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    Research update: 508

    The latest research highlights for 30 August 2021


    Discontinuation and loss to follow-up rates in clinical trials of intravitreal anti-vascular endothelial growth factor injections.

    Graefes Arch Clin Exp Ophthalmol. 2021 Aug 20.

    Rosenblatt TR, Rayess N, Al-Moujahed A, Khurana RN, Mruthyunjaya P.

    PURPOSE: Clinical trials are often designed to include homogenous, highly specific patient populations with many resources to reduce patient dropout. Results may not translate to real-world settings. We evaluated discontinuation and loss to follow-up (LTFU) rates in clinical trials of anti-vascular endothelial growth factor (anti-VEGF) injections for diabetic macular edema (DME), age-related macular degeneration (AMD), and retinal vein occlusion (RVO).

    METHODS: Retrospective meta-epidemiological study. The authors queried for all completed trials of anti-VEGF injections for DME, AMD, or RVO. Of 658 trials identified, 582 were excluded for being non-interventional, <100 patients, terminating early, or missing study results. The remaining 76 trials of 27,823 patients were analyzed for discontinuation and LTFU rates.

    RESULTS: Mean discontinuation rate was 12.44% (SD 8.12%, range 0-54.12%), with higher rates among control (18.87%) than treatment arms (10.78%, p = .006). Mean LTFU rate was 1.84% (SD 1.78%, range 0-7.76%), with no differences by disease, treatment type, or treatment frequency.

    CONCLUSION: Discontinuation rates of major intravitreal anti-VEGF clinical trials were highly variable, suggesting even trials struggle with overall patient retention. Though trial LTFU rates were low, real-world outcomes may differ due to higher reported LTFU rates, which should be considered when extrapolating trial results to clinical practice.

    DOI: 10.1007/s00417-021-05246-5

    Predictors of Visual Acuity After Treatment of Neovascular Age-Related Macular Degeneration – Current Perspectives.

    Clin Ophthalmol. 2021 Aug 11;15:3351-3367.

    Phan LT, Broadhead GK, Hong TH, Chang AA.

    Visual acuity is a key outcome measure in the treatment of neovascular age-related macular degeneration (nAMD) using anti-vascular endothelial growth factor agents. Large variations in visual responses between individuals within clinical trials and real-world studies may relate to underlying differences in patient and treatment factors. Most notably, a better baseline visual acuity, younger age and smaller choroidal neovascularization lesion size have been strongly associated with achieving better visual outcomes. In addition, there is emerging evidence for other roles including genetic factors and anatomical variables such as fluid status. Apart from patient-related factors, treatments that favor a higher number of injections tend to provide better visual outcomes. Overall, the identification of predictive factors does not currently play an essential role in the clinical management of patients with nAMD. However, they have allowed for the understanding that early detection, timely management and close monitoring of the disease are required to achieve optimal visual outcomes. Further investigation into predictive factors alongside the development of novel therapeutic agents may one day provide a means to accurately predict patient outcomes. Treatment regimens that offer flexible dosing patterns such as the treat-and-extend strategy currently provide a degree of personalization during treatment.

    DOI: 10.2147/OPTH.S205147

    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.

    Lupidi M, Schiavon S, Cerquaglia A, Fruttini D, Gujar R, Muzi A, Fiore T, Reibaldi M, Chhablani J, Cagini C.

    PURPOSE: To compare the 12 months visual and anatomical outcomes of treatment-naïve neovascular age-related macular degeneration (nAMD) patients diagnosed by optical coherence tomography angiography (OCT-A) compared with fluorescein angiography (FA)/indocyanine green angiography (ICGA), after anti-VEGF treatment in a real-world setting.

    METHODS: Monocentric, observational, parallel-group study of nAMD patients diagnosed with either FA/ICGA or non-invasive OCT-A 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.

    RESULTS: Seventy-two patients received FA/ICGA for the initial diagnosis of nAMD, while 73 received OCT-A. Overall, the mean BCVA gain at 12 months was 11.5 ± 9.6 letters. There were no statistically significant differences between the invasive and non-invasive 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.

    CONCLUSION: In a real-world setting, nAMD patients diagnosed with OCT-A showed meaningful improvements in visual and anatomical parameters during 12 months of treatment, without significant differences with those diagnosed by invasive modalities.

    DOI: 10.1111/aos.15005

    Long-term outcomes of intravitreal anti-VEGF therapies in patients affected by neovascular age-related macular degeneration: a real-life study.

    BMC Ophthalmol. 2021 Aug 14;21(1):300.

    Corazza P, D’Alterio FM, Kabbani J, Alam MMR, Mercuri S, Orlans HO, Younis S.

    PURPOSE: To describe real-life data from wet age-related macular degeneration (AMD) patients treated with anti-vascular endothelial growth factors (VEGFs) and to compare our results with previous studies and clinical trials.

    METHODS: This retrospective monocentric cohort study analyzed 865 eyes of 780 wet-AMD patients treated with an anti-VEGF treat-and-extend regimen over a long-term follow-up period. Aflibercept and Ranibizumab were considered first-line agents whereas Bevacizumab was reserved for use on a compassionate basis in patients not meeting treatment criteria. All patients underwent a best corrected visual acuity (BCVA) assessment at each follow-up visit.

    RESULTS: One-year follow-up figures were available for 82.5% of patients, whilst follow-up data was recorded for 55.6%, 37.6%, 25.1%, and 15.0% of the cohort at years 2, 3, 4, and 5 respectively. Patients treated with Bevacizumab received fewer yearly injections than those treated with Ranibizumab. However, no significant difference in the number of injections per year was detected in other comparisons between groups. Whilst our data showed no significant difference in mean BCVA between the three groups, there was a gradual deterioration of visual function over time for the patient cohort as a whole.

    CONCLUSION: No significant differences between the 3 anti-VEGF molecules were recorded in wet-AMD patients in real-life conditions. Despite the long-term therapy, we found a slight reduction in visual function especially after the third year of treatment.

    DOI: 10.1186/s12886-021-02055-6

    Are Dilated Fundus Examinations Needed for OCT-Guided Retreatment of Exudative Age-Related Macular Degeneration? A Prospective, Randomized, Pilot Study.

    Clin Ophthalmol. 2021 Aug 12;15:3401-3417.

    Solomon SD, Kyerematen V, Qutab M, Wenick AS, Wang J, Hawkins BS.

    PURPOSE: To report findings when dilated fundus examination (DFE) is omitted from follow-up of patients receiving anti-VEGF injections for neovascular age-related macular degeneration (NVAMD).

    DESIGN: Randomized pilot study.

    PARTICIPANTS: NVAMD patients with two or more injections of anti-VEGF within prior six months who were expected to require treatment for at least eight more months.

    METHODS AND INTERVENTIONS: Participants were assigned to either retinal imaging and DFE or retinal imaging without a DFE except at 16 weeks and 32 weeks and at study completion.

    OUTCOMES: Primary safety outcomes were change in usual-corrected visual acuity (UCVA) and central subfield thickness (CST). Primary efficacy outcomes included time spent in clinic and patient satisfaction with clinic visits.

    RESULTS: The 66 participants had mean baseline UCVA of 20/50 in the study eye. Median change in UCVA from baseline to each clinic visit in each arm was “no change”. Mean change in CST was less than 15 microns from baseline to any follow-up clinic visit. Time spent in the clinic at follow-up visits averaged 20 minutes less for participants in the Imaging Only group than those in the Full Exam group. More participants in the Imaging Only group were satisfied with the time spent in clinic and with the clinic visits overall than participants in the Full Exam group: means of 71 vs 91 minutes, respectively, per clinic visit.

    CONCLUSION: Based on findings from this randomized pilot study, follow-up retina clinic visits for established patients who have NVAMD and are under treatment with intravitreous injection of anti-VEGF agents could be streamlined by implementing longer intervals between DFE and by relying on imaging alone to make most decisions regarding the need for retreatment, thereby reducing the time spent by patients in clinic and increasing their satisfaction with care received, without excess adverse events.

    DOI: 10.2147/OPTH.S315554


    Optical Coherence Tomography Features of Polypoidal Lesion Closure in Polypoidal Choroidal Vasculopathy Treated with Aflibercept.

    Retina. 2021 Aug 16.

    Tan AC, Jordan-Yu JM, Vyas CH.

    PURPOSE: To evaluate whether optical coherence tomography (OCT) can determine polypoidal lesion (PL) perfusion in polypoidal choroidal vasculopathy (PCV) eyes following 12-months of aflibercept monotherapy. PL perfusion status, assessed by indocyanine green angiography (ICGA), is an important anatomical outcome in PCV management.

    METHODS: Post-hoc data from a prospective randomised, open-label, study in eyes with PCV undergoing monotherapy with aflibercept evaluated PL perfusion status based on ICGA (gold standard) and OCT features from baseline to 12-months.

    RESULTS: Individual PLs(110 in total) from 48 eyes(48 patients) showed at 12-months, 57/110 PLs(51.8%) were closed on ICGA. At 12-months, eyes with closed PLs were more likely to have the following OCT features: 1)no SRF(67.1% versus 32.9%), 2)smaller PED height(67.2(±43.8) versus 189.2(±104.9)μm), 3)densely hyper-reflective PED contents(84.0% versus 16.0%), 4)an absence of a hyper-reflective ring(64.0% versus 36.0%) and a 5)indistinct overlying RPE(71.4% versus 28.6%) (all p<0.05). The three highest performing OCT features that differentiated perfused from closed PLs were (1), (3) and (4); (Area under the receiver operating characteristic curve[AUC-ROC] 0.85, 0.73, 0.70, respectively). A combination of these three features achieved an AUC-ROC of 0.90.

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

    DOI: 10.1097/IAE.0000000000003285

    Fundus autofluorescence and optical coherence tomography biomarkers associated with the progression of geographic atrophy secondary to age-related macular degeneration.

    Eye (Lond). 2021 Aug 16.

    Bui PTA, Reiter GS, Fabianska M, Waldstein SM, Grechenig C, Bogunovic H, Arikan M, Schmidt-Erfurth U.

    OBJECTIVES: To investigate the impact of qualitatively graded and deep learning quantified imaging biomarkers on growth of geographic atrophy (GA) secondary to age-related macular degeneration.

    METHODS: This prospective study included 1062 visits of 181 eyes of 100 patients with GA. Spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) images were acquired at each visit. Hyperreflective foci (HRF) were quantitatively assessed in SD-OCT volumes using a validated deep learning algorithm. FAF images were graded for FAF patterns, subretinal drusenoid deposits (SDD), GA lesion configuration and atrophy enlargement. Linear mixed models were calculated to investigate associations between all parameters and GA progression.

    RESULTS: FAF patterns were significantly associated with GA progression (p < 0.001). SDD was associated with faster GA growth (p = 0.005). Eyes with higher HRF concentrations showed a trend towards faster GA progression (p = 0.072) and revealed a significant impact on GA enlargement in interaction with FAF patterns (p = 0.01). The fellow eye status had no significant effect on lesion enlargement (p > 0.05). The diffuse-trickling FAF pattern exhibited significantly higher HRF concentrations than any other pattern (p < 0.001).

    CONCLUSION: Among a wide range of investigated biomarkers, SDD and FAF patterns, particularly in interaction with HRF, significantly impact GA progression. Fully automated quantification of retinal imaging biomarkers such as HRF is both reliable and merited as HRF are indicators of retinal pigment epithelium dysmorphia, a central pathogenetic mechanism in GA. Identifying disease markers using the combination of FAF and SD-OCT is of high prognostic value and facilitates individualized patient management in a clinical setting.

    DOI: 10.1038/s41433-021-01747-z


    Effect of blue light-filtering intraocular lenses on age-related macular degeneration: A nationwide cohort study with 10-year follow-up.

    Am J Ophthalmol. 2021 Aug 16:S0002-9394(21)00403-7.

    Lee JS, Li PR, Hou CH, Lin KK, Kuo CF, See LC.

    PURPOSE: To estimate the incidence rate of age-related macular degeneration (AMD) after cataract surgery and to compare the relative incidence of AMD in pseudophakes with blue light-filtering intraocular lenses (BF-IOLs) and non-BF-IOLs.

    DESIGN: This is a nationwide cohort study conducted using the Taiwan National Health Insurance Research Database.

    METHODS: We enrolled 186,591 patients who underwent cataract surgery in both eyes between 2008 and 2013 and followed them from the index date (the date of first cataract surgery) until AMD; death; loss to follow-up; or December 31, 2017; whichever occurred first. Propensity score matching (PSM) was used to balance the baseline characteristics between the two IOL groups, namely BF-IOL and non-BF-IOL groups.

    RESULTS: In total, 21,126 (11.3%) and 165,465 (88.7%) patients had BF-IOL and non-BF-IOL implants, respectively. Patients in the BF-IOL group tended to be younger, with fewer males, different cataract surgery years, higher income, more non-manual workers, more patients from urban and suburban areas, and fewer chronic diseases compared to the non-BF-IOL group. With a mean follow-up period of 6.1 years (range: 1-10 years) after cataract surgery, 12,533 and 1,655 patients developed non-exudative AMD and exudative AMD, respectively. The incidence rate of non-exudative AMD and exudative AMD (per 1000 person-years) was 9.95 and 1.22 for the BF-IOL group, and 11.13 and 1.44 for the non-BF-IOL group, respectively. After PSM, no statistical difference in the incidence rate of non-exudative AMD [Hazards ratio = 0.95, 95% confidence interval = 0.88-1.03] and exudative AMD [Hazards ratio = 0.96, 95% confidence interval = 0.77-1.18] was observed between the two IOL groups.

    CONCLUSIONS: In Taiwan, the incidence rate of AMD after cataract surgery was 11.59 per 1000 person-years. The use of a BF-IOL for up to 10 years had no apparent advantage over non-BF-IOL in the incidence of AMD.

    DOI: 10.1016/j.ajo.2021.08.002


    Central Retinal Vein Occlusion in a 46-Year-Old Man with COVID-19: Case Report and Review of the Literature.

    Case Rep Ophthalmol. 2021 Jul 19;12(2):646-652.

    Miller CG, Kim BJ.

    A 46-year-old man with a history of well-controlled hypertension presented with a central retinal vein occlusion (CRVO) in his right eye, which was complicated by cystoid macular edema. When the patient noted new visual symptoms, he was also experiencing muscle aches and easy fatiguability. A standard hypercoagulability panel failed to identify an etiology for his CRVO. However, the patient underwent COVID-19 antibody testing, which returned positive. The patient received a series of aflibercept injections for his macular edema, and his vision improved. Further study is warranted to determine if there is any association between mild infection with COVID-19 and the development of CRVO.

    DOI: 10.1159/000517417

    Successful delivery of subretinal aflibercept (new surgical technique) for the treatment of submacular hemorrhage in idiopathic polypoidal choroidal vasculopathy.

    J Surg Case Rep. 2021 Aug 16;2021(8):rjab358.

    Chalam KV, Gasparian S.

    Submacular hemorrhage (SMH) is often a result of trauma, wet age-related macular degeneration or IPCV and frequently leads to blindness secondary to extreme toxicity of hemoglobin products on photoreceptors. We describe a new technique of subretinal aflibercept injection during pars plana vitrectomy for the treatment of SMH in idiopathic polypoidal choroidal vasculopathy (IPCV). A 55-old male presented with sudden loss of vision (HM) secondary to massive subretinal hemorrhage associated with IPCV. Subretinal injection of aflibercept with a 25 g/42 g cannula coupled to the viscous fluid control unit of a standard vitrectomy system was performed during parsplana vitrectomy. Controlled injection of aflibercept intra-operatively has resulted in a resolution of SMH (confirmed with OCT and ICG). Visual acuity improved from HM to 20/20. This combined approach delivered anti-VEGF agent to target tissue in controlled fashion with the assistance of VFC system (similar to gene therapy) and restored full vision with resolution of SMH.

    DOI: 10.1093/jscr/rjab358


    The Impact of Fluid Compartments on Functional Outcomes in Patients with Neovascular Age-Related Macular Degeneration: A Systematic Literature Review.

    Retina. 2021 Aug 12.

    Chaudhary V, Matonti F, Zarranz-Ventura J, Stewart MW.

    PURPOSE: Understanding the impact of fluid in different retinal compartments is critical to developing treatment paradigms that optimize visual acuity (VA) and reduce treatment burden in neovascular age-related macular degeneration (nAMD). This systematic review aimed to determine the impact of persistent/new subretinal fluid (SRF), intraretinal fluid (IRF), and sub-retinal pigment epithelial (sub-RPE) fluid on VA over 1-year of treatment.

    METHODS: Publication eligibility and data extraction were conducted according to Cochrane methods: 27/1,797 screened records were eligible.

    RESULTS: IRF negatively impacted VA at baseline and throughout treatment, with foveal IRF associated with lower VA than extrafoveal IRF. Some studies found that SRF (particularly sub-foveal) was associated with higher VA at Year 1 and longer-term; others suggested SRF did not affect VA at Years 1 and 2. Data on the effects of sub-RPE fluid were scarce and consensus was not reached. Few studies reported numbers of injections associated with fluid status.

    CONCLUSION: To optimally manage nAMD, clinicians should understand the impact of fluid compartments on VA. After initial treatment, anti-vascular endothelial growth factor regimens that tolerate stable SRF (if VA is stable/improved) but not IRF may enable patients to achieve their best possible VA. Confirmatory studies are required to validate these findings.

    DOI: 10.1097/IAE.0000000000003283

    Newly-found functions of metformin for the prevention and treatment of age-related macular degeneration.

    Int J Ophthalmol. 2021 Aug 18;14(8):1274-1280.

    Dang KR, Wu T, Hui YN, Du HJ.

    Metformin (MET), a first-line oral agent used to treat diabetes, exerts its function mainly by activating adenosine monophosphate-activated protein. The accumulation of oxidized phospholipids in the outer layer of the retina plays a key role in retinal pigment epithelium (RPE) cells death and the formation of choroidal neovascularization (CNV), which mean the development of age-related macular degeneration (AMD). Recent studies have shown that MET can regulate lipid metabolism, inhibit inflammation, and prohibit retinal cell death and CNV formation due to various pathological factors. Here, newly discovered functions of MET that may be used for the prevention and treatment of AMD were reviewed.

    DOI: 10.18240/ijo.2021.08.20

    Low vision devices for age-related macular degeneration: a systematic review.

    Disabil Rehabil Assist Technol. 2021 Aug 20:1-13.

    Macnamara A, Chen CS, Davies A, Sloan C, Loetscher T.

    PURPOSE: Age-related macular degeneration (AMD) is a degenerative condition impacting central vision. Evaluating the effectiveness of low vision devices provides empirical evidence on how devices can rehabilitate and overcome deficits caused by AMD. This evidence could help to facilitate discussion on necessary future improvements to vision enhancement technology.

    METHODS: A systematic review of the literature was conducted on low vision device use in AMD populations. Relevant peer-reviewed research articles from six databases were screened.

    RESULTS: The findings of thirty-five studies revealed a significant positive impact of low vision devices leading to improvements in visual acuity, reading performance, facial recognition, and more. While the studies were found to have moderate risks of bias, a GRADE assessment of the evidence suggested the certainty of the evidence was low-moderate.

    DISCUSSION: Simple hand-held low vision devices (e.g., magnifiers) appear to currently have greater preferential support than newer visual enhancement technology (e.g., head mounted devices). Financial, comfort or usability reasons may influence preferences more than performance-based findings. However, there is a lack of studies examining newer technologies in AMD populations, which future research should address. Moreover, given the presence of bias across the studies and limited controlled experiments, confidence in the results may be low.

    CONCLUSIONS: Most studies indicated that low vision devices have positive impacts on reading and visual performance. But, even though they are reported to be a valuable asset to AMD populations, more rigorous research is required to draw conclusive evidence.

    IMPLICATIONS FOR REHABILITATION: Low vision devices can improve patient outcomes (e.g., vision, reading ability) for age-related macular degeneration populations. A multidisciplinary combination of low vision devices and rehabilitative services (i.e., eccentric viewing training, counselling, education) may enhance quality of life.

    DOI: 10.1080/17483107.2021.1966523