Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial.

BACKGROUND: Intravitreal aflibercept 8 mg could improve treatment outcomes and provide sustained disease control in patients with neovascular age-related macular degeneration (nAMD), with extended dosing compared with aflibercept 2 mg. METHODS: PULSAR is a phase 3, randomised, three-group, double-masked, non-inferiority, 96-week trial conducted across 223 sites worldwide. Adults with nAMD were randomised 1:1:1 to aflibercept 8 mg every 12 weeks (8q12), aflibercept 8 mg every 16 weeks (8q16), or aflibercept 2 mg every 8 weeks (2q8), following three initial monthly doses in all groups. From week 16, patients in the aflibercept 8 mg groups had their dosing interval shortened if pre-specified dose regimen modification criteria denoting disease activity were met. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48. All patients with at least one dose of study treatment were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04423718) and is ongoing. FINDINGS: Of 1011 patients randomised to aflibercept 8q12 (n=336), 8q16 (n=338), or 2q8 (n=337) between Aug 11, 2020, and July 30, 2021, 1009 patients received study treatment (aflibercept 8q12 n=335; aflibercept 8q16 n=338; and aflibercept 2q8 n=336). Aflibercept 8q12 and 8q16 showed non-inferior BCVA gains versus aflibercept 2q8 (mean BCVA change from baseline +6·7 [SD 12·6] and +6·2 [11·7] vs +7·6 [12·2] letters). The least squares mean differences between aflibercept 8q12 versus 2q8 and 8q16 versus 2q8, respectively, were -0·97 (95% CI -2·87 to 0·92) and -1·14 (-2·97 to 0·69) letters (non-inferiority margin at 4 letters). The incidence of ocular adverse events in the study eye was similar across groups (aflibercept 8q12 n=129 [39%]; aflibercept 8q16 n=127 [38%]; and aflibercept 2q8 n=130 [39%]). INTERPRETATION: Aflibercept 8 mg showed efficacy and safety with extended dosing intervals, which has the potential to improve the management of patients with nAMD. FUNDING: Bayer AG and Regeneron Pharmaceuticals.

Associations of drusen location with risk factors and incidence of late age-related macular degeneration in the Alienor study.

PURPOSE: To test the hypothesis that central drusen location is strongly linked with known Age-related Macular Degeneration (AMD) risk factors and risk of incident late AMD. METHODS: The Alienor study is a prospective population-based cohort study of residents of Bordeaux, France, followed from 2009 to 2017. On retinal photographs, we defined central drusen as at least one soft drusen (>63 µm) within 500 µm from fovea and pericentral drusen as at least one drusen 500-3000 µm from fovea, in the absence of any central drusen. Late AMD (atrophic and/or neovascular) was diagnosed using multimodal imaging. In total, 481 eyes were included in the analysis: 160 central and 321 pericentral. We investigated associations with systemic (age, sex, smoking, medical prescriptions, plasma concentrations of lipids and nutrients, UV exposure, blood pressure), ocular (retinal thickness, cataract extraction) and genetic risk scores (GRS). RESULTS: In multivariate logistic regression central drusen were associated with smoking (OR, 2.95 for smoking more than 20 pack-years, p = 0.02), HDL-cholesterol (OR, 1.57 for 1 standard deviation (SD) increase, p = 0.0048), pulse pressure (OR, 0.77 for 1 SD increase, p = 0.04), Age-Related Maculopathy Susceptibility 2 (ARMS2) GRS (OR, 1.42; 95% CI, 1.11-1.83) and complement GRS (OR, 1.55; 95% CI, 1.15-2.10). In Cox modelling, the central location of drusen (at baseline or during the follow-up) was associated with a 4.41-fold increased risk (95% CI,1.98-9.81) for an incident late AMD. CONCLUSION: Central drusen were strongly associated with AMD risk factors and incident late AMD, suggesting that it represents a key marker for AMD progression.

Faricimab Treat-and-Extend for Diabetic Macular Edema: Two-Year Results from the Randomized Phase 3 YOSEMITE and RHINE Trials.

PURPOSE: To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME). DESIGN: Randomized, double-masked, noninferiority phase 3 trials. PARTICIPANTS: Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME. METHODS: Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change. MAIN OUTCOME MEASURES: Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100. RESULTS: In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 µm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept. CONCLUSIONS: Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

LIFETIME AMBIENT ULTRAVIOLET RADIATION EXPOSURE AND INCIDENCE OF AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate the link between lifelong exposure to ultraviolet radiation (UVR) and the development of age-related macular degeneration (AMD). METHODS: The Alienor study is a prospective population-based cohort involving 963 residents of Bordeaux, France, older than 73 years. A subset of 614 participants for advanced AMD and 422 participants for early AMD were included in the analysis. The participants' residential history combined with UVR estimates from the EuroSun satellite were used to estimate the amount of ambient UVR they have been exposed to over their lifetime. Age-related macular degeneration was classified from retinal fundus photographs and spectral domain optical coherence tomography at 2 to 3 years intervals over the 2006 to 2017 period. Associations between cumulative exposure to ultraviolet A, ultraviolet B, and total (total UV) and the incidence of early and advanced AMD were estimated using multivariate Cox models. RESULTS: Intermediate quartiles of total UV, ultraviolet A, and ultraviolet B exposures were associated with a higher risk for incident early AMD (Hazard Ratio [HR] =2.01 [95% confidence interval [CI] = 1.27-3.13], HR = 2.20 [95% CI = 1.38-3.50], HR = 1.79 [95% CI = 1.13-2.80], respectively) as compared with the lower quartile. However, this risk did not further increase in the highest quartiles of exposure. None of the three types of UVR exposure was significantly associated with incident advanced AMD. CONCLUSION: Despite an increased risk with intermediate compared with low UVR exposure, our study cannot confirm a dose-response relationship of UVR exposure with early AMD onset.

Ophthalmologic Phenotype-Genotype Correlations in Patients With Oculocutaneous Albinism Followed in a Reference Center.

Purpose: Albinism is a group of genetic disorders that includes several conditions related to a defect in melanin production. There is a broad phenotypic and genotypic variability between the different forms. The aim of this study was to assess the ophthalmologic characteristics according to patients' genotypes in a cohort followed in the Reference Center for oculocutaneous albinism (OCA) of Bordeaux University Hospital, France. Methods: A retrospective observational study was conducted in a cohort of patients with OCA seen in consultation in the ophthalmology department between 2017 and 2021 in whom a genetic analysis was performed. Results: In total, 127 patients with OCA were included in this study and matched with the results of the genetic analysis. In the population aged over 6 years, there was no statistical difference in binocular visual acuity between the OCA1, OCA2, and OCA4 forms (P = 0.27). There was difference in ametropia between the three forms (P = 0.003). A two-by-two comparison using the Bonferroni correction showed a significant difference in ametropia between the OCA2 and OCA4 forms (P = 0.007) and between the OCA1 and OCA2 forms (P = 0.0075). Regardless of the form, most patients (75.4%) had grade 4 foveal hypoplasia. There was no association between the grade of foveal hypoplasia and the gene involved (P = 0.87). Conclusions: We described a genotype-phenotype correlation for the three most represented forms of albinism in our cohort. This study allowed assessing the degree of visual deficiency in young children with OCA.

Optical Coherence Tomography Angiography in Diabetic Macular Edema Treated with Intravitreal Aflibercept: A 48-Week Observational Study (the DOCTA Study).

INTRODUCTION: Central vision loss due to diabetic macular edema (DME) is related to the macular edema itself but also, in some cases, to alterations of the foveal avascular zone (FAZ). The aim of this trial was to study changes in macular vessels in eyes with DME treated with aflibercept using optical coherence tomography angiography (OCTA). METHODS: This was a longitudinal, prospective, noncontrolled, single-arm study. The primary objective was the quantitative assessment of macular vessels over time in patients with DME treated with intravitreal aflibercept during a 48-week follow-up using OCTA. RESULTS: Twenty-six DME eyes from 26 patients were included (mean age, 64.6 years; women, 53.8%; prior anti-VEGF treatment, 46.1%). Each eye received a mean (SD) of 7.2 (2.2) injections. The following parameters of the FAZ did not change during the 48-week follow-up: the mean (SD) FAZ area varied from 0.19 (0.19) mm2 at baseline (n = 22) to 0.23 (0.20) mm2 at week 48 (n = 15), boundary from 1.54 (1.21) to 2.04 (1.20) mm, and circularity from 0.45 (0.33)% to 0.57 (0.20)%. There was no change in perfusion density and vessel density of the macula in the 3-mm circle. As expected, mean central retinal thickness, macular volume, and visual acuity improved during follow-up. CONCLUSION: No change in macular perfusion was observed in eyes with DME during a 48-week follow-up after intravitreal injections of aflibercept. Randomized controlled trials using OCT angiography in large populations with extended observation periods are needed to assess changes in macular vessels after intravitreal anti-VEGF treatment.

Two-year outcomes of the APOLLON observational study of intravitreal aflibercept monotherapy in France in patients with diabetic macular edema.

APOLLON (NCT02924311) was a prospective observational study to evaluate the effectiveness of intravitreal aflibercept (IVT-AFL) treatment of diabetic macular edema (DME) over 24 months in routine clinical practice in France. The primary endpoint was mean change from baseline in best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study letters) by 12 months, and safety was monitored throughout the study. Of 402 patients enrolled across 61 participating clinics and hospitals in France, 168 patients were followed for at least 24 months and included in the effectiveness analyses (79 treatment-naïve and 89 previously treated). After 24 months of IVT-AFL treatment, the mean (± standard deviation [SD]) change in BCVA from baseline was + 6.5 (± 10.7) letters in treatment-naïve patients (p < 0.001) and + 1.6 (± 17.0) letters in previously treated patients (p = 0.415) from a baseline of 63.8 (± 13.6) and 60.5 (± 16.5) letters. The mean number of IVT-AFL treatments over 24 months was 11.3 (± 4.9) and 11.9 (± 4.7) for treatment-naïve and previously treated patients. This final analysis of the APOLLON study indicated that following 24 months of IVT-AFL treatment in routine clinical practice in France, treatment-naïve patients with DME achieved significant gains in visual acuity and previously treated patients maintained prior visual acuity gains.Trial registration number: NCT02924311.

Epidemiology of Acute Endophthalmitis after Intraocular Procedures: A National Database Study.

OBJECTIVE: To describe the causes of postoperative acute endophthalmitis at the national level longitudinally. DESIGN: Cohort study from 2009 to 2018 in France. PARTICIPANTS: Patients diagnosed with acute endophthalmitis after intraocular procedures. METHODS: The French medical-administrative database was used. Endophthalmitis cases and intraocular procedures were identified based on billing codes in all French hospitals and private practices. MAIN OUTCOME MEASURES: The incidence of acute endophthalmitis within 42 days of the procedure. RESULTS: From January 1, 2009, to October 31, 2018, 7522 cases of acute endophthalmitis occurred after 14 438 854 intraocular procedures. Most cases occurred after standalone cataract surgery (4808 cases for 7 316 077 procedures; 63.92%), followed by after intravitreal (IVT) injections (1296 cases for 5 455 631 IVT injections; 17.23%), vitreoretinal surgery (698 for 442 263 procedures; 9.28%), anterior segment surgery (245 cases; 3.26%), combined cataract and vitreoretinal surgery (191 cases; 2.54%), cornea surgery (142 cases; 1.89%), and glaucoma surgery (80 cases; 1.06%). The overall incidence of acute endophthalmitis was 1 per 1920 procedures (0.0521%; 95% confidence interval [CI], 0.0520-0.0522). The surgery with the highest incidence of endophthalmitis was scleral and globe surgery, with an incidence of 0.1827% (95% CI, 0.1757-0.1898), followed by vitreoretinal surgery combined with cataract surgery, with an incidence of 0.1685% (95% CI, 0.1663-0.1706). The incidence of endophthalmitis after IVT injections was stable over the study period, and patients receiving IVT injections were the oldest, aged 75.4 years (standard deviation, 12.0 years; P < 0.001). The onset of endophthalmitis after IVT procedures, i.e, after receiving IVT injections or undergoing vitreoretinal surgery, was earlier than that after the other procedures (P < 0.001). CONCLUSIONS: The profile of patients referred for acute endophthalmitis has been evolving over the past decade, with a decrease in the raw number of endophthalmitis cases after cataract surgery as opposed to an increase in the number of patients presenting with endophthalmitis after IVT injections.

Real-life management of neovascular age-related macular degeneration (nAMD) in France: a nationwide observational study using retrospective claims data.

AIMS: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is standard care for neovascular age-related macular degeneration (nAMD), but the recommended monthly injection regimen is burdensome. Evidence suggests low injection/monitoring frequencies in clinical practice and suboptimal vision outcomes. This observational cohort study uses administrative claims data from the French national healthcare system to assess anti-VEGF treatment patterns and nAMD-specific healthcare resource demands and costs. PATIENTS AND METHODS: nAMD patients ≥50 years initiating intravitreal ranibizumab, aflibercept or bevacizumab treatment (2014‒2015), and propensity score-matched non-nAMD patients (controls), were identified from the Echantillon Généraliste de Bénéficiaires database. Outcomes of interest included anti-VEGF treatment patterns, and healthcare resource utilization and associated costs of patients vis-à-vis controls over 24 months. RESULTS: Study patients (n = 355) received (mean) 5.2 and 2.4 anti-VEGF injections over 0‒12 and 12‒24 months, respectively. Most patients (79.0%) remained on their initial anti-VEGF agent; among treatment switchers, the most common transition was from ranibizumab to aflibercept. During follow-up, nAMD patients were more likely than controls to require ophthalmology visits (99.7% vs. 44.8%), ocular procedures (optical coherence tomography/angiography/fundoscopy) (96.9% vs. 27.2%), cataract surgery (13.0% vs. 6.7%), and medical transports (38.0% vs. 31.9%). Mean numbers of ophthalmology visits (25.1 vs. 1.2) and medical transports (6.0 vs. 3.5) were higher (p<.01) among nAMD patients. Total reimbursed costs were two-fold higher for nAMD patients than controls (mean €16,799 vs. €8,255) due to higher treatment costs (€6,847 vs. €1,156), medical fees (€1,858 vs. €295), hospital fees (€6,396 vs. €5,235), and transport costs (€358 vs. €259). Excess total healthcare cost was (mean) €5,279 and €7,918 over the first 12 and 24 months of treatment, respectively. CONCLUSIONS: Current intravitreal anti-VEGF treatment and monitoring requirements place a considerable economic burden on the French healthcare system. New intravitreal therapies with extended dosing intervals and predictable efficacy might reduce demand for ophthalmology services.

ASSESSMENT OF EARLY CHANGES IN SPECTRAL DOMAIN-OPTICAL COHERENCE TOMOGRAPHY AFTER INITIATION OF TREATMENT WITH INTRAVITREAL AFLIBERCEPT (EYLEA) OVER A 12-WEEK PERIOD FOR PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Multicenter French Study (START).

PURPOSE: To assess early changes in spectral-domain optical coherence tomography during the loading phase with intravitreal aflibercept therapy in patients with neovascular age-related macular degeneration. METHODS: In this prospective, open-label, single-arm, multicenter study, patients with neovascular age-related macular degeneration, who were antivascular endothelial growth factor treatment-naïve, received three monthly initial doses of intravitreal aflibercept 2 mg. The primary outcome was the proportion of patients with dry spectral-domain optical coherence tomography at 12 weeks, defined as an absence of intraretinal edema, intraretinal cysts, subretinal fluid, and subretinal pigment epithelium fluid. RESULTS: Fifty eyes of 50 patients were investigated. At 12 weeks, 34.0% (17/50) had dry spectral-domain optical coherence tomography. Marked reductions were observed for all other spectral-domain optical coherence tomography parameters. The mean macular central thickness fell significantly from 463.2 ± 184.3 µm at baseline to 288.9 ± 76.8 µm at Week 12 (P < 0.0001). The mean best-corrected visual acuity also improved significantly from 61.0 ± 16.0 letters at baseline to 66.6 ± 19.0 letters at Week 12 (P = 0.0006). CONCLUSION: The anatomic and functional outcomes improved over the 12-week study period. All outcome variables peaked after the third aflibercept injection, confirming the benefit of three initial doses.

Anti-VEGF intravitreal injections in the era of COVID-19: responding to different levels of epidemic pressure.

PURPOSE: Following the first wave of the COVID-19 pandemic in early 2020, the easing of strict measures to reduce its spread has led to a resurgence of cases in many countries at both the national and local level. This article addresses how guidance for ophthalmologists on managing patients with retinal disease receiving intravitreal injections of anti-vascular endothelial growth factor (VEGF) during the pandemic should be adapted to the local epidemic pressure, with more or less stringent measures implemented according to the ebb and flow of the pandemic. METHODS: The Vision Academy's membership of international retinal disease experts analyzed guidance for anti-VEGF intravitreal injections during the COVID-19 pandemic and graded the recommendations according to three levels of increasing epidemic pressure. The revised recommendations were discussed, refined, and voted on by the 14-member Vision Academy Steering Committee for consensus. RESULTS: Protocols to minimize the exposure of patients and healthcare staff to COVID-19, including use of personal protective equipment, physical distancing, and hygiene measures, should be routinely implemented and intensified according to local infection rates and pressure on the hospital/clinic or healthcare system. In areas with many COVID-19-positive clusters, additional measures including pre-screening of patients, postponement of non-urgent appointments, and simplification of complex intravitreal anti-VEGF regimens should be considered. Treatment prioritization for those at greatest risk of irreversible vision loss should be implemented in areas where COVID-19 cases are increasing exponentially and healthcare resources are strained. CONCLUSION: Consistency in monitoring of local infection rates and adjustment of clinical practice accordingly will be required as we move forward through the COVID-19 era. Ophthalmologists must continue to carefully weigh the risk-benefits to minimize the exposure of patients and healthcare staff to COVID-19, ensure that patients receive sight-saving treatment, and avoid the potential long-term impact of prolonged treatment postponement.

Efficacy and Safety of Intravitreal Aflibercept Treat-and-Extend for Macular Edema in Central Retinal Vein Occlusion: the CENTERA Study.

PURPOSE: To evaluate the efficacy and safety of intravitreal aflibercept (IVT-AFL) treat-and-extend dosing in patients with macular edema secondary to central retinal vein occlusion (CRVO). DESIGN: CENTERA (Evaluation of a Treat and Extend Regimen of Intravitreal Aflibercept for Macular Edema Secondary to CRVO; NCT02800642) was an open-label, Phase 4 clinical study. METHODS: Patients received 2 mg of IVT-AFL at baseline and every 4 weeks thereafter, until disease stability criteria were met (or until week 20), at which point treatment intervals were adjusted in 2-week increments based on functional and anatomic outcomes. RESULTS: From baseline to week 76, 105 patients (65.6%) (P <.0001 [test against threshold of 40%]) gained ≥15 letters; and, during the treat-and-extend phase, 72 patients (45.0%) (P = 0.8822 [test against threshold of 50%]) achieved a mean treatment interval of ≥8 weeks. A last and next planned treatment interval of ≥8 weeks was achieved by 101 patients (63.1%) and by 108 patients (67.5%), respectively. Mean ± SD best-corrected visual acuity increased from 51.9 ± 16.8 letters at baseline to 72.3 ± 18.5 letters at week 76 (mean change: +20.3 ± 19.5 letters), and central retinal thickness decreased from 759.9 ± 246.0 µm at baseline to 265.4 ± 57.9 µm at week 76 (mean change: -496.1 ± 252.4 µm). The safety profile of IVT-AFL was consistent with that of previous studies. CONCLUSIONS: Clinically meaningful improvements in functional and anatomic outcomes were achieved with IVT-AFL treat-and-extend dosing. Most patients achieved a last actual and last intended treatment interval of ≥8 weeks; therefore, treatment intervals may have been extended even further with a longer study duration.

Standardization of OCT Angiography Nomenclature in Retinal Vascular Diseases: First Survey Results.

PURPOSE: To develop a consensus nomenclature for OCT angiography (OCTA) findings in retinal vascular diseases. DESIGN: Online survey using the Delphi Method. PARTICIPANTS: Members of The Retina Society, the European Society of Retina Specialists, and the Japanese Retina and Vitreous Society. METHODS: An online questionnaire on OCTA terminology in retinal vascular diseases was sent to members of The Retina Society, the European Society of Retina Specialists, and the Japanese Retina and Vitreous Society. The respondents were divided into 2 groups ("experts" vs. "users") according to the number of their publications in this field. The respondents who had more than 5 publications in the field of OCTA and retinal vascular diseases were considered the OCTA "experts" group. MAIN OUTCOME MEASURES: Consensus and near consensus on OCTA nomenclature. RESULTS: The complete responses of 85 retina specialists were included in the analysis. Thirty-one were categorized as "experts." There was a consensus in both groups that OCTA parameters such as foveal avascular zone (FAZ) parameters, areas of nonperfusion, and presence of neovascularization (NV) should be implemented in the identification and staging of diabetic retinopathy (DR) and that OCTA can be applied to differentiate between ischemic and nonischemic retinal vein occlusion (RVO). Diabetic macular ischemia (DMI) also can be assessed via OCTA. Further, there was consensus that the terminology should differ on the basis of the underlying causes of decreased vascular flow signal. There was disagreement in other areas, such as which terms should be applied to describe decreased OCTA signal from different causes, the definition of wide-field OCTA, and how to quantify DMI and area of decreased flow signal. These discrepancies form the basis for the upcoming expert Delphi rounds that aim to develop a standardized OCTA nomenclature. CONCLUSIONS: Although there was agreement in some areas, significant differences were found in many areas of OCTA terminology among all respondents, but also between the expert and user groups. This indicates the need for standardization of the nomenclature among all specialists in the field of retinal vascular diseases.

MANAGEMENT OF RETINAL PIGMENT EPITHELIUM TEAR DURING ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY.

PURPOSE: This article aims to review current evidence on the development, diagnosis, and management of retinal pigment epithelium (RPE) tear during anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Literature searches were performed using MEDLINE/PubMed databases (cut-off date: August 2019). RESULTS: Three key recommendations were made based on existing literature and clinical experience: 1) Multimodal imaging with color fundus photography, optical coherence tomography, near-infrared reflectance imaging, fundus autofluorescence imaging, optical coherence tomography-angiography, and/or fluorescein angiography are recommended to diagnose RPE tear and assess risk factors. Retinal pigment epithelium tears can be graded by size and foveal involvement. 2) Patients at high risk of developing RPE tear should be monitored after each anti-VEGF injection. If risk factors worsen, it is not yet definitively known whether anti-VEGF administration should be more frequent, or alternatively stopped in such patients. Prospective research into high-risk characteristics is needed. 3) After RPE tear develops, anti-VEGF treatment should be continued in patients with active disease (as indicated by presence of intraretinal or subretinal fluid), although cessation of therapy should be considered in eyes with multilobular tears. CONCLUSION: Although evidence to support the assumption that anti-VEGF treatment contributes to development of RPE tear is not definitive, some data suggest this link.

Predicting Progression to Advanced Age-Related Macular Degeneration from Clinical, Genetic, and Lifestyle Factors Using Machine Learning.

PURPOSE: Current prediction models for advanced age-related macular degeneration (AMD) are based on a restrictive set of risk factors. The objective of this study was to develop a comprehensive prediction model applying a machine learning algorithm allowing selection of the most predictive risk factors automatically. DESIGN: Two population-based cohort studies. PARTICIPANTS: The Rotterdam Study I (RS-I; training set) included 3838 participants 55 years of age or older, with a median follow-up period of 10.8 years, and 108 incident cases of advanced AMD. The Antioxydants, Lipids Essentiels, Nutrition et Maladies Oculaires (ALIENOR) study (test set) included 362 participants 73 years of age or older, with a median follow-up period of 6.5 years, and 33 incident cases of advanced AMD. METHODS: The prediction model used the bootstrap least absolute shrinkage and selection operator (LASSO) method for survival analysis to select the best predictors of incident advanced AMD in the training set. Predictive performance of the model was assessed using the area under the receiver operating characteristic curve (AUC). MAIN OUTCOME MEASURES: Incident advanced AMD (atrophic, neovascular, or both), based on standardized interpretation of retinal photographs. RESULTS: The prediction model retained (1) age, (2) a combination of phenotypic predictors (based on the presence of intermediate drusen, hyperpigmentation in one or both eyes, and Age-Related Eye Disease Study simplified score), (3) a summary genetic risk score based on 49 single nucleotide polymorphisms, (4) smoking, (5) diet quality, (6) education, and (7) pulse pressure. The cross-validated AUC estimation in RS-I was 0.92 (95% confidence interval [CI], 0.88-0.97) at 5 years, 0.92 (95% CI, 0.90-0.95) at 10 years, and 0.91 (95% CI, 0.88-0.94) at 15 years. In ALIENOR, the AUC reached 0.92 at 5 years (95% CI, 0.87-0.98). In terms of calibration, the model tended to underestimate the cumulative incidence of advanced AMD for the high-risk groups, especially in ALIENOR. CONCLUSIONS: This prediction model reached high discrimination abilities, paving the way toward making precision medicine for AMD patients a reality in the near future.

Risk of Inflammation, Retinal Vasculitis, and Retinal Occlusion-Related Events with Brolucizumab: Post Hoc Review of HAWK and HARRIER.

PURPOSE: An independent Safety Review Committee (SRC), supported by Novartis Pharma AG, analyzed investigator-reported cases of intraocular inflammation (IOI), endophthalmitis, and retinal arterial occlusion in the phase 3 HAWK and HARRIER trials of brolucizumab versus aflibercept in neovascular age-related macular degeneration (nAMD). DESIGN: A post hoc analysis of a subset of data from two 2-year, double-masked, multicenter, active-controlled randomized phase 3 trials (NCT02307682, NCT02434328). PARTICIPANTS: Patients (N = 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye were randomized and treated in HAWK/HARRIER. The SRC reviewed data from cases of investigator-reported IOI (60/1088 brolucizumab-treated eyes; 8/729 aflibercept-treated eyes). METHODS: The SRC received details and images (color fundus photography, fluorescein angiography, and OCT) for all investigator-determined cases of IOI, retinal arterial occlusion, and endophthalmitis. Cases were reviewed in detail by ≥2 readers, then adjudicated by the SRC as a group. MAIN OUTCOME MEASURES: Within this patient subset: incidence of IOI, signs and incidence of retinal vasculitis and/or retinal vascular occlusion, and visual acuity loss; time since first brolucizumab injection to IOI event onset; and frequency of visual acuity loss after brolucizumab injection by time of first IOI event onset. RESULTS: Fifty brolucizumab-treated eyes were considered to have definite/probable drug-related events within the spectrum of IOI, retinal vasculitis, and/or vascular occlusion. On the basis of these cases, incidence of definite/probable IOI was 4.6% (IOI + vasculitis, 3.3%; IOI + vasculitis + occlusion, 2.1%). There were 8 cases (incidence 0.74%) of at least moderate visual acuity loss (≥15 ETDRS letters) in eyes with IOI (7 in eyes with IOI + vasculitis + occlusion). Of the 8 cases, 5 experienced their first IOI-related event within 3 months of the first brolucizumab injection (increasing to 7/8 within 6 months). Incidence of IOI in aflibercept-treated eyes was 1.1%, with at least moderate visual acuity loss in 0.14%. CONCLUSIONS: This analysis of IOI cases after brolucizumab injection identified signs of retinal vasculitis with or without retinal vascular occlusion and an associated risk of visual acuity loss. The findings will help physicians to evaluate the risks and benefits of brolucizumab treatment for nAMD.

INCIDENCE, PROGRESSION, AND RISK FACTORS OF EPIRETINAL MEMBRANES IN THE ELDERLY.

PURPOSE: To determine the incidence, progression rate, and risk factors for epiretinal membranes (ERMs) in a population of French elderly subjects. METHODS: Seven hundred and thirty-five eyes of 413 participants of the population-based ALIENOR study were included between 2009 and 2010. Participants were re-evaluated every 2 years between 2011 and 2017 (i.e., three follow-up visits). The mean duration of follow-up was 5.09 years (SD, 1.8; range, 0.99-7.85). Epiretinal membranes were graded from spectral-domain optical coherence tomography images according to a standardized classification. RESULTS: The incidence rate of ERMs was 9.42 per 100 eye-years (95% confidence interval, 7.36-12.05), corresponding to a 5-year cumulative incidence of 37.6%. In the final multivariable model, ERM incidence was significantly associated with vitreomacular or vitreopapillary adhesion at baseline (hazard ratio, 2.15; P = 0.02), choroidal thinning (hazard ratio, 1.04 per 10 µm decrease; P = 0.02), ERM in the contralateral eye (P = 0.02), and smoking after 85 years (hazard ratio, 6.01; P = 0.003). The 5-year cumulative progression rate was 6.9%. CONCLUSION: Incidence of ERMs was higher in our population than that previously reported, most probably because of the use of spectral-domain optical coherence tomography images. Incident ERMs were found to be associated with vitreous adhesion at baseline, choroidal thinning, ERM in the contralateral eye, and smoking after 85 years.

Evolution of treatment paradigms in neovascular age-related macular degeneration: a review of real-world evidence.

The aim of this work was to evaluate the contribution of real-world evidence (RWE) in changing anti-vascular endothelial growth factor (VEGF) therapy treatment practices and improving real-world treatment strategies for neovascular age-related macular degeneration (nAMD).A PubMed literature search was performed to review the large number of English-language studies conducted to investigate the real-world effectiveness of anti-VEGF (aflibercept and ranibizumab) treatment paradigms available for nAMD.The evidence for pro re nata (PRN), treat-and-extend (T&E) and fixed bimonthly dosing regimens for anti-VEGF treatment of nAMD were reviewed and findings are summarised. RWE demonstrated that T&E regimens optimise visual outcomes while reducing burden on patients, clinics and physicians, compared with both fixed-dose and PRN regimens.RWE has helped to develop and improve real-world treatment strategies in nAMD, with the aim of optimising visual outcomes and reducing treatment burden in clinical practice. Of the various regimens, a T&E regimen is most likely to adequately balance clinical outcomes and treatment burden for patients with nAMD.

Anti-vascular endothelial growth factor in neovascular age-related macular degeneration - a systematic review of the impact of anti-VEGF on patient outcomes and healthcare systems.

BACKGROUND: Systematically review the evidence describing the impact of anti-vascular endothelial growth factor (anti-VEGF) therapy on neovascular age-related macular degeneration (nAMD) patient outcomes and healthcare resource utilization. METHODS: A systematic literature review was completed using Medline and EMBASE for publications prior to July 2018, and proceedings from major ophthalmology conferences (January 2016 to July 2018). The search strategy combined terms for nAMD with terms for anti-VEGF and study design. The review focused on publications describing the impact of anti-VEGF on blindness, visual impairment, vision-related quality of life (VRQoL), mortality, and costs. The search targeted data collected in epidemiological or observational studies to reflect real-world outcomes but also considered modeling-based approaches. RESULTS: The use of anti-VEGF in clinical practice was associated with significant reduction in the incidence of blindness by nAMD. Population-based analyses reported reduction in incidence among the general population of 47% (9.1 cases/100,000 in 2006 to 4.8 cases/100,000 in 2011). Among patients aged ≥50 years, a reduction of 50% was observed (52.2 cases/100,000 in 2000 to 25.7 cases/100,000 in 2010). In some cases, the odds of decreased vision (defined as decline from normal to moderate, moderate to severe, or severe to blindness) fell by 41% following introduction of anti-VEGF. Patients' VRQoL improved with treatment, with patients reporting a positive impact shortly after treatment was initiated. Change on National Eye Institute 25-Item Visual Function Questionnaire score from baseline to month 12 ranged from 0.7 to 4.4. Although nAMD patients report signs of depression and anxiety, the evidence suggests that there is no association between the use of anti-VEGF and the prevalence or diagnosis of depression. The introduction of anti-VEGF led to increased overall treatment costs due to replacement of existing less frequently administered treatments (e.g. photodynamic therapy) and increased number of patients treated (prior to anti-VEGF, only ~ 20% of patients were eligible for treatment). CONCLUSIONS: The introduction of anti-VEGF agents has been associated with a positive impact on patient-relevant outcomes, including a significant reduction in incidence of blindness and visual impairment by nAMD. Anti-VEGF agents replaced less-effective treatments, improving patient outcomes and broadening the patient population eligible for treatment.