Impact of treat and extend criteria on proportions that can be extended after loading phase of 2 mg aflibercept therapy for neovascular age related macular degeneration: PRECISE Report 5.

OBJECTIVE: To study the impact of definitions of various treatment extension criteria on the proportion of patients who could be extended at their first visit after the loading phase of 2 mg aflibercept therapy for neovascular age related macular degeneration (nAMD). METHODS: Patients with nAMD initiated on the loading phase of three intravitreal doses of 2 mg aflibercept in routine clinical practice were recruited from December 2019 to August 2021. The response to the loading phase was assessed at approximately 8 weeks post-loading (up to 140 days from first injection) based on different definitions of response. The proportion of patients that qualify for interval extension based on different clinical trial criteria was also evaluated. RESULTS: A total of 722 patients with visual acuity (VA) and optical coherence tomography (OCT) scans done at all 4 visits were included. Of these 32.4% of eyes responded with complete macular fluid resolution after the first injection with no recurrence through the loading phase (super-responders) while 26.9% had persistent macular fluid in all 4 visits (true non-responders). The rest were considered suboptimal responders. Change in VA showed marked variations within each of these categories of fluid resolution. For extension of next treatment interval, if presence of any macular fluid at the post-loading visit is the only criteria considered, about 50% could be extended to 8 weeks. If both VA worsening by ≥5 letters and a > 25 µm increase in central sub-field thickness (CST) are considered, 90% will be eligible for interval extension. CONCLUSION: Clinical trial designs and pre-defined treatment extension/shortening criteria determine the proportion of patients requiring treatment in the post-loading visit. The short and long-term impact of interval extension immediate post-loading on visual outcome in clinical practice is unknown.

Subretinal transient hyporeflectivity in neovascular age-related macular degeneration and its response to a loading phase of aflibercept: PRECISE report 4.

PURPOSE: To describe the prevalence of subretinal transient hyporeflectivity (STHR) in exudative neovascular age-related macular degeneration (nAMD) and its response to a loading phase of aflibercept. METHODS: Optical coherence tomography (OCT) scans of treatment-naïve nAMD patients captured at baseline and after a loading phase of aflibercept were graded for presence of STHR, defined as a small, well-defined, round, subretinal, hyporeflective area, delimited between the ellipsoid zone (EZ) and the retinal pigmented epithelium/Bruch membrane complex. OCT parameters recorded were macular neovascularisation (MNV) subtypes, location of retinal fluids (subretinal fluid, SRF and intraretinal fluid, IRF), central retinal and choroidal thickness. Response was defined as absence of IRF and SRF. Factors associated with completely resolved STHR versus persistent STHR post-loading phase were compared. RESULTS: 2039 eyes of 1901 patients were analysed. STHR was observed in 79 eyes of 78 patients, with an estimated prevalence of 3.87% (95% CI 3.08-4.81%). STHR were seen in 44 type 1 MNV (56%), 27 with type 2 (34%), and 8 with type 3 (10%). At baseline, a total of 303 STHR were present, ranging between 1-22 per eye. The total number of STHR reduced significantly after the loading phase to 173 (p = 0.002). Complete disappearance of STHR was seen in 44 eyes (56%) and persistent STHR in the rest (44%). CONCLUSIONS: STHR may represent a marker of low-grade exudation in nAMD eyes with good response to a loading phase of aflibercept. However, its potential role as an independent nAMD activity biomarker is limited as most resolve after the loading phase.

Suboptimal outcomes and treatment burden of anti-vascular endothelial growth factor treatment for diabetic macular oedema in phakic patients.

OBJECTIVES: In England and Wales, treatment options were limited for patients with diabetic macular oedema (DMO) with phakic eyes that failed anti-vascular endothelial growth factor (anti-VEGF) treatment pre-2022. This study aimed to quantify the response to, and treatment burden of, anti-VEGF treatment in phakic eyes. METHODS: Retrospective, cohort study using electronic patient record data from two UK centres between 2015 and 2020. Primary objective was proportion of phakic eyes with a suboptimal response after initial 6 months of anti-VEGF treatment. Data were available for 500 eyes from 399 patients. RESULTS: At 6 months significantly more eyes had a suboptimal response to anti-VEGF treatment: 65.8% (95% CI 61.5-70.0%) vs 34.2% (95% CI 30.0-38.5%), p < 0.0001. Baseline visual acuity (VA) predicted VA outcome, however, despite greater gains in eyes with poorer VA, such eyes did not achieve the same VA levels as those who started treatment with better VA. Only 53.6% of eyes had more than three injections in the first 6 months indicating difficulties in delivering high volume/high frequency treatment. Treatment and review burden were similar over the following years regardless of response to anti-VEGF treatment. CONCLUSIONS: Data confirm previous real world evidence around response to anti-VEGF treatment, importance of baseline VA and frequency of injections in predicting outcomes in a UK setting. Continuing treatment beyond 6 months in suboptimal responders imposes unnecessary treatment burden without significant change in VA. In suboptimal responders, consideration of early switch to longer acting steroid treatments may help to reduce treatment burden, whilst maintaining or improving vision.

Associations of presenting visual acuity with morphological changes on OCT in neovascular age-related macular degeneration: PRECISE Study Report 2.

PURPOSE: To study associations of optical coherence tomography (OCT) features with presenting visual acuity (VA) in treatment naive neovascular age-related macular degeneration (nAMD). METHODS: Patients with nAMD initiated on aflibercept therapy were recruited from December 2019 to August 2021. Demographic and OCT (Spectralis, Heidelberg Engineering) features associated with good VA (VA ≥ 68 ETDRS letters, Snellen ≥ 6/12) and poor VA (VA < 54 letters, Snellen < 6/18) were analysed using Generalised Estimating Equations to account for inter-eye correlation. RESULTS: Of 2274 eyes of 2128 patients enrolled, 2039 eyes of 1901 patients with complete data were analysed. Mean age was 79.4 (SD 7.8) years, female:male 3:2 and mean VA 58.0 (SD 14.5) letters. On multivariable analysis VA < 54 letters was associated with increased central subfield thickness (CST) (OR 1.40 per 100 µm; P < 0.001), foveal intraretinal fluid (OR 2.14; P < 0.001), polypoidal vasculopathy (PCV) relative to Type 1 macular neovascularisation (MNV) (OR 1.66; P = 0.049), presence of foveal subretinal hyperreflective material (SHRM) (OR 1.73; P = 0.002), foveal fibrosis (OR 3.85; P < 0.001), foveal atrophy (OR 5.54; P < 0.001), loss of integrity of the foveal ellipsoid zone (EZ) or external limiting membrane (ELM) relative to their preservation (OR 3.83; P < 0.001) and absence of subretinal drusenoid deposits (SDD) (presence vs absence; OR 0.75; P = 0.04). These features were associated with reduced odds of VA ≥ 68 letters except MNV subtypes and SDD. CONCLUSION: Presence of baseline fovea-involving atrophy, fibrosis, intraretinal fluid, SHRM, PCV EZ/ELM loss and increased CST determine poor presenting VA. This highlights the need for early detection and treatment prior to structural changes that worsen baseline VA.

Baseline characteristics of eyes with early residual fluid post loading phase of aflibercept therapy in neovascular AMD: PRECISE study report 3.

PURPOSE: To compare the baseline characteristics in patients with and without early residual fluid (ERF) after aflibercept loading phase (LP) in patients with treatment naïve neovascular age related macular degeneration (nAMD). METHODS: Patients with nAMD initiated on LP of three intravitreal aflibercept doses were recruited from December 2019 to August 2021. Baseline demographic and OCT features associated with any ERF were analysed using Generalised Estimating Equations to account for inter-eye correlation. Receiver operating characteristic (ROC) curve was performed for selection of CST threshold. RESULTS: Of 2128 patients enrolled, 1999 eyes of 1862 patients with complete data were included. After LP, ERF was present in 1000 (50.0%), eSRF in 746(37.3%) and eIRF in 428 (21.4%) eyes. In multivariable analysis of baseline features, eyes with increased central subfield thickness (CST) (OR 1.31 per 100 microns increase [95% CI 1.22 to 1.41]; P < 0.001), eyes with IRF and SRF at baseline (1.62 [95% CI 1.17 to 2.22]; P = 0.003), and those with SRF only (OR 2.26 [95% CI 1.59 to 3.20]; P < 0.001) relative to IRF only were determinants of ERF. CST ≥ 418 microns had 57% sensitivity and 58% specificity to distinguish ERF from no ERF at visit 4. CONCLUSION: On average, 50% of eyes have ERF after aflibercept LP. Clinically relevant baseline determinants of ERF include CST ≥ 418 µ and presence of only SRF. These eyes may require further monthly treatment before extending treatment intervals.

A Multi-Modal AI-Driven Cohort Selection Tool to Predict Suboptimal Non-Responders to Aflibercept Loading-Phase for Neovascular Age-Related Macular Degeneration: PRECISE Study Report 1.

Patients diagnosed with exudative neovascular age-related macular degeneration are commonly treated with anti-vascular endothelial growth factor (anti-VEGF) agents. However, response to treatment is heterogeneous, without a clinical explanation. Predicting suboptimal response at baseline will enable more efficient clinical trial designs for novel, future interventions and facilitate individualised therapies. In this multicentre study, we trained a multi-modal artificial intelligence (AI) system to identify suboptimal responders to the loading-phase of the anti-VEGF agent aflibercept from baseline characteristics. We collected clinical features and optical coherence tomography scans from 1720 eyes of 1612 patients between 2019 and 2021. We evaluated our AI system as a patient selection method by emulating hypothetical clinical trials of different sizes based on our test set. Our method detected up to 57.6% more suboptimal responders than random selection, and up to 24.2% more than any alternative selection criteria tested. Applying this method to the entry process of candidates into randomised controlled trials may contribute to the success of such trials and further inform personalised care.

Evaluation of care with intravitreal aflibercept treatment for UK patients with diabetic macular oedema: DRAKO study 24-month real-world outcomes.

BACKGROUND/ OBJECTIVES: DRAKO (NCT02850263) was a 24-month, prospective, observational, multi-centre cohort study that enrolled patients diagnosed with diabetic macular oedema (DMO) including central involvement. The study aimed to evaluate standard of care intravitreal aflibercept (IVT-AFL) treatment in the UK. This analysis describes the 12-month outcomes for patients with prior anti-vascular endothelial growth factor (VEGF) treatment for DMO other than IVT-AFL (C2), and 2-year outcomes for both anti-VEGF treatment-naïve patients (C1) and C2 patients. METHODS: Study eyes were treated with IVT-AFL as per local standard of care. Mean changes in best-corrected visual acuity (BCVA) in ETDRS letters and central subfield thickness (CST) were stratified by baseline factors. Changes in diabetic retinopathy assessments, glycated haemoglobin A1c levels and vision-related quality of life (QoL) were evaluated alongside numbers of injections administered and safety outcomes. RESULTS: For C1, mean (SD) changes from baseline in BCVA of +0.7 (12.7) letters and CST of -123.3 (104.3) µm were observed at Month 24. For C2, mean (SD) changes from baseline for BCVA of + 0.2 (10.2) letters and -0.3 (13.0) letters, and CST of -79.1 (137.6) µm and -91.6 (132.9) µm, were observed at 12 and 24 months, respectively. In Year 2, C1 and C2 patients received a mean of 3.7 and 4.3 injections, respectively. CONCLUSIONS: Year 2 results indicate that IVT-AFL is an effective treatment for DMO in real-world UK clinical practice, despite relatively low injection numbers. The high baseline visual acuity and QoL scores were maintained and there was further improvement in anatomical outcomes.

Evaluation of standard-of-care intravitreal aflibercept treatment practices in patients with diabetic macular oedema in the UK: DRAKO study outcomes.

BACKGROUND/OBJECTIVES: DRAKO (NCT02850263) was a 24-month, prospective, non-interventional, multi-centre cohort study enrolling patients with diabetic macular oedema (DMO) including central involvement. The study evaluated UK standard-of-care intravitreal aflibercept (IVT-AFL) treatment. This analysis describes the treatment pathway and service provision for the anti-vascular endothelial growth factor (VEGF) treatment-naïve (C1) and non-naïve patients (C2) who received prior anti-VEGF treatment for DMO other than IVT-AFL. METHODS: Mean changes in best-corrected visual acuity and central subfield thickness were measured and stratified by baseline factors, including ethnicity and administration of five initial monthly injections within predefined windows. Clinic visits were classified as treatment only (T1), monitoring assessment only (T2), combined visits (T3) or post-injection visits with no treatment or assessment (T4). RESULTS: Median time from decision to treat to treatment was 6 days. As a percentage of total visits, T1, T2, T3 and T4 were 7%, 42%, 48% and 3% for C1 and 11%, 39%, 48% and 2% for C2. Most IVT-AFL injections were administered by healthcare professionals (HCPs) other than doctors (C1, 57.4%; C2, 58.5%). The percentage of treatments associated with a procedure-related adverse event where at least 75% of injections were completed by the same injector role were similar for doctors and other HCPs (C1, 1.1% and 0.8%; C2, 0.7%, and 1.0%). CONCLUSIONS: Results indicate that upon DMO diagnosis, patients were treated promptly, and most visits were combined (treatment and assessment) or monitoring only. Most IVT-AFL was administered by non-physicians with a similar treatment-related safety profile as IVT-AFL administered by physicians.

Diabetic Macular Edema and Diode Subthreshold Micropulse Laser: A Randomized Double-Masked Noninferiority Clinical Trial.

PURPOSE: To determine clinical effectiveness, safety, and cost-effectiveness of subthreshold micropulse laser (SML), compared with standard laser (SL), for diabetic macular edema (DME) with central retinal thickness (CRT) < 400 µm. DESIGN: Pragmatic, multicenter, allocation-concealed, double-masked, randomized, noninferiority trial. PARTICIPANTS: Adults with center-involved DME < 400 µm and best-corrected visual acuity (BCVA) of > 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in one/both eyes. METHODS: Randomization 1:1 to 577 nm SML or SL treatment. Retreatments were allowed. Rescue with intravitreal anti-vascular endothelial growth factor therapies or steroids was permitted if 10 or more ETDRS letter loss occurred, CRT increased > 400 µm, or both. MAIN OUTCOME MEASURES: Primary outcome was mean change in BCVA in the study eye at 24 months (noninferiority margin 5 ETDRS letters). Secondary outcomes were mean change from baseline to month 24 in binocular BCVA; CRT and mean deviation of Humphrey 10-2 visual field in the study eye; percentage meeting driving standards; EuroQoL EQ-5D-5L, 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), and Vision and Quality of Life Index (VisQoL) scores; cost per quality-adjusted life-years (QALYs) gained; adverse effects; and number of laser and rescue treatments. RESULTS: The study recruited fully (n = 266); 87% of SML-treated and 86% of SL-treated patients had primary outcome data. Mean ± standard deviation BCVA change from baseline to month 24 was -2.43 ± 8.20 letters and -0.45 ± 6.72 letters in the SML and SL groups, respectively. Subthreshold micropulse laser therapy was deemed not only noninferior but also equivalent to SL therapy because the 95% confidence interval (CI; -3.9 to -0.04 letters) lay wholly within both upper and lower margins of the permitted maximum difference (5 ETDRS letters). No statistically significant difference was found in binocular BCVA (0.32 ETDRS letters; 95% CI, -0.99 to 1.64 ETDRS letters; P = 0.63); CRT (-0.64 µm; 95% CI, -14.25 to 12.98 µm; P = 0.93); mean deviation of the visual field (0.39 decibels (dB); 95% CI, -0.23 to 1.02 dB; P = 0.21); meeting driving standards (percentage point difference, 1.6%; 95% CI, -25.3% to 28.5%; P = 0.91); adverse effects (risk ratio, 0.28; 95% CI, 0.06-1.34; P = 0.11); rescue treatments (percentage point difference, -2.8%; 95% CI, -13.1% to 7.5%; P = 0.59); or EQ-5D, NEI-VFQ-25, or VisQoL scores. Number of laser treatments was higher in the SML group (0.48; 95% CI, 0.18-0.79; P = 0.002). Base-case analysis indicated no differences in costs or QALYs. CONCLUSIONS: Subthreshold micropulse laser therapy was equivalent to SL therapy, requiring slightly higher laser treatments.

Retinal Vein Occlusion with COVID-19: A Case Report and Review of Literature.

OBJECTIVES: To provide a case report of Retinal Vein Occlusion (RVO) with COVID-19 infection. CASE: A 15-year-old healthy male presented with blurring of vision, 2+ vitreous cells, retinal haemorrhages and dilated and tortuous retinal vessels in the left eye within 28 days of a positive COVID-19 reverse transcriptase polymerase chain reaction (RT-PCR) assay. He was diagnosed with left non-ischaemic CRVO, with a suspected aetiology of COVID-19. DISCUSSION: A literature review found 12 reported cases of RVO associated with COVID-19. All but one patient was younger than 60, with a mean age of 42 years. Management varied, but in the majority (8/12), visual acuity (VA) improved with follow-up, and five (42%) had a final VA of 20/20. CONCLUSION: In the absence of other known aetiological factors, ophthalmologists should consider COVID-19 as a cause of RVO. The outcome can vary, but the majority can expect improvement in VA with time.

Standard threshold laser versus subthreshold micropulse laser for adults with diabetic macular oedema: the DIAMONDS non-inferiority RCT.

BACKGROUND: The National Institute for Health and Care Excellence recommends macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm on optical coherence tomography. The DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial compared standard threshold macular laser with subthreshold micropulse laser to treat diabetic macular oedema suitable for macular laser. OBJECTIVES: Determining the clinical effectiveness, safety and cost-effectiveness of subthreshold micropulse laser compared with standard threshold macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm. DESIGN: A pragmatic, multicentre, allocation-concealed, double-masked, randomised, non-inferiority, clinical trial. SETTING: Hospital eye services in the UK. PARTICIPANTS: Adults with diabetes and centre-involving diabetic macular oedema with a central retinal subfield thickness of < 400 µm, and a visual acuity of > 24 Early Treatment Diabetic Retinopathy Study letters (Snellen equivalent > 20/320) in one/both eyes. INTERVENTIONS: Participants were randomised 1 : 1 to receive 577 nm subthreshold micropulse laser or standard threshold macular laser (e.g. argon laser, frequency-doubled neodymium-doped yttrium aluminium garnet 532 nm laser); laser treatments could be repeated as needed. Rescue therapy with intravitreal anti-vascular endothelial growth factor therapies or steroids was allowed if a loss of ≥ 10 Early Treatment Diabetic Retinopathy Study letters between visits occurred and/or central retinal subfield thickness increased to > 400 µm. MAIN OUTCOME MEASURES: The primary outcome was the mean change in best-corrected visual acuity in the study eye at 24 months (non-inferiority margin 5 Early Treatment Diabetic Retinopathy Study letters). Secondary outcomes included the mean change from baseline to 24 months in the following: binocular best-corrected visual acuity; central retinal subfield thickness; the mean deviation of the Humphrey 10-2 visual field in the study eye; the percentage of people meeting driving standards; and the EuroQol-5 Dimensions, five-level version, National Eye Institute Visual Function Questionnaire - 25 and Vision and Quality of Life Index scores. Other secondary outcomes were the cost per quality-adjusted life-years gained, adverse effects, number of laser treatments and additional rescue treatments. RESULTS: The DIAMONDS trial recruited fully (n = 266); 87% of participants in the subthreshold micropulse laser group and 86% of participants in the standard threshold macular laser group had primary outcome data. Groups were balanced regarding baseline characteristics. Mean best-corrected visual acuity change in the study eye from baseline to month 24 was -2.43 letters (standard deviation 8.20 letters) in the subthreshold micropulse laser group and -0.45 letters (standard deviation 6.72 letters) in the standard threshold macular laser group. Subthreshold micropulse laser was deemed to be not only non-inferior but also equivalent to standard threshold macular laser as the 95% confidence interval (-3.9 to -0.04 letters) lay wholly within both the upper and lower margins of the permitted maximum difference (5 Early Treatment Diabetic Retinopathy Study letters). There was no statistically significant difference between groups in any of the secondary outcomes investigated with the exception of the number of laser treatments performed, which was slightly higher in the subthreshold micropulse laser group (mean difference 0.48, 95% confidence interval 0.18 to 0.79; p = 0.002). Base-case analysis indicated no significant difference in the cost per quality-adjusted life-years between groups. FUTURE WORK: A trial in people with ≥ 400 µm diabetic macular oedema comparing anti-vascular endothelial growth factor therapy alone with anti-vascular endothelial growth factor therapy and macular laser applied at the time when central retinal subfield thickness has decreased to < 400 µm following anti-vascular endothelial growth factor injections would be of value because it could reduce the number of injections and, subsequently, costs and risks and inconvenience to patients. LIMITATIONS: The majority of participants enrolled had poorly controlled diabetes. CONCLUSIONS: Subthreshold micropulse laser was equivalent to standard threshold macular laser but required a slightly higher number of laser treatments. TRIAL REGISTRATION: This trial is registered as EudraCT 2015-001940-12, ISRCTN17742985 and NCT03690050. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 50. See the NIHR Journals Library website for further project information.

The retina is a layer at the back of the eye. Its centre is called the macula and is responsible for central vision. Some people with diabetes develop diabetic macular oedema. In diabetic macular oedema fluid leaks from retinal blood vessels and builds up at the macula, resulting in sight loss. Diabetic macular oedema can be mild or severe; this can be determined measuring the thickness of the macula, which is measured in micrometres (µm). One micrometre is one thousandth of a millimetre. In mild diabetic macular oedema, the thickness of the macula increases, but is less than 400 µm. Patients with mild diabetic macular oedema can be treated with a laser and there are two laser types. The standard threshold macular laser has been available for many years. It clears the diabetic macular oedema but produces a 'burn' in the retina. The subthreshold micropulse laser is newer. It does not produce a burn but also clears the diabetic macular oedema. The lack of a burn, however, has led to doubts about whether or not this laser works as well as the standard threshold macular laser because 'no burn' was taken to mean 'less benefit'. These doubts led to our establishing the DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial, which compared these two lasers for people with mild diabetic macular oedema. A total of 266 people suitable for either laser joined the study at 16 NHS hospitals across the UK; 133 received standard threshold macular laser and 133 received subthreshold micropulse laser. The choice of laser was determined by chance. The DIAMONDS trial found that the subthreshold micropulse laser was as good as the standard threshold macular laser (i.e. 'clinically equivalent') in terms of improving people's vision, reducing macula thickness, allowing people to meet driving standards and maintaining their quality of life, both in general terms and for vision in particular. There was a small increase (less than one session on average per person) in the number of laser treatment sessions needed with subthreshold micropulse laser. The costs of both laser treatments were about the same.

Patterns of treatment discontinuation in patients receiving anti-vascular endothelial growth factor for neovascular age-related macular degeneration.

Purpose: To report the reasons for treatment discontinuation within 5 years in patients receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy for neovascular age-related macular degeneration (nAMD). Methods: A retrospective case-notes review of patients commenced on anti-VEGF for nAMD who failed to complete 5 years of follow-up was undertaken. The reasons for treatment discontinuation, baseline age, baseline visual acuity (VA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and the VA change at the last follow-up were recorded. Age-specific all-cause mortality was calculated for deceased patients. Results: Of the 1177 patients, 551 patients (46.8%) failed to complete the 5-year follow-up. The reasons for treatment discontinuation were death (251), early discharge due to stable disease (110), further treatment deemed futile (100), failure to attend (15), ill health (14), patient choice (7), and transfer of care (1). In 53 patients, no reason was documented. The mean baseline age of those who completed the 5-year follow-up (77.4 ± 7.8 years, 95% confidence interval (CI): 76.8-77.9) was significantly lower than those who discontinued the treatment for any reason (82 ± 7.7 years, 95% CI: 81.4-82.6) (P < 0.0001). Survival analysis showed that baseline VA was not a factor in treatment discontinuation; however, visual stability (±5 letters from baseline) was associated with treatment continuation. The age-specific all-cause mortality in deceased patients was lower than that in the general population. Conclusion: At 5 years, only 53% of patients remained in active care, and death was the most common reason for treatment discontinuation. Lower baseline age and VA stability during therapy were associated with treatment continuation.

The changing landscape for the management of patients with neovascular AMD: brolucizumab in clinical practice.

Untreated neovascular age-related macular degeneration (nAMD) can lead to severe and permanent visual impairment. The chronic nature of the disease can have a significant impact on patients' quality of life and an economic and time burden on medical retina (MR) services, with the care need outweighing the growth of resources that clinical services can access. The introduction of a new treatment into clinical services can be challenging, especially for services that are already under capacity constraints. Guidance for practical implementation is therefore helpful. Roundtable meetings, facilitated by Novartis UK, between a working group of MR experts with experience of leading and managing NHS retinal services in the intravitreal era were conducted between 2020 and 2021. These meetings explored various aspects and challenges of introducing a new anti-vascular endothelial growth factor (VEGF) therapy to the UK medical retina services. Provision of clear expert recommendations and practical guidance nationally, that can be adapted locally as required to support clinicians and healthcare professionals (HCPs), is valuable in supporting the introduction of a new anti-VEGF therapy within the NHS environment. The experts provide ophthalmologic HCPs with a collation of insights and recommendations to support the introduction and delivery of brolucizumab in their local service in the face of current and projected growth in demand for retina care.

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.

An update on long-acting therapies in chronic sight-threatening eye diseases of the posterior segment: AMD, DMO, RVO, uveitis and glaucoma.

In the real-world setting, there is suboptimal compliance with treatments that require frequent administration and assessment visits. This undertreatment frequently has negative consequences in eye disease and carries a real risk to vision. For example, patients with glaucoma risk progression of visual loss even with a small number of missed doses, and patients with neovascular age-related degeneration (nAMD) who fail to attend a bi-monthly clinic appointment to receive an intravitreal anti-vascular endothelial growth factor (VEGF) drug injections may lose the initial vision gains in vision. Protracted regular treatment schedules represent a high burden not only for patients and families, but also healthcare professionals, systems, and ultimately society too. There has been a clear need for longer-acting therapies that reduce the frequency, and therefore the burden, of treatment interventions. Several longer-acting interventions for nAMD, diabetic macular oedema, retinal vein occlusion, uveitis and glaucoma have either been developed or are in late-phase development, some of which employ novel mechanisms of actions, and all of which of promise longer (≥3 month) treatment intervals. This review delivers an overview of anti-VEGF agents with longer durations of action, DARPins, bispecific anti-VEGF/Ang2 therapies, anti-PDGF and anti-integrin therapy, Rho-kinase inhibitors, the Port Delivery System, steroids, gene therapy for retina and uveitis, and for glaucoma, ROCK inhibitors, implants and plugs, and SLT laser and MIGS. The review also refers to the potential of artificial intelligence to tailor treatment efficacy with a resulting reduction in treatment burden.

Evaluation of standard of care intravitreal aflibercept treatment of diabetic macular oedema treatment-naive patients in the UK: DRAKO study 12-month outcomes.

OBJECTIVES: DRAKO (NCT02850263) is a 24-month, prospective, non-interventional, multi-centre cohort study which enroled patients diagnosed with centre-involving diabetic macular oedema (DMO). The study aims to evaluate standard of care with intravitreal aflibercept (IVT-AFL) treatment in the UK. This analysis describes the anti-vascular endothelial growth factor (anti-VEGF) treatment-naive patient cohort after 12-month follow-up. METHODS: Study eyes were treated with IVT-AFL as per local standard of care. The mean change in best-corrected visual acuity (BCVA) and central subfield thickness (CST) from baseline at 12 months were measured and stratified by baseline factors. The number of injections and safety data were also evaluated. RESULTS: A total of 507 patients were enroled from 35 centres. Mean (SD) baseline BCVA was 71.4 (12.0) letters and CST was 448.7 (88.7) µm, with 63.1% of patients presenting with baseline BCVA ≥ 70 letters (mean 78.1). Mean (SD) change in BCVA of 2.5 (12.2) letters and CST of -119.1 (116.4) µm was observed at month 12. A 7.3 letter gain was observed in patients with baseline BCVA < 70 letters. Mean number (SD) of injections in year one was 6.4 (2.1). No significant adverse events were recorded. CONCLUSION: Year one results indicated that IVT-AFL was an effective treatment for DMO in standard of care UK clinical practice, maintaining or improving visual acuity in treatment-naive patients with good baseline visual acuity, despite some patients being undertreated versus the summary of product characteristics. These results also demonstrated the clinical importance and meaningful impact of diabetic retinopathy screening in the UK.

Diagnostic Accuracy of Monitoring Tests of Fellow Eyes in Patients with Unilateral Neovascular Age-Related Macular Degeneration: Early Detection of Neovascular Age-Related Macular Degeneration Study.

PURPOSE: To evaluate the diagnostic accuracy of routinely used tests of visual function and retinal morphology compared with fundus fluorescein angiography (FFA) to detect onset of active macular neovascularization in unaffected fellow eyes of patients with unilateral neovascular age-related macular degeneration (nAMD). DESIGN: Prospective diagnostic accuracy cohort study conducted in 24 eye clinics in the United Kingdom over 3 years. PARTICIPANTS: Older adults (>50 years) with recently diagnosed unilateral nAMD with a fellow (study) eye free of nAMD. METHODS: Self-reported vision, Amsler, clinic-measured visual acuity (VA), fundus assessment, and spectral domain OCT. The reference standard is FFA. MAIN OUTCOME MEASURES: Sensitivity and specificity of the 5 index tests. RESULTS: Of 552 participants monitored for up to 3 years, 145 (26.3%) developed active nAMD in the study eye, of whom 120 had an FFA at detection and constituted the primary analysis cohort. Index test positives at nAMD detection in those confirmed by FFA were self-reported vision much worse (5), distortion on Amsler (33), 10-letter decrease in acuity from baseline (36), fundus examination (64), and OCT (110). Percentage index test sensitivities were: self-reported vision 4.2 (95% confidence interval [CI], 1.6-9.8); Amsler 33.7 (95% CI, 25.1-43.5); VA 30.0 (95% CI, 22.5-38.7); fundus examination 53.8 (95% CI, 44.8-62.5); and OCT 91.7 (95% CI, 85.2-95.6). All 5 index test specificities were high at 97.0 (95% CI, 94.6-98.5), 81.4 (95% CI, 76.4-85.5), 66.3 (95% CI, 61.0-71.1), 97.6 (95% CI, 95.3-98.9), and 87.8 (95% CI, 83.8-90.9), respectively. The combination of OCT with one other index test that was a secondary outcome measure increased sensitivity marginally and decreased specificity for all combinations except fundus examination. CONCLUSIONS: Tests of self-reported change in vision, unmasking of new distortion, measurements of acuity, and fundus checks to diagnose active nAMD performed poorly in contrast to OCT. Our findings support a change to guidelines in clinical practice to monitor for onset of nAMD.

Multimodal imaging interpreted by graders to detect re-activation of diabetic eye disease in previously treated patients: the EMERALD diagnostic accuracy study.

BACKGROUND: Owing to the increasing prevalence of diabetes, the workload related to diabetic macular oedema and proliferative diabetic retinopathy is rising, making it difficult for hospital eye services to meet demands. OBJECTIVE: The objective was to evaluate the diagnostic performance, cost-effectiveness and acceptability of a new pathway using multimodal imaging interpreted by ophthalmic graders to detect reactivation of diabetic macular oedema/proliferative diabetic retinopathy in previously treated patients. DESIGN: This was a prospective, case-referent, cross-sectional diagnostic study. SETTING: The setting was ophthalmic clinics in 13 NHS hospitals. PARTICIPANTS: Adults with type 1 or type 2 diabetes with previously successfully treated diabetic macular oedema/proliferative diabetic retinopathy in one/both eyes in whom, at the time of enrolment, diabetic macular oedema/proliferative diabetic retinopathy could be active or inactive. METHODS: For the ophthalmic grader pathway, review of the spectral domain optical coherence tomography scans to detect diabetic macular oedema, and seven-field Early Treatment Diabetic Retinopathy Study/ultra-wide field fundus images to detect proliferative diabetic retinopathy, by trained ophthalmic graders. For the current standard care pathway (reference standard), ophthalmologists examined patients face to face by slit-lamp biomicroscopy for proliferative diabetic retinopathy and, in addition, spectral domain optical coherence tomography imaging for diabetic macular oedema. OUTCOME MEASURES: The primary outcome measure was sensitivity of the ophthalmic grader pathway to detect active diabetic macular oedema/proliferative diabetic retinopathy. The secondary outcomes were specificity, agreement between pathways, cost-consequences, acceptability and the proportion of patients requiring subsequent ophthalmologist assessment, unable to undergo imaging and with inadequate quality images/indeterminate findings. It was assumed for the main analysis that all patients in whom graders diagnosed active disease or were 'unsure' or images were 'ungradable' required examination by an ophthalmologist. RESULTS: Eligible participants with active and inactive diabetic macular oedema (152 and 120 participants, respectively) and active and inactive proliferative diabetic retinopathy (111 and 170 participants, respectively) were recruited. Under the main analysis, graders had a sensitivity of 97% (142/147) (95% confidence interval 92% to 99%) and specificity of 31% (35/113) (95% confidence interval 23% to 40%) to detect diabetic macular oedema. For proliferative diabetic retinopathy, graders had a similar sensitivity and specificity using seven-field Early Treatment Diabetic Retinopathy Study [sensitivity 85% (87/102), 95% confidence interval 77% to 91%; specificity 48% (77/160), 95% confidence interval 41% to 56%] or ultra-wide field imaging [sensitivity 83% (87/105), 95% confidence interval 75% to 89%; specificity 54% (86/160), 95% confidence interval 46% to 61%]. Participants attending focus groups expressed preference for face-to-face evaluations by ophthalmologists. In the ophthalmologists' absence, patients voiced the need for immediate feedback following grader's assessments, maintaining periodic evaluations by ophthalmologists. Graders and ophthalmologists were supportive of the new pathway. When compared with the reference standard (current standard pathway), the new grader pathway could save £1390 per 100 patients in the review of people with diabetic macular oedema and, depending on the imaging modality used, between £461 and £1189 per 100 patients in the review of people with proliferative diabetic retinopathy. CONCLUSIONS: For people with diabetic macular oedema, the ophthalmic grader pathway appears safe and cost saving. The sensitivity of the new pathway to detect active proliferative diabetic retinopathy was lower, but may still be considered acceptable for patients with proliferative diabetic retinopathy previously treated with laser. Suggestions from focus group discussions should be taken into consideration if the new pathway is introduced to ensure its acceptability to users. LIMITATIONS: Lack of fundus fluorescein angiography to confirm diagnosis of active proliferative diabetic retinopathy. FUTURE WORK: Could refinement of the new pathway increase its sensitivity to detect proliferative diabetic retinopathy? Could artificial intelligence be used for automated reading of images in this previously treated population? TRIAL REGISTRATION: Current Controlled Trials ISRCTN10856638 and ClinicalTrials.gov NCT03490318. 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 AssessmentVol. 25, No. 32. See the NIHR Journals Library website for further project information.

More and more people are developing diabetes. Diabetic macular oedema and proliferative diabetic retinopathy are complications of diabetes, which could cause blindness. Thus, people with diabetic macular oedema and proliferative diabetic retinopathy need to be treated in a timely manner and reviewed in clinic for life. The population in the world is ageing. As a result, there are more people with eye diseases. There are also more treatments now for people with eye diseases. The workload in hospitals is increasing, making it difficult for the NHS to cope with the demand. There are not enough ophthalmologists (eye doctors) to look after patients. Delayed appointments and treatment mean that patients may lose sight. The goal of EMERALD (Effectiveness of Multimodal imaging for the Evaluation of Retinal oedema And new vesseLs in Diabetic retinopathy) was to see if patients with treated and stable diabetic macular oedema or proliferative diabetic retinopathy could be followed by 'ophthalmic graders', who are not doctors but are trained to diagnose diabetic macular oedema and proliferative diabetic retinopathy. In EMERALD, trained ophthalmic graders examined photographs of the back of the eye of people with diabetic macular oedema and proliferative diabetic retinopathy. They checked if diabetic macular oedema and proliferative diabetic retinopathy remain inactive. If so, patients could continue follow-up with the ophthalmic graders. If diabetic macular oedema or proliferative diabetic retinopathy were active, graders would immediately refer patients to ophthalmologists. EMERALD found that graders were excellent at detecting diabetic macular oedema, and this could give ophthalmologists time to see other patients. Graders were not quite as good at detecting active proliferative diabetic retinopathy. However, considering that patients had already had treatment, this may still be safe. Patients participating in focus group discussions mentioned that they would prefer to see ophthalmologists, so they could ask questions about their eye condition. If this was not possible, they would like to have immediate results from graders and still see the ophthalmologist from time to time.

Optical coherence tomography angiography for identifying choroidal neovascular membranes: a masked study in clinical practice.

BACKGROUND/OBJECTIVES: Optical coherence tomography angiography (OCT-A) allows non-invasive imaging of chorio-retinal vasculature, and is a potential alternative to fluorescein angiography (FA). Sensitivity and specificity of OCT-A for detecting choroidal neovascularisation (CNV) in treatment-naïve neovascular age-related macular degeneration (nAMD) patients is examined, using the Heidelberg Spectralis in a 'real world' setting. SUBJECT/METHODS: Overall, 43 eyes from 26 patients were included in the study. Spectral domain OCT (SD-OCT), OCT-A and FA images were obtained at baseline. Each of the three retinal image modalities was systematically assessed by three masked clinicians. Decisions about the presence/absence of CNV were recorded using an automated segmentation for OCT-A, a manual method, and using both OCT-A and SD-OCT in conjunction. Additional information about the presence of sub-retinal hyper-reflective material (SHRM) and the 'double layer sign' (DLS) were recorded. RESULTS: The average sensitivity and specificity of the OCT-A for the detection of CNV in treatment naïve AMD was 89% and 87% for the combined SD-OCT and OCT-A, 76% and 91% for the automated segmentation and 84% and 85% for the manual segmentation, respectively. Inter-clinician agreement was 0.59-65 kappa. In patients without CNV, SHRM was present in only 6% while DLS was present in 28%. Sensitivity and specificity was >78% for both SHRM and DLS. CONCLUSIONS: OCT-A provides a reliable tool for detecting CNV in treatment naïve nAMD patients, with high sensitivity and specificity. Combined use of SD-OCT images and SHRM as an additional bio-marker, OCT-A could become an alternative to FA in routine clinical practice.