A randomised controlled trial evaluating internal limiting membrane peeling forceps in macular hole surgery.

PURPOSE: To assess study design and a range of anatomical and functional changes after internal limiting membrane (ILM) peeling using forceps developed for atraumatic ILM pick-up compared to standard forceps. METHODS: We conducted a masked proof-of concept randomised controlled trial (RCT) on 65 patients who underwent ILM peeling for idiopathic full-thickness macular hole (FTMH) using etched-tip forceps (etched-tip group, 33 eyes) compared to standard ILM forceps (smooth-tip group, 32 eyes). Patients were assessed preoperatively, 3 weeks, 3 and 6 months postoperatively. RESULTS: The primary closure rate was 95.4%. There was no statistically significant difference between the groups in terms of final visual acuity (66.9 vs 70.9 ETDRS letters, p = 0.13), difference of visual field mean deviation (1.32 vs 1.14 decibels), and number of eyes with pick-up-related retinal haemorrhages (16% vs 16%, p = 0.96), swelling of arcuate nerve fibre layer lesions (63% vs 55%, p = 0.54), number of dissociated optic nerve fibre layer lesions (31.4 vs 41.0, p = 0.16), nor inner retina defects (37% vs 22%, p = 0.17). Similar changes in inner retinal volumes were detected in all 9 sectors of an ETDRS grid except for a trend (p = 0.06) towards a lower reduction in the inferior inner sector in the etched-tip group. CONCLUSIONS: The study was successfully completed with masking maintained and a low risk of bias. Multiple endpoints relating to ILM peeling were assessed, and estimates were provided that can be used for future studies. Although the study was not powered to assess any specific endpoint, the anatomical and functional outcomes assessed did not significantly differ.

Epimacular Brachytherapy for Previously Treated Neovascular Age-Related Macular Degeneration (MERLOT): A Phase 3 Randomized Controlled Trial.

PURPOSE: To assess the safety and efficacy of epimacular brachytherapy (EMB) for patients with chronic, active, neovascular age-related macular degeneration (AMD). DESIGN: Phase 3 randomized controlled trial. PARTICIPANTS: Patients (n = 363) with neovascular AMD already receiving intravitreal ranibizumab injections. INTERVENTION: Either pars plana vitrectomy with 24-gray EMB and ongoing pro re nata (PRN) ranibizumab (n = 224) or ongoing PRN ranibizumab monotherapy (n = 119). MAIN OUTCOME MEASURES: The coprimary outcomes, at 12 months, were the number of PRN ranibizumab injections and Early Treatment of Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (VA). Secondary outcomes included the proportion of participants losing fewer than 15 ETDRS letters, angiographic total lesion size, choroidal neovascularization (CNV) size, and optical coherence tomography (OCT) foveal thickness. A predefined subgroup analysis tested the influence of baseline ocular characteristics on the response to EMB. RESULTS: The mean number of PRN ranibizumab injections was 4.8 in the EMB arm and 4.1 in the ranibizumab monotherapy arm (P = 0.068). The mean VA change was -4.8 letters in the EMB arm and -0.9 letters in the ranibizumab arm (95% confidence interval of difference between groups, -6.6 to -1.8 letters). The proportion of participants losing fewer than 15 letters was 84% in the EMB arm and 92% in the ranibizumab arm (P = 0.007). In the EMB arm, the mean total lesion size increased by 1.2 mm(2) versus 0.4 mm(2) in the ranibizumab arm (P = 0.27). The CNV size decreased by 0.5 mm(2) in the EMB arm and by 1.3 mm(2) in the ranibizumab arm (P = 0.27). The OCT foveal thickness decreased by 1.0 µm in the EMB arm and by 15.7 µm in the ranibizumab arm (P = 0.43). Most subgroups favored ranibizumab monotherapy, some significantly so. One participant showed retinal vascular abnormality attributed to radiation, but otherwise safety was acceptable. CONCLUSIONS: These results do not support the use of EMB for chronic, active, neovascular AMD. Safety is acceptable out to 12 months, but radiation retinopathy can occur later, so further follow-up is planned.

Stereotactic radiotherapy for neovascular age-related macular degeneration: year 2 results of the INTREPID study.

PURPOSE: To determine the safety and efficacy of low-voltage, external-beam, stereotactic radiotherapy (SRT) for patients with neovascular age-related macular degeneration (AMD). DESIGN: Randomized, double-masked, sham-controlled, multicenter, clinical trial. PARTICIPANTS: A total of 230 participants with neovascular AMD who received ≥ 3 ranibizumab or bevacizumab injections within the preceding year and requiring treatment at enrollment. METHODS: Participants received 16 Gray, 24 Gray, or sham SRT. All arms received pro re nata (PRN) ranibizumab for 12 months, with PRN bevacizumab or ranibizumab thereafter. MAIN OUTCOME MEASURES: Mean number of PRN injections; best-corrected visual acuity (BCVA); loss of <15 Early Treatment of Diabetic Retinopathy Study letters; change in optical coherence tomography central subfield thickness; and change in angiographic total lesion area and choroidal neovascularization (CNV) area. RESULTS: At year 2, the 16 and 24 Gray arms received fewer PRN treatments compared with sham (mean 4.5, P = 0.008; mean 5.4, P = 0.09; and mean 6.6, respectively). Change in mean BCVA was -10.0, -7.5, and -6.7 letters for the 16 Gray, 24 Gray, and sham arms, respectively, with 46 (68%), 51 (75%), and 58 participants (79%), respectively, losing <15 letters. Mean central subfield thickness decreased by 67.0 µm, 55.4 µm, and 33.3 µm, respectively. Mean total active lesion area increased by 1.0, 4.2, and 2.7 mm(2), respectively. Mean CNV area decreased by 0.1 mm(2) in all groups. An independent reading center detected microvascular abnormalities in 6 control eyes and 29 SRT eyes, of which 18 were attributed to radiation; however, only 2 of these possibly affected vision. An exploratory subgroup analysis found that lesions with a greatest linear dimension ≤ 4 mm (the size of the treatment zone) and a macular volume greater than the median (7.4 mm(3)) were more responsive to SRT, with 3.9 PRN injections versus 7.1 in comparable sham-treated participants (P = 0.001) and mean BCVA 4.4 letters superior to sham (P = 0.24). CONCLUSIONS: A single dose of SRT significantly reduces intravitreal injections over 2 years. Radiation can induce microvascular change, but in only 1% of eyes does this possibly affect vision. The best response occurs when AMD lesions fit within the treatment zone and they are actively leaking.

Self-Supervised Learning for Improved Optical Coherence Tomography Detection of Macular Telangiectasia Type 2.

Importance: Deep learning image analysis often depends on large, labeled datasets, which are difficult to obtain for rare diseases. Objective: To develop a self-supervised approach for automated classification of macular telangiectasia type 2 (MacTel) on optical coherence tomography (OCT) with limited labeled data. Design, Setting, and Participants: This was a retrospective comparative study. OCT images from May 2014 to May 2019 were collected by the Lowy Medical Research Institute, La Jolla, California, and the University of Washington, Seattle, from January 2016 to October 2022. Clinical diagnoses of patients with and without MacTel were confirmed by retina specialists. Data were analyzed from January to September 2023. Exposures: Two convolutional neural networks were pretrained using the Bootstrap Your Own Latent algorithm on unlabeled training data and fine-tuned with labeled training data to predict MacTel (self-supervised method). ResNet18 and ResNet50 models were also trained using all labeled data (supervised method). Main Outcomes and Measures: The ground truth yes vs no MacTel diagnosis is determined by retinal specialists based on spectral-domain OCT. The models' predictions were compared against human graders using accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under precision recall curve (AUPRC), and area under the receiver operating characteristic curve (AUROC). Uniform manifold approximation and projection was performed for dimension reduction and GradCAM visualizations for supervised and self-supervised methods. Results: A total of 2636 OCT scans from 780 patients with MacTel and 131 patients without MacTel were included from the MacTel Project (mean [SD] age, 60.8 [11.7] years; 63.8% female), and another 2564 from 1769 patients without MacTel from the University of Washington (mean [SD] age, 61.2 [18.1] years; 53.4% female). The self-supervised approach fine-tuned on 100% of the labeled training data with ResNet50 as the feature extractor performed the best, achieving an AUPRC of 0.971 (95% CI, 0.969-0.972), an AUROC of 0.970 (95% CI, 0.970-0.973), accuracy of 0.898%, sensitivity of 0.898, specificity of 0.949, PPV of 0.935, and NPV of 0.919. With only 419 OCT volumes (185 MacTel patients in 10% of labeled training dataset), the ResNet18 self-supervised model achieved comparable performance, with an AUPRC of 0.958 (95% CI, 0.957-0.960), an AUROC of 0.966 (95% CI, 0.964-0.967), and accuracy, sensitivity, specificity, PPV, and NPV of 90.2%, 0.884, 0.916, 0.896, and 0.906, respectively. The self-supervised models showed better agreement with the more experienced human expert graders. Conclusions and Relevance: The findings suggest that self-supervised learning may improve the accuracy of automated MacTel vs non-MacTel binary classification on OCT with limited labeled training data, and these approaches may be applicable to other rare diseases, although further research is warranted.

Associations and Outcomes of Patients with Submacular Hemorrhage Secondary to Age-related Macular Degeneration in the IVAN Trial.

PURPOSE: To compare demographics, visual acuity (VA) and retinal morphology between those with, and without baseline submacular hemorrhage (SMH) for patients enrolled in the Inhibit VEGF in Age-related Choroidal Neovascularization trial (IVAN). DESIGN: Secondary analyses of a randomized, controlled trial of image and clinical data. METHODS: Setting; The IVAN trial collected data in 23 UK hospitals. Study population; IVAN study eyes (with untreated neovascular age-related macular degeneration at randomization) with at least 12 months of follow-up and adequate imaging. Intervention; Study eyes were randomly assigned between monthly ranibizumab, as-needed ranibizumab, monthly bevacizumab, or as-needed bevacizumab. Imaging at baseline was graded independently for the presence, type, position, and extent of SMH. Main outcome measures; The main outcome measures were VA (primary outcome), subretinal fibrosis, atrophic scarring, and retinal thickness outcomes at 12 and 24 months RESULTS: Of 605 IVAN trial participants, 535 were included in this analysis. Patients with SMH at baseline (286 [53%]) were older (P = .010) and affected eyes were more likely to have intraretinal fluid present (P = .038). The VA was significantly worse in those with baseline SMH at month 0 (P < .001; estimate of difference 6 letters; 95% CIs, 4-8 letters), but the difference decreased and was not significant at month 12 or 24. No significant association was found between baseline SMH and subretinal fibrosis, atrophic scarring, or central retinal thickness. CONCLUSIONS: The presence of SMH at baseline was associated with age, intraretinal fluid, and decreased baseline VA. By month 12, VA was no longer significantly different in those who presented with SMH at baseline.

Long-term Retinal Morphology and Functional Associations in Treated Neovascular Age-Related Macular Degeneration: Findings from the Inhibition of VEGF in Age-Related Choroidal Neovascularisation Trial.

PURPOSE: To describe the frequency of long-term morphologic features and their relationships with visual function in participants who exited the Inhibition of VEGF in Age-Related Choroidal Neovascularisation (IVAN; ISRCTN92166560) trial. DESIGN: Multicenter cohort study up to 7 years after enrollment. PARTICIPANTS: Patients enrolled in the IVAN trial, excluding participants who died or withdrew during the trial. METHODS: Multimodal fundus images, best-corrected visual acuity (BCVA), and low-luminance visual acuity (LLVA) were obtained for a subset of 199 participants who attended a research visit. Clinical sites (n = 20) also provided all visual acuity and clinical information from usual care records for 532 participants and submitted the most recent color, OCT, and other fundus images for 468 participants to a reading center. MAIN OUTCOME MEASURES: Assessed the following from the most recent images: intralesional macular atrophy (ILMA) within the footprint of the neovascular lesion; hyperreflective material (HRM); intraretinal fluid (IRF); subretinal fluid (SRF); pigment epithelial detachment (PED); and disorganized retinal outer layers (DROLs). Cross-sectional relationships between morphologic features and BCVA/LLVA were estimated. RESULTS: Intralesional macular atrophy was present in 31.8% of the study eyes at IVAN exit (mean follow-up, 1.96 years) and 89.5% at the most recent imaging visit (mean follow-up, 6.18 years). Hyperreflective material, IRF, SRF, PED, and DROLs were present in 78.8%, 47.7%, 7.6%, 94.5%, and 55% of the study eyes, respectively. In the subset with complete imaging data, in eyes without DROL, the BCVA was worst in the thinnest outer fovea tertile (thinnest minus middle and thickest tertiles, -19.7 and -19.5 letters, respectively), whereas in eyes with DROL, the BCVA was worst in the thickest (thinnest and middle tertiles minus thickest, 12.5 and 12.2, respectively). Regression models showed that the presence of ILMA and HRM was independently associated with BCVA (22 letters worse [95% confidence interval {CI}, -11.2 to -32.8; P < 0.001] and 9.8 letters worse [95% CI, -0.1 to -19.4; P = 0.047], respectively). Subretinal fluid and foveal PED were associated with better BCVA (5.9 letters [95% CI, -7.9 to 19.7; P = 0.399] and 6.4 letters [95% CI, -1.1 to 14.0; P = 0.094], respectively). The model with LLVA was similar. A sensitivity analysis involving the entire eligible cohort yielded similar estimates. CONCLUSIONS: Macular atrophy and HRM were common after 7 years of follow-up and strongly associated with visual outcomes.

Functional and morphologic benefits in early detection of neovascular age-related macular degeneration using the preferential hyperacuity perimeter.

PURPOSE: To estimate the usefulness of preferential hyperacuity perimetry (PHP) in detecting conversion of early to late age-related macular degeneration in the Carotenoids and co-antioxidants in patients with Age-Related Maculopathy, a multicenter randomized controlled clinical trial. METHODS: This was a nested case control study within the Carotenoids and co-antioxidants in patients with Age-Related Maculopathy (CARMA) clinical trial and included all participants enrolled in a single center (n = 200). Data are from participants who progressed to neovascular age-related macular degeneration (nvAMD) during time on study, Group 1 (n = 10) before the use of PHP and Group 2 (n = 10) during use of PHP. We also randomly selected 21 other participants (Group 3) who did not progress to nvAMD during time on study as a control group. Change in best-corrected visual acuity and contrast sensitivity and size of neovascular lesion at detection of conversion to nvAMD in Groups 1 and 2. RESULTS: At detection of nvAMD, mean best-corrected visual acuity in Group 1 was 57.5 letters versus 67.4 in Group 2. In Group 1, the change in best-corrected visual acuity from baseline to detection of nvAMD was twice that of Group 2 (21.6 ± 9.0 versus 11.9 ± 10.7) with a mean difference of 9.7 letters (95% confidence interval, 0.41 to 19.0, P = 0.04, independent-samples t-test). The size of the neovascular lesion at detection was 3.06 mm in Group 1 versus 0.89 mm in Group 2 (P = 0.02). Two thirds of the participants in Group 2 were asymptomatic at detection of nvAMD compared with one fifth in Group 1. Preferential hyperacuity perimetry distortion maps were abnormal in 9 of 10 eyes in Group 2, which were confirmed by optical coherence tomography. Of the 21 eyes in Group 3, PHP maps were normal in 18 and abnormal in 3. CONCLUSION: Preferential hyperacuity perimetry detected abnormalities in central visual function with high reliability. Eyes with nvAMD lesions detected by PHP had smaller lesions and better function when compared with the group before the introduction of PHP. The false-negative rate was <10% on PHP. The PHP distortion map was helpful in alerting clinicians to the presence of subclinical nvAMD.

Associations of Variation in Retinal Thickness With Visual Acuity and Anatomic Outcomes in Eyes With Neovascular Age-Related Macular Degeneration Lesions Treated With Anti-Vascular Endothelial Growth Factor Agents.

Importance: When initiating anti-vascular endothelial growth factor (VEGF) treatment for patients with neovascular age-related macular degeneration (nAMD), knowledge of prognostic factors is important for advising patients and guiding treatment. We hypothesized that eyes with greater fluctuation in retinal thickness over time have worse outcomes than eyes with less variation. Objective: To investigate whether visual and anatomic outcomes in eyes with nAMD initiating anti-VEGF treatment are associated with fluctuations in retinal thickness. Design, Setting, and Participants: In this study using data from the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and the Inhibition of VEGF in Age-Related Choroidal Neovascularization (IVAN) randomized clinical trial, people with previously untreated nAMD were included. Data were collected from February 2008 to November 2012, and data were analyzed from April 2017 to April 2020. Main Outcomes and Measures: Foveal center point thicknesses (FCPTs) were extracted from 1165 study eyes from CATT and 566 study eyes from the IVAN trial, excluding those with 3 measurements or less. For each eye, the SD of FCPT was calculated. Eyes were grouped by FCPT SD quartile. Associations of FCPT SD quartile with outcomes were quantified at month 24 or the last available visit by linear or logistic regression, adjusting for baseline best-corrected visual acuity (BCVA) and randomized allocations to drug and treatment regimen, for BCVA, development of fibrosis, and development of macular atrophy. Results: Of the 1731 included patients, 1058 (61.1%) were female, and the mean (SD) age was 78.6 (7.4) years. The median (interquartile range) FCPT SD was 40.2 (27.1-61.2) in the IVAN cohort and 59.0 (38.3-89.4) in the CATT cohort. After adjustment for baseline BCVA and trial allocations, BCVA worsened significantly across the quartiles of FCPT SD; the difference between the first and fourth quartiles was -6.27 Early Treatment Diabetic Retinopathy Study letters (95% CI, -8.45 to -4.09). The risk of developing fibrosis and macular atrophy also increased across FCPT SD quartiles. Odds ratios ranged from 1.40 (95% CI, 1.03 to 1.91) for quartile 2 to 1.95 (95% CI, 1.42 to 2.68) for quartile 4 for fibrosis and from 1.32 (95% CI, 0.90 to 1.92) for quartile 2 to 2.10 (95% CI, 1.45 to 3.05) for quartile 4 for macular atrophy. Conclusions and Relevance: Greater variation in retinal thickness in eyes with nAMD during treatment with anti-VEGF was associated with worse BCVA and development of fibrosis and macular atrophy in these post hoc analyses, despite protocol-directed treatment frequency. Practitioners may want to consider variation in retinal thickness when advising patients about their prognosis.

Evaluation of Month-24 Efficacy and Safety of Epimacular Brachytherapy for Previously Treated Neovascular Age-Related Macular Degeneration: The MERLOT Randomized Clinical Trial.

Importance: Although anti-vascular endothelial growth factor (VEGF) treatment offers better outcomes than the natural history of neovascular age-related macular degeneration (ARMD), a less burdensome, less expensive, and more durable treatment is needed. Objective: To assess the efficacy and safety of epimacular brachytherapy (EMB) for chronic, active, neovascular ARMD. Design, Setting, and Participants: The Macular Epiretinal Brachytherapy vs Ranibizumab (Lucentis) Only Treatment (MERLOT) pivotal device trial was conducted at 24 National Health Service hospitals across the UK. Patients who had neovascular ARMD and received intravitreal ranibizumab were enrolled between November 10, 2009, and January 30, 2012. Eligible patients were randomized 2:1 and were stratified by lens status and angiographic lesion type to receive either EMB plus as-needed ranibizumab or as-needed ranibizumab monotherapy. Participants were followed up monthly for 24 months and then assessed at a final visit at month 36. Masking of participants and clinicians was not possible, but best-corrected visual acuity (BCVA) and imaging were analyzed by masked assessors. Analysis followed the intent-to-treat approach. Interventions: Pars plana vitrectomy with 24 Gy EMB plus as-needed ranibizumab vs as-needed ranibizumab monotherapy. Main Outcomes and Measures: Coprimary outcomes were the number of as-needed ranibizumab injections and the mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA with a noninferiority margin of -5 ETDRS letters. Secondary outcomes were the percentage of participants losing fewer than 15 ETDRS letters and gaining 0 or more or 15 or more ETDRS letters and the mean change in angiographic total lesion size, choroidal neovascularization size, and foveal thickness on optical coherence tomography. Results: Of 363 participants, 329 (90.6%) completed 24 months of follow-up (222 participants in the EMB group and 107 in the ranibizumab group). The mean (SD) age of the combined groups was 76.5 (7.4) years. The mean (SD) number of ranibizumab injections was 9.3 (6.7) in the EMB group and 8.3 (4.5) in the ranibizumab group, with a difference of 1.0 injection (95% CI, -0.3 to 2.3; P = .13). The mean (SD) BCVA change was -11.2 (15.7) ETDRS letters in the EMB group and -1.4 (10.9) ETDRS letters in the ranibizumab group, with a difference of 9.8 ETDRS letters (95% CI, -6.7 to -12.9). In the EMB group, 65.6% of participants (160 of 244) lost fewer than 15 ETDRS letters vs 86.6% (103 of 119) in the ranibizumab group, with a difference of 21% (95% CI, 12.4%-29.5%; P < .001). Microvascular abnormalities occurred in 20 of 207 eyes (9.7%) in the EMB group and 1 of 97 eyes (1.0%) in the ranibizumab group. These abnormalities occurred outside the foveal center, and there were no unexpected safety concerns. Conclusions and Relevance: The MERLOT trial found that despite the acceptable safety of EMB, it did not reduce the number of ranibizumab injections and was associated with worse visual acuity than anti-VEGF treatment alone; these results do not support EMB use as an adjunct treatment for chronic, active neovascular ARMD. Trial Registration: ClinicalTrials.gov Identifier: NCT01006538.

Assessment of the Vitreomacular Interface Using High-Resolution OCT in a Population-Based Cohort Study of Older Adults.

PURPOSE: To describe the prevalence of vitreomacular interface (VMI) features and their associated risk factors in the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA) Study. DESIGN: Cross-sectional population-based study. PARTICIPANTS: Noninstitutionalized Northern Irish adults 40 years of age or older. METHODS: Using geographic stratification, a representative sample of people in Northern Ireland was invited to participate in the NICOLA Study. SD OCT images of participants were graded for vitreomacular traction (VMT), macular hole (MH), and epiretinal membrane (ERM) according to the International Vitreomacular Traction Study Group. A subsample was graded in more detail to estimate the prevalence of VMA and VMA area detailing size and location of VMA. Descriptive analysis and risk factors for each VMI feature were determined using generalized estimating equations. Results were standardized to the Northern Ireland population census (2011). MAIN OUTCOME MEASURES: Cohort profile, standardized prevalence, and risk factor associations of each VMI feature. RESULTS: Three thousand three hundred fifty-one NICOLA participants had gradable SD OCT images available for at least 1 eye. The prevalence of VMT was 0.5% (CI, 0.31%-0.70%), that for MH was 0.3% (CI, 0.23%-0.52%), and that for ERM was 7.6% (CI, 7.0%-8.3%). A detailed VMA analysis was performed on a subsample consisting of the first 1481 participants. The prevalence of VMA was 22.6% (CI, 21.1-24.2), and VMA area ranged from 0.25 to 42.7 mm2 (mean, 12.53 mm2; standard deviation, 6.90 mm2). In multivariate analyses, increased age was associated with an increased odds ratio (OR) of VMT, MH, and ERM. VMA area was positively associated with younger age and normal blood pressure. ERM and MH were present more often in more myopic eyes, associated with an increase in levels of high-density lipoprotein (HDL) cholesterol and triglycerides. CONCLUSIONS: The epidemiologic characteristics of VMI features indicated that VMI interactions throughout life are age dependent. Vitreous separation reduced to a greater extent in the horizontal meridians compared with the vertical, differing from previous studies. Future longitudinal studies of the evolution of these VMI changes over time would be of great interest.

Grading of age-related maculopathy: slit-lamp biomicroscopy versus an accredited grading center.

PURPOSE: To compare clinical age-related maculopathy (ARM) grading using slit-lamp biomicroscopy (SLB) versus photographic grading of stereoscopically captured fundus photographs (FP) using a high-resolution fundus camera. METHODS: A subset (129) of participants in the Carotenoids in ARM study were clinically graded for ARM signs and the corresponding FPs were graded in an accredited reading center. RESULTS: Drusen were said to be present in 192 (94.5%) eyes graded by FP, and in 165 (82.5%) eyes examined by SLB (agreement = 84%, k = 0.23). A good and modest degree of agreement was observed between SLB and FP for quantification of total drusen number (agreement = 81%, k = 0.33) and for classification of drusen subtypes (agreement = 60%, k = 0.33), respectively. Localization of drusen to either the inner zone or the outer zone was comparable for both techniques of ARM grading (inner zone: agreement = 89%; outer zone: agreement = 88%, k = 0.39). Agreement between SLB and FP was 76% (k = 0.46) for identification of any pigment abnormality; however, agreement was less for hypo-pigmentation abnormalities (agreement = 64%, k = 0.21). CONCLUSIONS: From the statistical perspective, SLB grading of ARM is generally comparable with findings from standardized grading of FP. However, the lower levels of agreement for classification of drusen subtypes and detection of hypo-pigmentation suggest these features may go unrecorded in a study which relies on SLB for grading ARM.

Microvascular abnormalities secondary to radiation therapy in neovascular age-related macular degeneration: findings from the INTREPID clinical trial.

PURPOSE: To report the incidence and features of retinal microvascular abnormalities (MVAs) occurring secondary to stereotactic radiotherapy (SRT) in a randomised double-masked sham-controlled clinical trial at 21 European sites. METHODS: Two hundred and thirty participants with neovascular age-related macular degeneration (AMD) treated with at least three intravitreal antivascular endothelial growth factor (anti-VEGF) injections prior to enrolment, and demonstrating a continuing need for re-treatment. INTERVENTIONS: 16 Gy, 24 Gy or sham SRT. All three groups received pro re nata anti-VEGF injections if the lesion was judged to be active at review visits. Colour fundus images from baseline and 6 months and fluorescein angiograms from baseline and annual visits were graded for measures of morphological outcome and safety using a prespecified protocol with accompanying definitions to distinguish RT-related MVA from non-specific retinal vessel abnormalities that are known to occur in neovascular AMD. The main outcome measure was MVA detected by months 12, 24 and 36 after enrolment. RESULTS: The frequency of MVAs in the combined SRT arms was 0% in year 1, 13.1% in year 2 and 30.3% in year 3. The area of MVA was small and the mean change in visual acuity in year 2 was similar in a subset of SRT eyes with MVAs, versus those without MVAs. MVA was considered to have possibly contributed to vision loss in 2 of 18 cases with MVA in year 2, and 5 of 37 cases in year 3. CONCLUSION: Treatment with SRT is associated with development of subtle MVAs that have little or no impact on visual outcome. These findings can help clinicians recognise the retinal MVAs that occur in response to SRT.

Quantitative fluorescein angiographic analysis of choroidal neovascular membranes: validation and correlation with visual function.

PURPOSE: To compare computerized analysis with traditional grading methods in the analysis of fluorescein angiograms from patients with choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) and to examine the clinical relevance of parameters generated by computerized analysis by testing their relationships with clinical measures of vision. METHODS: Custom quantitative fluorescein analysis (QFA) software was used to analyze 62 angiograms from patients with CNV for whom distance visual acuity (DVA) data were available. On applying QFA, we obtained three mathematical parameters for each lesion component: pixel area (PA), integrated intensity (II), and positive fluorescence (PF). Quotients (Q) were derived for the latter two parameters by correcting against background (b) or optic nerve (o) fluorescence (IIQ(b), IIQ degrees , PFQ(b), and PFQ degrees ). The new metrics were compared with traditional grading parameters of classic CNV and lesion area. The relationships of both sets of angiographic data with measures of vision were explored by regression analyses. RESULTS: Weighted kappa between QFA and traditional grading for lesion subtype assessment was high (kappa = 0.7). Regression analyses with PA, IIQ(b), IIQ degrees , PFQ(b), and PFQ degrees for each lesion descriptor (leakage, classic CNV, occult CNV, total lesion) as independent variables and DVA as the dependent variable showed that in every case PFQ(b) exhibited the most significant relationship with vision (adjusted r(2) = 0.26). Parameter estimates showed that for a change of 30 units on the PFQ(b) for classic CNV, a loss of 20 letters of DVA may be expected. No parameters from traditional grading methods showed statistically significant relationships with DVA. CONCLUSIONS: The markers of dynamic change in area and intensity of fluorescence exhibited stronger relationships with visual function than did area measurements alone.

Effectiveness of Community versus Hospital Eye Service follow-up for patients with neovascular age-related macular degeneration with quiescent disease (ECHoES): a virtual non-inferiority trial.

OBJECTIVES: To compare the ability of ophthalmologists versus optometrists to correctly classify retinal lesions due to neovascular age-related macular degeneration (nAMD). DESIGN: Randomised balanced incomplete block trial. Optometrists in the community and ophthalmologists in the Hospital Eye Service classified lesions from vignettes comprising clinical information, colour fundus photographs and optical coherence tomographic images. Participants' classifications were validated against experts' classifications (reference standard). SETTING: Internet-based application. PARTICIPANTS: Ophthalmologists with experience in the age-related macular degeneration service; fully qualified optometrists not participating in nAMD shared care. INTERVENTIONS: The trial emulated a conventional trial comparing optometrists' and ophthalmologists' decision-making, but vignettes, not patients, were assessed. Therefore, there were no interventions and the trial was virtual. Participants received training before assessing vignettes. MAIN OUTCOME MEASURES: Primary outcome-correct classification of the activity status of a lesion based on a vignette, compared with a reference standard. Secondary outcomes-potentially sight-threatening errors, judgements about specific lesion components and participants' confidence in their decisions. RESULTS: In total, 155 participants registered for the trial; 96 (48 in each group) completed all assessments and formed the analysis population. Optometrists and ophthalmologists achieved 1702/2016 (84.4%) and 1722/2016 (85.4%) correct classifications, respectively (OR 0.91, 95% CI 0.66 to 1.25; p=0.543). Optometrists' decision-making was non-inferior to ophthalmologists' with respect to the prespecified limit of 10% absolute difference (0.298 on the odds scale). Optometrists and ophthalmologists made similar numbers of sight-threatening errors (57/994 (5.7%) vs 62/994 (6.2%), OR 0.93, 95% CI 0.55 to 1.57; p=0.789). Ophthalmologists assessed lesion components as present less often than optometrists and were more confident about their classifications than optometrists. CONCLUSIONS: Optometrists' ability to make nAMD retreatment decisions from vignettes is not inferior to ophthalmologists' ability. Shared care with optometrists monitoring quiescent nAMD lesions has the potential to reduce workload in hospitals. TRIAL REGISTRATION NUMBER: ISRCTN07479761; pre-results registration.

The Effectiveness, cost-effectiveness and acceptability of Community versus Hospital Eye Service follow-up for patients with neovascular age-related macular degeneration with quiescent disease (ECHoES): a virtual randomised balanced incomplete block trial.

BACKGROUND: Patients with neovascular age-related macular degeneration (nAMD) usually attend regular reviews, even when the disease is quiescent. Reviews are burdensome to health services, patients and carers. OBJECTIVES: To compare the proportion of correct lesion classifications made by community-based optometrists and ophthalmologists from vignettes of patients; to estimate the cost-effectiveness of community follow-up by optometrists compared with follow-up by ophthalmologists in the Hospital Eye Service (HES); to ascertain views of patients, their representatives, optometrists, ophthalmologists and clinical commissioners on the proposed shared care model. DESIGN: Community-based optometrists and ophthalmologists in the HES classified lesions from vignettes comprising clinical information, colour fundus photographs and optical coherence tomography images. Participants' classifications were validated against experts' classifications (reference standard). SETTING: Internet-based application. PARTICIPANTS: Ophthalmologists had to have ≥ 3 years post-registration experience in ophthalmology, have passed part 1 of the Royal College of Ophthalmologists, Diploma in Ophthalmology or equivalent examination, and have experience in the age-related macular degeneration service. Optometrists had to be fully qualified, be registered with the General Optical Council for ≥ 3 years and not be participating in nAMD shared care. INTERVENTIONS: The trial sought to emulate a conventional trial in comparing optometrists' and ophthalmologists' decision-making, but vignettes, not patients, were assessed; therefore, there were no interventions. Participants received training prior to assessing vignettes. MAIN OUTCOME MEASURES: Primary outcome - correct classification of the activity status of a lesion based on a vignette, compared with a reference standard. Secondary outcomes - frequencies of potentially sight-threatening errors, participants' judgements about specific lesion components, participant-rated confidence in their decisions and cost-effectiveness of follow-up by community-based optometrists compared with HES ophthalmologists. RESULTS: In total, 155 participants registered for the trial; 96 (48 in each professional group) completed training and main assessments and formed the analysis population. Optometrists and ophthalmologists achieved 1702 out of 2016 (84.4%) and 1722 out of 2016 (85.4%) correct classifications, respectively [odds ratio (OR) 0.91, 95% confidence interval (CI) 0.66 to 1.25; p = 0.543]. Optometrists' decision-making was non-inferior to ophthalmologists' with respect to the pre-specified limit of 10% absolute difference (0.298 on the odds scale). Frequencies of sight-threatening errors were similar for optometrists and ophthalmologists [57/994 (5.7%) vs. 62/994 (6.2%), OR 0.93, 95% CI 0.55 to 1.57; p = 0.789]. Ophthalmologists assessed lesion components as present less often than optometrists and were more confident about their lesion classifications than optometrists. The mean care-pathway cost for assessment was very similar by group, namely £397.33 for ophthalmologists and £410.78 for optometrists. The optometrist-led monitoring reviews were slightly more costly and less effective than ophthalmologist-led reviews, although the differences were extremely small. There was consensus that optometrist-led monitoring has the potential to reduce clinical workload and be more patient-centred. However, potential barriers are ophthalmologists' perceptions of optometrists' competence, the need for clinical training, the ability of the professions to work collaboratively and the financial feasibility of shared care for Clinical Commissioning Groups. CONCLUSIONS: The ability of optometrists to make nAMD retreatment decisions from vignettes is non-inferior to that of ophthalmologists. Various barriers to implementing shared cared for nAMD were identified. FUTURE WORK RECOMMENDATIONS: The Effectiveness, cost-effectiveness and acceptability of Community versus Hospital Eye Service follow-up for patients with neovascular age-related macular degeneration with quiescent disease (ECHoES) study web application was robust and could be used for future training or research. The benefit of reducing HES workload was not considered in the economic evaluation. A framework of programme budgeting and marginal analysis could explicitly explore the resource implications of shifting resources within a given health service area, as the benefit of reducing HES workload was not considered in the economic evaluation. Future qualitative research could investigate professional differences of opinion that were identified in multidisciplinary focus groups. TRIAL REGISTRATION: Current Controlled Trials ISRCTN07479761. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 80. See the NIHR Journals Library website for further project information.

A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN).

BACKGROUND: Bevacizumab (Avastin®, Roche), which is used in cancer therapy, is the 'parent' molecule from which ranibizumab (Lucentis®, Novartis) was derived for the treatment of neovascular age-related macular degeneration (nAMD). There were reports in the literature on the effectiveness of bevacizumab in treating nAMD, but no trials. The cost per dose of bevacizumab is about 5-10% that of ranibizumab. This trial was a head-to-head comparison of these two drugs. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of ranibizumab and bevacizumab, and two treatment regimens, for nAMD. DESIGN: Multicentre, factorial randomised controlled trial with within-trial cost-utility and cost-minimisation analyses from the perspective of the UK NHS. Participants, health professionals and researchers were masked to allocation of drug but not regimen. Computer-generated random allocations to combinations of ranibizumab or bevacizumab, and continuous or discontinuous regimen, were stratified by centre, blocked and concealed. SETTING: Twenty-three ophthalmology departments in NHS hospitals. PARTICIPANTS: Patients ≥ 50 years old with active nAMD in the study eye with best corrected distance visual acuity (BCVA) ≥ 25 letters measured on a Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Previous treatment for nAMD, long-standing disease, lesion diameter > 6000 µm, thick blood at the fovea and any other confounding ocular disease were exclusion criteria. One eye per participant was studied; the fellow eye was treated according to usual care, if required. INTERVENTIONS: Ranibizumab and bevacizumab were procured commercially. Doses were ranibizumab 0.5 mg or bevacizumab 1.25 mg. The repackaged bevacizumab was quality assured. All participants were treated at visits 0, 1 and 2. Participants randomised to the continuous regimen were treated monthly thereafter. Participants randomised to the discontinuous regimen were not retreated after visit 2 unless pre-specified criteria for active disease were met. If retreatment was needed, monthly injections over 3 months were mandated. MAIN OUTCOME MEASURES: The primary outcome was BCVA. The non-inferiority margin was 3.5 letters. Secondary outcomes were contrast sensitivity; near visual acuity; reading index; neovascular lesion morphology; generic and disease-specific patient-reported outcomes, including macular disease-specific quality of life; survival free from treatment failure; resource use; quality-adjusted life-years (QALYs); and development of new geographic atrophy (GA) (outcome added during the trial). Results are reported for the study eye, except for patient-reported outcomes. RESULTS: Between 27 March 2008 and 15 October 2010, 610 participants were allocated and treated (314 ranibizumab, 296 bevacizumab; at 3 months, 305 continuous, 300 discontinuous). After 2 years, bevacizumab was neither non-inferior nor inferior to ranibizumab [-1.37 letters, 95% confidence interval (CI) -3.75 to +1.01 letters] and discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1.63 letters, 95% CI -4.01 to +0.75 letters). Lesion thickness at the fovea was similar by drug [geometric mean ratio (GMR) 0.96, 95% CI 0.90 to 1.03; p = 0.24] but 9% less with continuous treatment (GMR 0.91, 95% CI 0.85 to 0.97; p = 0.004). Odds of developing new GA during the trial were similar by drug [odds ratio (OR) 0.87, 95% CI 0.61 to 1.25; p = 0.46] but significantly higher with continuous treatment (OR 1.47, 95% CI 1.03 to 2.11; p = 0.033). Safety outcomes did not differ by drug but mortality was lower with continuous treatment (OR 0.47, 95% CI 0.22 to 1.03; p = 0.05). Continuous ranibizumab cost £3.5M per QALY compared with continuous bevacizumab; continuous bevacizumab cost £30,220 per QALY compared with discontinuous bevacizumab. These results were robust in sensitivity analyses. CONCLUSIONS: Ranibizumab and bevacizumab have similar efficacy. Discontinuing treatment and restarting when required results in slightly worse efficacy. Safety was worse with discontinuous treatment, although new GA developed more often with continuous treatment. Ranibizumab is not cost-effective, although it remains uncertain whether or not continuous bevacizumab is cost-effective compared with discontinuous bevacizumab at £20,000 per QALY threshold. Future studies should focus on the ocular safety of the two drugs, further optimisation of treatment regimens and criteria for stopping treatment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92166560. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 78. See the NIHR Journals Library website for further project information.