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Purpose To describe the imaging standards, grading protocol and baseline characteristics of polypoidal choroidal vasculopathy (PCV) from the EVEREST study. Methods In a prospective, multicentre study, confocal scanning laser ophthalmoscope indocyanine green angiography (ICGA) was performed using a standardised imaging protocol. All images were graded using standardised, calibrated equipment by fellowship-trained ophthalmologists at the Central Reading Center. Results Sixty-one patients with PCV were included in the study. ICGA characteristics included: nodular appearance stereoscopically (56 eyes, 91.8%), hypofluorescent halo (42, 68.9%), abnormal vascular network (54, 88.5%) and pulsation of the polyps (4, 6.6%). Colour fundus photography revealed orange subretinal nodules (34, 55.7%) and massive submacular haemorrhage (8, 13.1%). The mean area of the PCV lesion was 3.11 mm2 (range, 0.2–10.7 mm2). The vascular channels filled within 7.3–32.0 s (mean: 17.9 s) while the mean filling time for polyps was 21.9 s (range, 7.3–40.4 s). Patients with massive submacular haemorrhage were less likely to have abnormal vascular channels seen on ICGA (28.6% vs 83.3% for those without massive haemorrhage, p=0.001). Conclusions The imaging and grading protocols and baseline characteristics of a multicentre, randomised controlled trial of PCV are described in detail, and may serve as reference for future randomised, controlled trials on PCV. Clinical trial number This work was supported by Novartis Pharma AG, Basel, Switzerland grant number NCT00674323 (clinicaltrials.gov).

Background/aimsTo evaluate the diagnostic accuracy of spectral-domain optical coherence tomography (SD OCT) combined with OCT angiography (OCTA) for myopic myopic macular neovascularisation (MNV) activity.MethodsBoth eyes of patients with myopic MNV diagnosed with fluorescein angiography (FA), SD OCT and OCTA were assessed by unmasked investigators. The images were deidentified and randomised before graded by masked investigators, who determined the presence of active myopic MNV by using SD OCT together with OCTA without FA and by FA alone, respectively. The findings of masked investigators were compared with unmasked investigators.Results213 eyes of 110 patients comprising 499 imaging episodes were eligible for grading. For diagnosing new-onset myopic MNV without FA, combined use of SD OCT and OCTA had a sensitivity of 0.94, specificity of 0.84 and area under the curve (AUC) of 0.92. FA had a sensitivity of 0.52 (p<0.01), specificity of 0.80 (p=0.38) and AUC of 0.66 (p<0.01). For recurrent myopic MNV, the combination of SD OCT and OCTA had a sensitivity of 0.98, specificity of 0.78 and AUC of 0.88. FA had a sensitivity of 0.50 (p=0.04), specificity of 0.76 (p=0.85) and AUC of 0.63 (p=0.01). Myopic traction maculopathy was more frequently associated with recurrent myopic MNV (p<0.01).ConclusionSD OCT with dense volumetric scan was highly sensitive for diagnosing myopic MNV. The addition of OCTA improved the diagnostic specificity without FA. Monitoring of the longitudinal changes on SD OCT and judicious use of FA is a reliable surveillance strategy for myopic MNV.

PurposeTo characterize relationships between Consensus on Neovascular Age-Related Macular Degeneration Nomenclature (CONAN) Study Group classifications of macular neovascularization (MNV) and visual responses to ranibizumab in patients with neovascular age-related macular degeneration (nAMD).MethodsThis was a post hoc analysis of the phase 3 HARBOR trial of ranibizumab in nAMD. Analyses included ranibizumab-treated eyes with baseline multimodal imaging data; baseline MNV; subretinal and/or intraretinal fluid at screening, baseline, or week 1; and spectral-domain optical coherence tomography images through month 24 (n = 700). Mean best-corrected visual acuity (BCVA) over time and mean BCVA change at months 12 and 24 were compared between eyes with type 1, type 2/mixed type 1 and 2 (type 2/M), and any type 3 MNV at baseline.ResultsAt baseline, 263 (37.6%), 287 (41.0%), and 150 (21.4%) eyes had type 1, type 2/M, and any type 3 lesions, respectively. Type 1 eyes had the best mean BCVA at baseline (59.0 [95% CI: 57.7–60.3] letters) and month 24 (67.7 [65.8–69.6] letters), whereas type 2/M eyes had the worst (50.0 [48.6–51.4] letters and 60.8 [58.7–62.9] letters, respectively). Mean BCVA gains at month 24 were most pronounced for type 2/M eyes (10.8 [8.9–12.7] letters) and similar for type 1 (8.7 [6.9–10.5] letters) and any type 3 eyes (8.3 [6.3–10.3] letters).ConclusionDifferences in BCVA outcomes between CONAN lesion type subgroups support the use of an anatomic classification system to characterize MNV and prognosticate visual responses to anti-vascular endothelial growth factor therapy for nAMD.Trial registrationClinicalTrials.gov identifier: NCT00891735. Date of registration: April 29, 2009.

Background and Objective This was a prospective multicenter, randomized, double-masked, active-controlled study, the aim of which was to demonstrate the efficacy and safety of intravitreal ONS-5010 (bevacizumab-vikg) in eyes with neovascular age-related macular degeneration (nAMD). This was a phase III trial on ONS-5010 (NORSE TWO). Materials and Methods Treatment-naïve nAMD patients aged 50 years and older with a best-corrected distance visual acuity (BCVA) of 25 to 67 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and evidence of disease activity were included. Subjects randomized to ONS-5010 received monthly intravitreal doses of 1.25 mg of ONS-5010, bevacizumab-vikg (Outlook Therapeutics) for 12 months. Subjects randomized to ranibizumab received 0.50 mg of ranibizumab on days 0, 30, 60, 150, and 240 based on the PIER study dosing regimen. Results The primary end point was the proportion of subjects who gained ≥ 15 letters from baseline in BCVA at 11 months, and evaluating the safety and tolerability of intravitreal injections of ONS-5010 administered monthly from baseline to 12 months. One hundred thirteen subjects were included in the ONS-5010 group and 115 subjects were included in the ranibizumab group. Respectively, 41.7% and 23.1% of patients gained ≥ 15 letters (3 lines) of visual acuity, with a risk difference of 0.1859 [95% CI = 0.0442, 0.3086]; P = 0.0052. The change in BCVA from baseline to 11 months was found to be 11.2 ± 12.19 and 5.8 ± 14.80 ETDRS letters, respectively. The number of subjects gaining ≥ 5 and ≥ 10 letters and subjects losing < 15 letters was significantly higher in the ONS-5010 group. Similarly, subjects with a Snellen visual acuity equivalent of 20/200 (35 ETDRS letters) or worse at 11 months were significantly fewer in the ONS-5010 group. Only one subject in the ONS-5010 group had a study-related serious ocular adverse event (SAE), namely, elevated intraocular pressure. The most common adverse event in the ONS-5010 group was conjunctival hemorrhage (8.8%), and reduced visual acuity in the ranibizumab group (12.2%). Conclusions In the prescribed treatment plan, ONS-5010 exhibited strong effectiveness in improving or stabilizing visual acuity and was also well tolerated. Bevacizumab and ranibizumab displayed a comparable safety profile. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX–XX.]

IntroductionThe diagnosis of neovascular age-related macular degeneration (nAMD), the leading cause of visual impairment in the developed world, relies on the interpretation of various imaging tests of the retina. These include invasive angiographic methods, such as Fundus Fluorescein Angiography (FFA) and, on occasion, Indocyanine-Green Angiography (ICGA). Newer, non-invasive imaging modalities, predominately Optical Coherence Tomography (OCT) and Optical Coherence Tomography Angiography (OCTA), have drastically transformed the diagnostic approach to nAMD. The aim of this study is to undertake a comprehensive diagnostic accuracy assessment of the various imaging modalities used in clinical practice for the diagnosis of nAMD (OCT, OCTA, FFA and, when a variant of nAMD called Polypoidal Choroidal Vasculopathy is suspected, ICGA) both alone and in various combinations.Methods and analysisThis is a non-inferiority, prospective, randomised diagnostic accuracy study of 1067 participants. Participants are patients with clinical features consistent with nAMD who present to a National Health Service secondary care ophthalmology unit in the UK. Patients will undergo OCT as per standard practice and those with suspicious features of nAMD on OCT will be approached for participation in the study. Patients who agree to take part will also undergo both OCTA and FFA (and ICGA if indicated). Interpretation of the imaging tests will be undertaken by clinicians at recruitment sites. A randomised design was selected to avoid bias from consecutive review of all imaging tests by the same clinician. The primary outcome of the study will be the difference in sensitivity and specificity between OCT+OCTA and OCT+FFA (±ICGA) for nAMD detection as interpreted by clinicians at recruitment sites.Ethics and disseminationThe study has been approved by the South Central—Oxford B Research Ethics Committee with reference number 21/SC/0412.Dissemination of study results will involve peer-review publications, presentations at major national and international scientific conferences.Trial registration number ISRCTN18313457.

Background/aimsTo understand changes in disease activity as assessed by leakage and retinal fluid status in patients with neovascular age-related macular degeneration (nAMD) receiving fixed dosing with an anti-vascular endothelial growth factor (anti-VEGF) agent.MethodsIn the phase III VIEW 1 (NCT00509795) and VIEW 2 (NCT00637377) studies, eyes with nAMD were treated with intravitreal aflibercept or ranibizumab. Independent, masked reading centres determined the presence/absence of leakage (fluorescein angiography) and retinal fluid (optical coherence tomography) at baseline, week 24 and week 52. In this integrated, post hoc analysis of the VIEW studies, the relationship between leakage/fluid status and best-corrected visual acuity (BCVA) was assessed. The impact of baseline lesion type (predominantly classic (PC), minimally classic (MC), occult) was also evaluated. Data from all treatment groups were pooled.Results2373 eyes were included in this analysis. At baseline, 95.4% of eyes presented with both leakage and fluid. By week 52, leakage and fluid were present in 16.0% of eyes. Mean BCVA gains at week 52 were numerically greater in eyes without leakage and fluid versus eyes with both leakage and fluid (10.3 vs 9.2 letters). At week 52, 11.6%, 15.3% and 20.1% of eyes with PC, MC and occult lesions, respectively, had both leakage and fluid present.ConclusionIn this post hoc analysis, fixed dosing with an anti-VEGF agent over 52 weeks eliminated disease activity (absence of both leakage and fluid) in most eyes. The effect of anti-VEGF treatment on leakage/fluid status favoured PC versus occult lesions.

AimsTo investigate the impact of posterior vitreous detachment (PVD) on the efficacy of treat-and-extend (T&E) ranibizumab in neovascular age-related macular degeneration.MethodsIn a post hoc analysis of a randomised controlled clinical trial, spectral-domain optical coherence tomography images of treatment-naïve patients randomised to receive T&E (n=265) or monthly (n=264) ranibizumab for 12 months were included. Certified, masked graders diagnosed the presence or the absence of complete PVD. The main outcome measures were the mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) at month 12, the number of administered ranibizumab injections and the proportion of patients extended to more than 8 weeks.ResultsAt baseline, complete PVD was present in 51% and 56% of patients in the monthly and T&E arms, respectively. Mean change in BCVA at month 12 was +9.0 (PVD) vs +9.5 letters (no PVD, p=0.78) in monthly treated eyes, and +6.0 (PVD) vs +7.5 letters (no PVD, p=0.42) in T&E treated eyes. Conversely, mean change in CRT at month 12 was −174 (PVD) vs −173 µm (no PVD, p=0.98) in the monthly arm, and −175 (PVD) vs −164 µm (no PVD, p=0.58) in the T&E arm. In T&E treated patients, the median number of injections was eight vs nine (p=0.035). 71% of PVD eyes were extended successfully, compared with 55% of eyes without PVD (p=0.005).ConclusionPVD was not found to impact functional and anatomical outcomes of T&E ranibizumab therapy. However, patients without a complete PVD required more retreatments and were significantly less likely to be successfully extended.Trial registration number NCT01948830

Purpose: To evaluate real-world outcomes with neovascular age-related macular degeneration (nAMD) in relation to anatomical success, visual outcomes, and safety of intravitreal brolucizumab (IVBr) injection at 1.5 years. Methods: Prospective, randomized, single-center study between December 2020 and December 2022 that included 71 eyes of 62 patients with nAMD, who received IVBr. Patients were divided into three groups, i.e., naïve choroidal neovascular membrane (CNVM), switched therapy (st) CNVM, and st polypoidal choroidal vasculopathy (stPCV). They were subdivided into dry, minimal fluid (fluid <50 microns)/pigment epithelial detachment (PED) and persistent fluid (fluid >100 microns)/PED subgroups depending upon the fluid level at the end of 1.5 years. Best-corrected visual acuity (BCVA), central macular thickness (CMT), status of fluid, and number of injections at 1.5 years were evaluated. From the beginning, patients were treated on pro re nata (PRN) basis. Results: Of the 71 eyes, 27 eyes (38%) were naïve CNVM, 35 eyes (49.3%) were stCNVM, and 9 (12.7%) were stPCV cases. Significant vision improvement after 1.5 years was seen in the stCNVM category (P = 0.001), while CMT reduction was significant in all three groups (P < 0.05). The mean number of injections required in naïve CNVM and stCNVM groups was significantly less as compared to the stPCV group (P = 0.017). Further, vision improvement was significant in the \"Minimal fluid\" subgroup (P = 0.002), while the CMT improvement was significant in the \"Minimal fluid\" and \"Dry\" subgroups each with P < 0.0001. No ocular/systemic adverse events including intraocular inflammation (IOI) were noted. Conclusion: In a real-world scenario, with 203 procedures and 1.5-year follow-up, brolucizumab is found to be efficacious and safe with the need for a lesser number of injections and more interval-free period in the management of naïve CNVM, stCNVM, and stPCV patients.

Purpose To evaluate the long-term effectiveness and safety of ranibizumab 0.5 mg in patients with choroidal neovascularization (CNV) secondary to pseudoxanthoma elasticum (PXE) in a real-world setting. Methods A descriptive, observational, multicenter study in a retrospective and prospective cohort was conducted in France that included patients who had received at least one injection of ranibizumab 0.5 mg during the period October 2011 to October 2014, for CNV secondary to PXE. Eligible patients were identified by review of medical records or during routine consultations. The main objectives were to describe patient characteristics, assess changes in best-corrected visual acuity [VA, Early Treatment Diabetic Retinopathy Study (ETDRS) letters] over time, the number and reasons for ranibizumab treatment and overall safety. Results Of the 72 enrolled patients (98 eyes) from 23 centers, 39 (54.2%) were male and mean [±standard deviation (SD)] age was 59.6 (±8.3) years. The mean VA was 64.6 letters at the first ranibizumab injection, which was maintained at the 1-year follow-up (64.7 letters). Thereafter, the mean VA was stable until the 4-year follow-up. At 4 years, the proportion of eyes with VA gain of ≥15 letters was 3/19 (15.8%) and stable VA (change between −15 and +15 letters) was 10/19 (52.6%). Mean (±SD) annual number of ranibizumab injections was 4.1 (±4.0), lower in the second versus first year. The most common reason for ranibizumab treatment was progression of neovascular activity (42.9%). No deaths or new safety findings were reported. Conclusions In patients with CNV secondary to PXE, ranibizumab 0.5 mg resulted in stable VA over 4 years with a limited number of injections. Safety findings were consistent with the established safety profile of ranibizumab.

Purpose To describe screening failures in the EVEREST study by examining the imaging characteristics that enabled differentiation of polypoidal choroidal vasculopathy (PCV) from cases that were subsequently diagnosed not to be PCV. Methods Post-hoc analysis of 34 patients with PCV reported as screening failures from EVEREST study. Standardised confocal scanning laser indocyanine green angiography (ICGA) images were graded by the Central Reading Centre to confirm PCV diagnosis based on the presence of early focal sub-retinal hyperfluorescence on ICGA and at least one of the following six diagnostic criteria: (1) nodular appearance of polyp(s) on stereoscopic examination, (2) hypofluorescent halo around nodule(s), (3) presence of a branching vascular network, (4) pulsation of polyp(s) on dynamic ICGA, (5) orange sub-retinal nodules on colour fundus photography, or (6) massive sub-macular haemorrhage (≥4 disc areas in size). Additional detailed image grading was performed with stereo-imaging and dynamic early-phase ICGA. Results Of the 95 screened PCV cases, 34 were excluded: (1) cases not suitable for recruitment as per the study protocol ( n  = 14), (2) equivocal lesions on ICGA characterised by small hyperfluorescent dots ( n  = 9), and (3) cases that were definitely not PCV (non-PCV, n  = 11), identified by definitive diagnoses which included one case each of micro-aneurysm, retinal angiomatous proliferation, retino-choroidal anastomosis, small type-2 choroidal neovascularisation, retinal pigment epithelial (RPE) window defect and disciform scar; two cases of lesions where the choroidal vessel changed its course; and three cases of late-onset RPE staining. Conclusions Standardised image grading techniques used in EVEREST study enabled effective differentiation of non-PCV from actual PCV.