Real-world service costs for neovascular-AMD clinics in the United Kingdom: structured literature review and scenario analysis.

OBJECTIVE: Current cost-effectiveness analyses (CEA) emphasize drug costs as the differentiator between NICE recommended anti-VEGF treatments but may neglect real-world non-drug costs of running nAMD services in the UK. To address this, this study identified real-world non-drug service cost items relevant to UK NHS nAMD clinics, including costs arising from operational strain (demand exceeding capacity). METHODS: Cost items were identified by a structured literature review of peer-reviewed and grey literature, and an expert panel of 10 UK-based ophthalmologists with relevance to real-world practice. These items underwent meta-synthesis and were then determined in a consensus exercise. RESULTS: Of 237 cost items identified, 217 (91.6%) met the consensus threshold of >0.51 and were included in the nAMD Service Non-Drug Cost Instrument (nAS). Sensitivity of cost items taken from UK Health Technology Assessment (HTA) using the nAS as the reference standard was low (HTAmin: 1.84%, 95% CI 0.50-4.65%; HTAmax: 70.51%, 95% CI 63.96-76.49%). False negative rates showed variable likelihood of misclassifying a service by cost burden depending on prevalence. Scenario analysis using cost magnitudes estimated annual per-patient clinic cost at £845 (within capacity) to £13,960 (under strain) compared to an HTAmin estimate of £210. Accounting for cost of strain under an assumed 50% increase in health resource utilization influenced cost-effectiveness in a hypothetical genericisation scenario. CONCLUSION: Findings suggested that HTA underestimates UK NHS nAMD clinic cost burden with cost of strain contributing substantial additional unmeasured expense with impact on CEA. Given potential undertreatment due to strain, durability is suggested as one of the relevant factors in CEA of nAMD anti-VEGF treatments due to robustness under limited capacity conditions affecting UK ophthalmology services.

When considering how well treatments work versus how much they cost, the focus is usually only on the price of the medicine itself. However, other real-world costs exist. In the UK, when treating certain eye problems such as neovascular age-related macular degeneration (nAMD), there are additional expenses related to running clinics and managing treatments that often go unnoticed. To get a better understanding of these hidden costs, the study examined factors like clinic workload and the extra expenses that come with it. Ten eye doctors in the UK were consulted for their expert opinions and numerous research papers were reviewed to identify these additional costs. The study grouped different costs in a tool called the nAMD Service Non-Drug Cost Instrument (nAS). When the findings of the nAS tool were compared to the usual methods of calculating costs, it was found that the conventional approach overlooked many of the actual expenses. Busy clinics face unique challenges, such as higher operational costs associated with staffing for extended hours, emergency appointments, extended waiting times and the potential to miss optimal treatment windows. This can lead to disease progression and the onset of comorbidities, which require more complex and costly treatments. Recognizing these real costs is crucial when making decisions about treatments, especially when treatments require more frequent visits to eye clinics. This study emphasizes the importance of considering all expenses, not just the obvious ones like medication and doctor visits when determining the most effective way to manage eye conditions like nAMD in the UK.

Treatment of age-related macular degeneration with aflibercept using a treat, extend and fixed protocol; A 4-year study of treatment outcomes, durability, safety and quality of life (An extension to the MATE randomised controlled trial).

PURPOSE: Data are limited pertaining to the long-term benefits of aflibercept treatment for neovascular age-related macular degeneration (nAMD). The aim of this study was to provide outcomes, safety, durability and quality-of-life data with aflibercept using a modified treat, extend and fixed regime over 4 years. METHODS: Prospective, multicentre, single cohort observational study of treatment-naïve nAMD participants treated with aflibercept as 2-year extension of the MATE-trial that compared early and late Treat-and-Extend for 2 years. Refracted ETDRS best corrected visual acuity (BCVA), central retinal thickness (CRT), treatment interval and adverse events were assessed. Quality-of-life was measured using the Macular Disease Dependent Quality of Life (MacDQoL) and Macular Disease Treatment Satisfaction Questionnaires (MacTSQ). RESULTS: Twenty-six of 40 participants completing the MATE-trial were enrolled with 20 completing the total 4-year study. Mean BCVA was 60.7 at Month 0 and 64.8 ETDRS letters at Month 48 while CRT decreased from 423.7 µm to 292.2 µm. Five participants discontinued treatment due to inactivity. The mean number of treatments and visits for the remaining participants was 27 and 30.0, respectively, with treatment intervals extended to 12 weeks in four participants at Month 48. Both AMD-specific QoL and treatment satisfaction remained stable between Months 0 and 48 and mean BCVA significantly correlated with AMD-specific QoL scores at Months 12, 24 and 48. CONCLUSIONS: Results suggest that BCVA can be maintained over 48 months when following a treat-extend-and-fix regimen of aflibercept with intervals out to 12 weeks, while maintaining AMD-specific QoL and treatment satisfaction.

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.

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.

Impact of direct-access IBD physician delivered endoscopy on clinical outcomes: a pre-implementation and post-implementation study.

Introduction: Patients with suspected inflammatory bowel disease (IBD) referred from primary care often face diagnostic and treatment delays. This study aimed to compare a novel direct-access IBD endoscopy pathway with the traditional care model. Method: Single centre real-world study analysing primary care referrals with suspected IBD. Group A: patients triaged to direct-access IBD endoscopy. Group B: patients undergoing traditional outpatient appointments before the availability of direct-access IBD endoscopy. Demographics, fecal calprotectin (FCP), C-reactive protein (CRP), disease activity score, endoscopy findings, treatment and follow-up were collected and statistically analysed. Ranked semantic analysis of IBD symptoms contained within referral letters was performed. Results: Referral letters did not differ significantly in Groups A and B. Demographic data, FCP and CRP values were similar. Referral to treatment time (RTT) at the time of IBD endoscopy was reduced from 177 days (Group B) to 24 days (Group A) (p<0.0001). Diagnostic yield of IBD was 35.6% (Group B) versus 62.0% (Group A) (p=0.0003). 89.2% of patients underwent colonoscopy in Group B versus 46.4% in Group A. DNA rates were similar in both groups. The direct to IBD endoscopy pathway saved 100% of initial IBD consultant clinics with a 2.5-fold increase in IBD nurse-led follow-up. Conclusion: Our novel pathway resulted in an 86% reduction in RTT with associated increased diagnostic yield while saving 100% of initial IBD consultant outpatient appointments. Replication in other trusts may improve patient experience and accelerate time to diagnosis/treatment while optimising the use of healthcare resources.

Patient Preferences in the Management of Wet Age-Related Macular Degeneration: A Conjoint Analysis.

INTRODUCTION: To identify patient preference drivers related to the management of wet age-related macular degeneration (wet AMD). METHODS: In this cross-sectional study, a self-explicated 'conjoint analysis' survey was administered online to eligible patients with wet AMD (receiving anti-vascular endothelial growth factor [VEGF] treatment for at least 12 months) from the USA, Canada, UK, France, Spain, Germany, Italy, Japan, Taiwan, and Australia. The survey consisted of six domains with 21 attributes, which were selected on the basis of a literature review, social media listening, and tele-interviews/discussions with patients, clinical experts, and patient groups. Utility and relative importance scores were generated for each attribute and utility difference significance testing was performed using 'unequal variances t tests'. The Patient Activation Measure (PAM-13) questionnaire was administered to assess patients' knowledge, skill, and confidence in self-management. RESULTS: A total of 466 patients (mean age, 68 years; women, 54%; binocular wet AMD, 28%) with an average anti-VEGF treatment duration of 3.9 years completed the survey. The most important preference domains were 'treatment effects on vision' (non-significant) and 'vision-related symptom burdens' (p < 0.001), followed by 'treatment risk' (p < 0.05), 'impact on daily activities' (p < 0.05), 'burden of clinic/hospital visits' (p < 0.001), and 'impact on psychological well-being'. The five most important attributes in order of importance were clarity of vision, treatment effect on symptoms, quality of vision, time to treatment effect, and time to re-administration. The two most important attributes globally were also in the top three attributes across countries. The majority of participants in the study were level 3 or level 4 of the PAM-13 questionnaire. CONCLUSIONS: This study identified the most important disease and treatment attributes to patients using patient-centred methods. The data showed the degree of harmonization of preferences across geographies and that participants actively adopt behaviours required for improved treatment outcomes. The identified preference drivers may inform future clinical development.

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.

Management of Crohn's disease in an immunosuppressed COVID-19-positive patient: safety-driven prioritisation of nutritional therapy as a bridge to restarting immunosuppression.

Active inflammatory bowel disease (IBD), combined immunosuppression and corticosteroid therapy have all been identified as risk factors for a poor outcome in COVID-19 infection. The management of patients with both COVID-19 infection and active IBD is therefore complex. We present the case of a 31-year-old patient with Crohn's disease, on dual immunosuppression with infliximab and mercaptopurine presenting with inflammatory small bowel obstruction and COVID-19 infection. The case highlights the use of nutritional therapy, which remains underused in the management of adults with IBD, to manage his flare acutely. Following negative SARS-CoV-2 PCR testing and SARS-CoV-2 IgG testing confirming an antibody response, ustekinumab (anti-interleukin 12/23) was prescribed for long-term maintenance.

Diabetic retinopathy and diabetic macular oedema pathways and management: UK Consensus Working Group.

The management of diabetic retinopathy (DR) has evolved considerably over the past decade, with the availability of new technologies (diagnostic and therapeutic). As such, the existing Royal College of Ophthalmologists DR Guidelines (2013) are outdated, and to the best of our knowledge are not under revision at present. Furthermore, there are no other UK guidelines covering all available treatments, and there seems to be significant variation around the UK in the management of diabetic macular oedema (DMO). This manuscript provides a summary of reviews the pathogenesis of DR and DMO, including role of vascular endothelial growth factor (VEGF) and non-VEGF cytokines, clinical grading/classification of DMO vis a vis current terminology (of centre-involving [CI-DMO], or non-centre involving [nCI-DMO], systemic risks and their management). The excellent UK DR Screening (DRS) service has continued to evolve and remains world-leading. However, challenges remain, as there are significant variations in equipment used, and reproducible standards of DMO screening nationally. The interphase between DRS and the hospital eye service can only be strengthened with further improvements. The role of modern technology including optical coherence tomography (OCT) and wide-field imaging, and working practices including virtual clinics and their potential in increasing clinic capacity and improving patient experiences and outcomes are discussed. Similarly, potential roles of home monitoring in diabetic eyes in the future are explored. The role of pharmacological (intravitreal injections [IVT] of anti-VEGFs and steroids) and laser therapies are summarised. Generally, IVT anti-VEGF are offered as first line pharmacologic therapy. As requirements of diabetic patients in particular patient groups may vary, including pregnant women, children, and persons with learning difficulties, it is important that DR management is personalised in such particular patient groups. First choice therapy needs to be individualised in these cases and may be intravitreal steroids rather than the standard choice of anti-VEGF agents. Some of these, but not all, are discussed in this document.

Recommendations by a UK expert panel on an aflibercept treat-and-extend pathway for the treatment of neovascular age-related macular degeneration.

OBJECTIVES: This report aims to provide clear recommendations and practical guidance from a panel of UK retinal experts on an aflibercept treat-and-extend (T&E) pathway that can be implemented in clinical practice. These recommendations may help service providers across the NHS intending to implement a T&E approach, with the aim of effectively addressing the capacity and resource issues putting strain on UK neovascular age-related macular degeneration (nAMD) services while promoting patients' best interests throughout. METHODS: Two structured roundtable meetings of retinal specialists were held in London, UK on 7 December 2018 and 1 March 2019. These meetings were organised and funded by Bayer. RESULTS: The panel provided recommendations for an aflibercept T&E pathway and developed specific criteria based on visual acuity, retinal morphology and optical coherence tomography imaging to guide reduction, maintenance and extension of injection intervals. They also discussed the extension of treatment intervals by 2- or 4-week adjustments to a maximum treatment interval of 16 weeks, the management of retinal fluid and the stopping of treatment. CONCLUSIONS: The long-term benefits of implementing a T&E pathway may include superior visual outcomes compared with a pro re nata (PRN; as needed) protocol, and a lower treatment burden compared with a fixed protocol, which is likely to improve service capacity. Furthermore, the predictable nature of a T&E approach compared with a PRN service may aid capacity planning for the future nAMD treatment demand.

Direct Ophthalmic Healthcare Resource Use among Patients with Geographic Atrophy in a Large Cohort from the United Kingdom.

PURPOSE: To estimate the direct ophthalmic healthcare resource use in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). DESIGN: Retrospective analysis of anonymized data derived from electronic medical records (EMRs) acquired at 10 clinical sites in the United Kingdom. PARTICIPANTS: Patients aged ≥50 years with ≥1 eye with a clinical record of GA or, for comparison, bilateral early/intermediate AMD. Four subgroups were identified: GA in both eyes (GA:GA); GA in 1 eye, choroidal neovascularization (CNV) in the fellow eye (GA:CNV); GA in 1 eye with early or intermediate AMD in the fellow eye (GA:E); and early/intermediate AMD in both eyes (E:E). METHODS: The EMRs were analyzed to derive the median number of visits over the first 2 years after diagnosis of GA or early/intermediate AMD. Clinical tests recorded at visits were used to calculate estimated costs (payer perspective) of monitoring. Analyses were restricted to patients with an initial diagnosis on or after January 1, 2011, to represent present day monitoring and costs associated with AMD. MAIN OUTCOME MEASURES: Median number of visits and estimated monitoring costs per patient (in £) over the first 2 years among patients with ≥2 years of follow-up and in the individual subgroups. Intravitreal treatment costs in the GA:CNV group were excluded. RESULTS: For all 3 GA subgroups (n = 1080), the median number of visits over the first 2 years was 5, and monitoring costs were £460.80 per patient. The GA:CNV subgroup (n = 355) had the highest number of visits (median, 15), with a cost of £1581, compared with the GA:E subgroup (n = 283; median 4 visits; cost ∼£369) and the GA:GA subgroup (n = 442; median 3 visits; cost ∼£277). Ophthalmic tests were conducted most frequently in the GA:CNV subgroup. Visits and costs in the E:E subgroup (n = 6079) were lower. CONCLUSIONS: Resource use in patients with GA varies considerably and is strongly influenced by the concomitant presence of CNV and lack of monitoring strategies for GA.

Action on neovascular age-related macular degeneration (nAMD): recommendations for management and service provision in the UK hospital eye service.

This report by a group of UK retina specialists and health professionals considers best practice recommendations for the management of sight-threatening neovascular age-related macular degeneration (nAMD), based on collective experience and expertise in routine clinical practice. The authors provide an update for ophthalmologists, allied healthcare professionals and commissioners on practice principles for optimal patient care and service provision standards. Refinement of care pathways for nAMD has improved access to intravitreal anti-vascular endothelial growth factor therapy but there are still variations in care and reported outcomes between clinic centres. Innovative organisational models of service provision allow providers to better match capacity with increasing demand. The authors review the recent NICE guideline for diagnosis and management of AMD, considerations for switching therapies and stopping treatment and need for regular monitoring of non-affected fellow eyes in patients with unilateral nAMD. Actions for delivery of high-quality care and to improve long-term patient outcomes are discussed. Local pathways need to detail nAMD target time to treat, maintenance of review intervals to ensure proactive treatment regimens are delivered on time and appropriate discharge for patients deemed low risk or no longer benefiting from treatment. Actual visual acuity outcomes achieved and maintenance of the level of vision when disease stability is achieved are considered good measures for judging the quality of care in the treatment of patients with nAMD. Robust community referral pathways must be in place for suspected reactivation of choroidal neovascularisation and rapid referral for second eye involvement. Practical considerations for intravitreal injection therapy are outlined.

Diabetic macular oedema and diode subthreshold micropulse laser (DIAMONDS): study protocol for a randomised controlled trial.

BACKGROUND: In the UK, macular laser is the treatment of choice for people with diabetic macular oedema with central retinal subfield thickness (CST) < 400 µm, as per National Institute for Health and Care Excellence guidelines. It remains unclear whether subthreshold micropulse laser is superior and should replace standard threshold laser for the treatment of eligible patients. METHODS: DIAMONDS is a pragmatic, multicentre, allocation-concealed, randomised, equivalence, double-masked clinical trial that aims to determine the clinical effectiveness and cost-effectiveness of subthreshold micropulse laser compared with standard threshold laser, for the treatment of diabetic macular oedema with CST < 400 µm. The primary outcome is the mean change in best-corrected visual acuity in the study eye from baseline to month 24 post treatment. Secondary outcomes (at 24 months) include change in binocular best corrected visual acuity; CST; mean deviation of the Humphrey 10-2 visual field; change in percentage of people meeting driving standards; European Quality of Life-5 Dimensions, National Eye Institute Visual Functioning Questionnaire-25 and VisQoL scores; incremental cost per quality-adjusted life year gained; side effects; number of laser treatments and use of additional therapies. The primary statistical analysis will be per protocol rather than intention-to-treat analysis because the latter increases type I error in non-inferiority or equivalence trials. The difference between lasers for change in best-corrected visual acuity (using 95% CI) will be compared to the permitted maximum difference of five Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Linear and logistic regression models will be used to compare outcomes between treatment groups. A Markov-model-based cost-utility analysis will extend beyond the trial period to estimate longer-term cost-effectiveness. DISCUSSION: This trial will determine the clinical effectiveness and cost-effectiveness of subthreshold micropulse laser, when compared with standard threshold laser, for the treatment of diabetic macular oedema, the main cause of sight loss in people with diabetes mellitus. TRIAL REGISTRATION: International Standard Randomised Controlled Trials, ISRCTN17742985 . Registered on 19 May 2017 (retrospectively registered).

Randomised trial of wide-field guided PRP for diabetic macular oedema treated with ranibizumab.

BACKGROUND: Diabetic macular oedema (DMO) is effectively treated with ranibizumab but multiple injections are required. Where there is also peripheral ischaemia, it has been promoted that targeted panretinal photocoagulation (PRP) may reduce the number of injections. METHOD: Patients with optical coherence tomography confirmed DMO and Ultra-widefield Fundus Fluorescein Angiography confirmed peripheral retinal ischaemia were randomised to PRP plus ranibizumab or ranibizumab monotherapy. After three injections, repeat injections were given until the visual acuity was stable and the macula was dry. Re-treatment was given if there was a drop of visual acuity and/or a recurrence of intra-retinal fluid. The primary outcome was the number of repeat injections required after the first 6 months up until 1 year. RESULTS: There were 49 patients, 25 in the ranibizumab only group and 24 in the ranibizumab + PRP group recruited at seven UK sites. The average number of injections in the ranibizumab-only arm was 6.84 over 1 year and 2.52 between months 6 and 12. The average number of injections in the combined arm was 6.67, with the number of injections in the second 6 months 1.92. For the primary outcome, comparing the number of 6- to 12-month injections, the result was not statistically significant (p = 0.33). CONCLUSION: The addition of targeted PRP to areas of non-perfusion in a patient with DMO does not reduce the number of injections required in the first year. It seems most likely that local VEGF at the macula is the main cause of DMO.

United Kingdom Diabetic Retinopathy Electronic Medical Record (UK DR EMR) Users Group: report 4, real-world data on the impact of deprivation on the presentation of diabetic eye disease at hospital services.

AIM: To assess the impact of deprivation on diabetic retinopathy presentation and related treatment interventions, as observed within the UK hospital eye service. METHODS: This is a multicentre, national diabetic retinopathy database study with anonymised data extraction across 22 centres from an electronic medical record system. The following were the inclusion criteria: all patients with diabetes and a recorded, structured diabetic retinopathy grade. The minimum data set included, for baseline, age and Index of Multiple Deprivation, based on residential postcode; and for all time points, visual acuity, ETDRS grading of retinopathy and maculopathy, and interventions (laser, intravitreal therapies and surgery). The main  outcome measures were (1) visual acuity and binocular visual state, and (2) presence of sight-threatening complications and need for early treatment. RESULTS: 79 775 patients met the inclusion criteria. Deprivation was associated with later presentation in patients with diabetic eye disease: the OR of being sight-impaired at entry into the hospital eye service (defined as 6/18 to better than 3/60 in the better seeing eye) was 1.29 (95% CI 1.20 to 1.39) for the most deprived decile vs 0.77 (95% CI 0.70 to 0.86) for the least deprived decile; the OR for being severely sight-impaired (3/60 or worse in the better seeing eye) was 1.17 (95% CI 0.90 to 1.55) for the most deprived decile vs 0.88 (95% CI 0.61 to 1.27) for the least deprived decile (reference=fifth decile in all cases). There is also variation in sight-threatening complications at presentation and treatment undertaken: the least deprived deciles had lower chance of having a tractional retinal detachment (OR=0.48 and 0.58 for deciles 9 and 10, 95% CI 0.24 to 0.90 and 0.29 to 1.09, respectively); in terms of accessing treatment, the rate of having a vitrectomy was lowest in the most deprived cohort (OR=0.34, 95% CI 0.19 to 0.58). CONCLUSIONS: This large real-world study suggests that first presentation at a hospital eye clinic with visual loss or sight-threatening diabetic eye disease is associated with deprivation. These initial hospital visits represent the first opportunities to receive treatment and to formally engage with support services. Such patients are more likely to be sight-impaired or severely sight-impaired at presentation, and may need additional resources to engage with the hospital eye services over complex treatment schedules.

VISUAL ACUITY IMPROVEMENT WHEN SWITCHING FROM RANIBIZUMAB TO AFLIBERCEPT IS NOT SUSTAINED.

PURPOSE: To assess whether visual benefits exist in switching to aflibercept in patients who have been chronically treated with ranibizumab for neovascular age-related macular degeneration. METHODS: A multicenter, national, electronic medical record database study was performed. Patients undergoing six continuous monthly ranibizumab injections and then switched to continuous aflibercept were matched to those on continuous ranibizumab therapy. Matching was performed in a 2:1 ratio and based on visual acuity 6 months before and at the time of the switch, and the number of previous ranibizumab injections. RESULTS: Patients who were switched to aflibercept demonstrated transiently significant improvement in visual acuity that peaked at an increase of 0.9 Early Treatment Diabetic Retinopathy Study letters 3 months after the switch, whereas control patients continued on ranibizumab treatment showed a steady decline in visual acuity. Visual acuity differences between the groups were significant (P < 0.05) at 2, 3, and 5 months after the switch. Beginning at 4 months after the switch, the switch group showed a visual acuity decline similar to the control group. CONCLUSION: Transient, nonsustained improvement in visual acuity occurs when switching between anti-vascular endothelial growth factor agents, which may have implications in treating patients on chronic maintenance therapy on one anti-vascular endothelial growth factor medication.

CLINICAL EVIDENCE OF THE MULTIFACTORIAL NATURE OF DIABETIC MACULAR EDEMA.

PURPOSE: To report functional and morphologic outcomes, based on diabetic macular edema (DME) chronicity and baseline best-corrected visual acuity (BCVA), from a subanalysis of the fluocinolone acetonide for macular edema (FAME) trials. METHODS: Patients were categorized by DME duration (nonchronic [ncDME] or chronic [cDME] DME) and three nonexclusive baseline vision strata. Anatomic and visual acuity VA outcomes of these cohorts were compared with treatment assignment. RESULTS: For all patients with ncDME and cDME who received sham control, 27.8% and 13.4%, respectively, gained ≥15 BCVA letters, whereas 22.3% and 34.0% of 0.2 µg/day fluocinolone acetonide (FAc)-treated patients, respectively, gained ≥15 BCVA letters. Among patients with ncDME who received sham control, as baseline vision decreased, the percentage gaining ≥15 BCVA letters increased; however, among those with cDME, the percentage gaining ≥15 BCVA letters did not change as baseline vision decreased. Conversely, among 0.2 µg/day FAc-treated patients, the percentage gaining ≥15 BCVA letters increased with decreasing baseline vision, regardless of DME chronicity. Anatomical outcomes were similar within treatment arms, regardless of the DME duration. CONCLUSION: Patients with cDME and poor baseline vision who were exposed to low-dose FAc experienced BCVA improvements that were not observed in a similar group from the sham-control arm. These data support the multifactorial pathogenesis of cDME.

Defects in the Cell Signaling Mediator ß-Catenin Cause the Retinal Vascular Condition FEVR.

Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder characterized by the abnormal development of the retinal vasculature. The majority of mutations identified in FEVR are found within four genes that encode the receptor complex (FZD4, LRP5, and TSPAN12) and ligand (NDP) of a molecular pathway that controls angiogenesis, the Norrin-ß-catenin signaling pathway. However, half of all FEVR-affected case subjects do not harbor mutations in these genes, indicating that further mutated genes remain to be identified. Here we report the identification of mutations in CTNNB1, the gene encoding ß-catenin, as a cause of FEVR. We describe heterozygous mutations (c.2142_2157dup [p.His720∗] and c.2128C>T [p.Arg710Cys]) in two dominant FEVR-affected families and a de novo mutation (c.1434_1435insC [p.Glu479Argfs∗18]) in a simplex case subject. Previous studies have reported heterozygous de novo CTNNB1 mutations as a cause of syndromic intellectual disability (ID) and autism spectrum disorder, and somatic mutations are linked to many cancers. However, in this study we show that Mendelian inherited CTNNB1 mutations can cause non-syndromic FEVR and that FEVR can be a part of the syndromic ID phenotype, further establishing the role that ß-catenin signaling plays in the development of the retinal vasculature.

The UK Diabetic Retinopathy Electronic Medical Record (UK DR EMR) Users Group, Report 2: real-world data for the impact of cataract surgery on diabetic macular oedema.

AIM: To assess the rate of 'treatment-requiring diabetic macular oedema (DMO)' in eyes for the two years before and after cataract surgery. METHODS: Multicentre national diabetic retinopathy (DR) database study with anonymised data extraction across 19 centres from an electronic medical record system. INCLUSION CRITERIA: eyes undergoing cataract surgery in patients with diabetes with no history of DMO prior to study start. The minimum dataset included: age, visual acuity (all time-points), injection episodes, timing of cataract surgery and ETDRS grading of retinopathy and maculopathy. MAIN OUTCOME MEASURE: rate of developing first episode of treatment-requiring DMO in relation to timing of cataract surgery in the same eye. RESULTS: 4850 eyes met the inclusion criteria. The rate of developing treatment-requiring DMO in this cohort was 2.9% in the year prior to surgery versus 5.3% in the year after surgery (p<0.01). The risk of 'treatment-requiring DMO' increased sharply after surgery, peaking in the 3-6 months' period (annualised rates of 5.2%, 6.8%, 5.6% and 4.0% for the 0-3, 3-6, 6-9 and 9-12 months' post-operative time periods respectively). Risk was associated with pre-operative grade of retinopathy: risk of DMO in the first year post-operatively being 1.0% (no DR pre-operatively), 5.4% (mild non-proliferative diabetic retinopathy; NPDR), 10.0% (moderate NPDR), 13.1% (severe NPDR) and 4.9% (PDR) (p<0.01). CONCLUSIONS: This large real-world study demonstrates that the rate of developing treatment-requiring DMO increases sharply in the year after cataract surgery for all grades of retinopathy, peaking in the 3-6 months' postoperative period. Patients with moderate and severe NPDR are at particularly high risk.