the placebo group (67.6%) required rescue by Day 84 (p = 0.8466). Secondary and subgroup analysis did not support evidence of efficacy. Twenty-one of 46 patients administered LHA510 developed a reversible corneal haze that resolved with cessation of treatment and did not recur in patients restarted at once daily frequency.

    Conclusions: In spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy.

    DOI: 10.1016/j.ajo.2022.02.019


    Rare complement factor I variants associated with reduced macular thickness and age-related macular degeneration in the UK biobank.

    Hum Mol Genet. 2022 Mar 14

    Tzoumas N, Kavanagh D, Cordell HJ, Lotery AJ, Patel PJ, Steel DH.

    To evaluate potential diagnostic and therapeutic biomarkers for age-related macular degeneration (AMD), we identified 8433 UK Biobank participants with rare complement factor I gene (CFI) variants, 579 with optical coherence tomography-derived macular thickness data. We stratified these variants by predicted gene expression and measured their association with retinal pigment epithelium-Bruch’s membrane (RPE-BM) complex and retinal thicknesses at nine macular subfields, as well as AMD risk, using multivariable regression models adjusted for the common CFH p.Y402H and ARMS2 p.A69S risk genotypes. CFI variants associated with low Factor I levels predicted a thinner mean RPE-BM (95% CI -1.66 to -0.37 μm, P = 0.002) and retina (95% CI -5.88 to -0.13 μm, P = 0.04), and a higher AMD risk (OR = 2.26, 95% CI 1.56-3.27, P < 0.001). CFI variants associated with normal Factor I levels did not impact mean RPE-BM/retinal thickness (P = 0.28; P = 0.99), or AMD risk (P = 0.97). CFH p.Y402H was associated with a thinner RPE-BM (95% CI -0.31 to -0.18 μm, P < 0.001 heterozygous; 95% CI -0.62 to -0.42 μm, P < 0.001 homozygous) and retina (95% CI -0.73 to -0.12 μm, P = 0.007 heterozygous; 95% CI -1.08 to -0.21 μm, P = 0.004 homozygous). ARMS2 p.A69S did not influence RPE-BM (P = 0.80 heterozygous; P = 0.12 homozygous) or retinal thickness (P = 0.75 heterozygous; P = 0.07 homozygous). p.Y402H and p.A69S exhibited a significant allele-dose response with AMD risk. Thus, CFI rare variants associated with low Factor I levels are robust predictors of reduced macular thickness and AMD. The observed association between macular thickness and CFH p.Y402H, but not ARMS2 p.A69S, highlights the importance of complement dysregulation in early pathogenesis.

    DOI: 10.1093/hmg/ddac060

    Reticular Pseudodrusen on the Risk of Progression in Intermediate Age-Related Macular Degeneration.

    American Journal of Ophthalmology. 2022 Mar 11

    Wu Z, Kumar H, Hodgson LAB, Guymer RH.

    Purpose: To examine the association between reticular pseudodrusen (RPD) and progression to late age-related macular degeneration (AMD) in individuals with intermediate AMD.

    Design: Prospective cohort study.

    Methods: 280 eyes from 140 participants with bilateral large drusen underwent multimodal imaging (MMI), including optical coherence tomography (OCT), near-infrared reflectance (NIR), fundus autofluorescence and color fundus photography (CFP), at 6-monthly intervals up over a 36-month follow-up period. The presence of RPD per eye was determined based on either a combined MMI criteria, as well as based on each individual imaging modality, and their extent measured on combined OCT and NIR imaging. The association between the presence of RPD on different imaging modalities, and their extent, with the development of late AMD (including OCT-defined atrophy) was evaluated.

    Results: The presence of RPD on MMI, or any of its individual modalities at baseline, was not significantly associated with an increased rate of developing late AMD, with or without adjusting for risk factors for AMD progression (age, drusen volume on OCT, and pigmentary abnormalities on CFP; all P ≥ 0.205). The extent of RPD present was also not significantly associated with an increased rate of developing late AMD, with or without adjustment for risk factors for AMD progression (both P ≥ 0.522).

    Conclusions: In this cohort with bilateral large drusen, the presence of RPD was not significantly associated with an increased risk of developing late AMD. Additional longitudinal studies in all stages of AMD are needed to understand the implications of RPD on vision loss in this condition.

    DOI: 10.1016/j.ajo.2022.03.007

    Evaluation of vascular endothelial growth factor (VEGF) level in the tears and serum of age-related macular degeneration patients.

    Science Reports. 2022 Mar 15

    Shahidatul-Adha M, Zunaina E, Aini-Amalina MN.

    Age-related macular degeneration (AMD) is an important cause of irreversible central blindness worldwide. Clinical manifestations range from asymptomatic in early and intermediate AMD to significant vision loss in late AMD. Approximately 10% of cases of early AMD eventually progress to the late advanced stage, influenced by the upregulation of vascular endothelial growth factor (VEGF). In this study, we evaluated VEGF concentration in the tears and serum of AMD patients. Our study revealed a significantly higher level of VEGF in the tears of patients with AMD compared with controls. The tear VEGF level has high sensitivity and specificity, and is significantly related to the severity of AMD, whilst serum VEGF level is non-specific and non-predictive of AMD severity. Thus, VEGF level in the tears may be used as a non-invasive biomarker for AMD progression. A large cohort study is needed for further verification.

    DOI: 10.1038/s41598-022-08492-7


    Suprachoroidal versus Intravitreal Triamcinolone Acetonide for the Treatment of Diabetic Macular Edema.

    Clinical Ophthalmology. 2022 Mar

    Zakaria YG, Salman AG, Said AMA, Abdelatif MK.

    Purpose: This article aims to compare between intravitreal (IV) and suprachoroidal (SC) triamcinolone acetonide (TA) injection for the treatment of diabetic macular edema (DME) in terms of improvement in both best-corrected visual acuity (BCVA) and central macular thickness (CMT), and development of complications (intraocular pressure (IOP) rise and cataract progression), and to identify the efficient dose of TA using the SC route.

    Patients and methods: This prospective interventional randomized comparative study included 45 eyes of 32 patients, randomly divided into three groups, group I received 4 mg/0.1 mL intravitreal TA (IVTA), group II received 4 mg/0.1 mL suprachoroidal TA (SCTA), and group III received 2mg/0.1 mL SCTA. Patients were followed up for 6 months.

    Results: At 1 month, a maximum reduction in CMT (147.33 ± 110.97 µm, 160.80 ± 98.25 µm and 65.64 ± 46.19 µm in groups I, II, and III, respectively) was observed, which was associated with the greatest improvement of BCVA (0.09 ± 0.09, 0.19 ± 0.10 and 0.10 ± 0.09 logMAR lines) in groups I, II, and III, respectively. At 3 months, CMT started to increase, and reduction was not statistically significant compared to baseline, except in group II (4 mg SCTA group) (149.80 ± 106.57 µm with P-value = 0.013). At 6 months, CMT and BCVA returned close to baseline except for group II which had a sustained reduction of 60.16 µm from baseline. Regarding steroid-related complications, IOP elevation of 10 mmHg or more was noted in 1 eye (6.7%), 2 eyes (13.3%), and 1 eye in groups I, II, and III, respectively. Three phakic eyes per group showed cataract progression.

    Conclusion: SCTA is a safe and effective route for the treatment of DME, which has comparable effects to IVTA, and may even last longer.

    DOI: 10.2147/OPTH.S351853