Stereotactic radiotherapy for neovascular age-related macular degeneration (STAR): a pivotal, randomised, double-masked, sham-controlled device trial.

BACKGROUND: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The first-line therapy is anti-vascular endothelial growth factor (anti-VEGF) agents delivered by intravitreal injection. Ionising radiation mitigates key pathogenic processes underlying nAMD, and therefore has therapeutic potential. STAR aimed to assess whether stereotactic radiotherapy (SRT) reduces the number of anti-VEGF injections required, without sacrificing visual acuity. METHODS: This pivotal, randomised, double-masked, sham-controlled trial enrolled participants with pretreated chronic active nAMD from 30 UK hospitals. Participants were randomly allocated in a 2:1 ratio to 16-Gray (Gy) SRT delivered using a robotically controlled device or sham SRT, stratified by treatment centre. Eligible participants were aged 50 years or older and had chronic active nAMD, with at least three previous anti-VEGF injections, including at least one in the last 4 months. Participants and all trial and image reading centre staff were masked to treatment allocation, except one unmasked statistician. The primary outcome was the number of intravitreal ranibizumab injections required over 2 years, tested for superiority (fewer injections). The main secondary outcome was Early Treatment Diabetic Retinopathy Study visual acuity at two years, tested for non-inferiority (five-letter margin). The primary analysis used the intention-to-treat principle, and safety was analysed per-protocol on participants with available data. The study is registered with ClinicalTrials.gov (NCT02243878) and is closed for recruitment. FINDINGS: 411 participants enrolled between Jan 1, 2015, and Dec 27, 2019, and 274 were randomly allocated to the 16-Gy SRT group and 137 to the sham SRT group. 240 (58%) of all participants were female, and 171 (42%) of all participants were male. 241 participants in the 16-Gy SRT group and 118 participants in the sham group were included in the final analysis, and 409 patients were treated and formed the safety population, of whom two patients allocated to sham treatment erroneously received 16-Gy SRT. The SRT group received a mean of 10·7 injections (SD 6·3) over 2 years versus 13·3 injections (5·8) with sham, a reduction of 2·9 injections after adjusting for treatment centre (95% CI -4·2 to -1·6, p<0·0001). The SRT group best-corrected visual acuity change was non-inferior to sham (adjusted mean letter loss difference between groups, -1·7 letters [95% CI -4·2 to 0·8]). Adverse event rates were similar across groups, but reading centre-detected microvascular abnormalities occurred in 77 SRT-treated eyes (35%) and 13 (12%) sham-treated eyes. Overall, eyes with microvascular abnormalities tended to have better best-corrected visual acuity than those without. Fewer ranibizumab injections offset the cost of SRT, saving a mean of £565 per participant (95% CI -332 to 1483). INTERPRETATION: SRT can reduce ranibizumab treatment burden without compromising vision. FUNDING: Medical Research Council and National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme.

Three-year outcomes of an optometrist-led virtual clinic for new glaucoma referrals.

INTRODUCTION: The purpose of this study was to describe and evaluate the outcomes of an optometrist-led virtual glaucoma clinic (VGC). METHODS: New patients referred to the glaucoma service who were consultant triaged as 'low risk' were assessed virtually by specialist-trained optometrists in the VGC and either discharged or monitored for a period of 3 years. Ten percent of virtual case notes were audited by a glaucoma consultant to verify quality and generate learning objectives. Retrospective case-note review and analysis of all patients seen in the virtual clinic between 2014 and 2016 was undertaken to determine 3-year outcomes. RESULTS: A total of 1710 new patients were seen in the clinic between 1 January 2014 and 31 December 2016. Of these, 1033 (60.4%) patients required no outpatient input in 3 years of follow-up. Additionally, 320 (18.7%) were discharged at the first visit, and the proportion of glaucoma suspect and ocular hypertension patients who converted to glaucoma was 12.1% and 5.8%, respectively. At 3 years, 95 patients had died, 159 were lost to follow-up, 576 were discharged and 371 were diagnosed with glaucoma at baseline or during the 3-year follow-up. The cumulative discharge proportion from the service at the end of 3 years was 82.6%. No patients required emergency eye treatment or sight-impairment registration, and of the 12 referred back to the clinic on discharge, only five required ongoing monitoring. CONCLUSION: This optometrist-led VGC combined two aspects of novel service delivery to reduce the burden of glaucoma monitoring in outpatient departments and consolidate consultant contact to patients requiring more intervention. This model will be of value in units establishing virtual services and looking to expand the role of allied health professionals.

Referrals for proliferative diabetic retinopathy from two UK diabetic retinopathy screening services: a 10-year analysis of visual outcomes, requirement for vitrectomy, and mortality.

BACKGROUND/OBJECTIVES: To determine long-term outcomes of patients referred with proliferative diabetic retinopathy (PDR) from diabetic eye screening programmes (DESP) to tertiary care centres in the United Kingdom (UK). METHODS: Retrospective multicentre study of patients referred from two DESPs in the UK over a 36-month period (2007-9) and followed-up for 10 years. Critical outcomes included severe vision loss (SVL) and the need for vitrectomy. Other outcomes assessed included moderate vision loss (MVL), and patient survival time. Univariate and multiple variable Cox proportional hazards regressions were used to analyse survival outcomes. RESULTS: 212 eyes of 150 patients were referred with a diagnosis of PDR. 109 eyes of 72 patients were confirmed to have active PDR and included in the study. 61% of patients had low-risk PDR, while 39% exhibited high-risk features in at least one eye. Eight (7.3%) eyes developed SVL and 16 (14.7%) MVL during follow up. Vitrectomy was required in 24% (95% CI: 15 to 31%) of all PDR eyes and was most commonly performed for vitreous haemorrhage (65%). The 10-year survival in all PDR patients was 76% (95% CI: 63 to 85%) with the mean time to death for all deceased patients being 5.4 ± 3.6 years. On multivariable analysis, only age was found to have a significant association with the survival of patients with PDR. CONCLUSIONS: During the 10 year follow up SVL was uncommon, but MVL occurred in almost one-fifth of the eyes. Approximately 1 in 4 eyes required vitrectomy, highlighting its significance in patient management.

A Systematic Review of Clinical Practice Guidelines for Cataract: Evidence to Support the Development of the WHO Package of Eye Care Interventions.

The World Health Organization (WHO) is developing a Package of Eye Care Interventions (PECI) to facilitate the integration of eye care into Universal Health Coverage. This paper presents the results of a systematic review of clinical practice guidelines for cataract in adults, to help inform PECI development. We searched academic and guideline databases, and websites of professional associations, for guidelines published between January 2010 and April 2020. Guidelines were excluded if there was commercial funding or unmanaged conflicts of interest. Quality appraisal was conducted using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool. We identified 3778 reports, 35 related to cataract guidelines, four of which met the inclusion criteria (United Kingdom: 2, United States: 1, Iran: 1). The recommendations across the four guidelines covered pre-operative (43%), intra-operative (37%), and post-operative interventions (20%). Most 'strong' recommendations were supported by good quality evidence. Differences in recommendations across guidelines may be attributable to time of publication or regional differences in surgical practice. Few guidelines met the quality criteria, and only three countries were represented. The results of this step of the PECI development process will inform subsequent phases for development of the WHO's package of evidence-based eye care interventions for cataract.

Vitrectomy, subretinal Tissue plasminogen activator and Intravitreal Gas for submacular haemorrhage secondary to Exudative Age-Related macular degeneration (TIGER): study protocol for a phase 3, pan-European, two-group, non-commercial, active-control, observer-masked, superiority, randomised controlled surgical trial.

BACKGROUND: Neovascular (wet) age-related macular degeneration (AMD) can be associated with large submacular haemorrhage (SMH). The natural history of SMH is very poor, with typically marked and permanent loss of central vision in the affected eye. Practice surveys indicate varied management approaches including observation, intravitreal anti-vascular endothelial growth factor therapy, intravitreal gas to pneumatically displace SMH, intravitreal alteplase (tissue plasminogen activator, TPA) to dissolve the clot, subretinal TPA via vitrectomy, and varying combinations thereof. No large, published, randomised controlled trials have compared these management options. METHODS: TIGER is a phase 3, pan-European, two-group, active-control, observer-masked, superiority, randomised controlled surgical trial. Eligible participants have large, fovea-involving SMH of no more than 15 days duration due to treatment-naïve or previously treated neovascular AMD, including idiopathic polypoidal choroidal vasculopathy and retinal angiomatous proliferation. A total of 210 participants are randomised in a 1:1 ratio to pars plana vitrectomy, off-label subretinal TPA up to 25 µg in 0.25 ml, intravitreal 20% sulfahexafluoride gas and intravitreal aflibercept, or intravitreal aflibercept monotherapy. Aflibercept 2 mg is administered to both groups monthly for 3 doses, then 2-monthly to month 12. The primary efficacy outcome is the proportion of participants with best-corrected visual acuity (BCVA) gain of ≥ 10 Early Treatment Diabetic Retinopathy (ETDRS) letters in the study eye at month 12. Secondary efficacy outcomes (at 6 and 12 months unless noted otherwise) are proportion of participants with a BCVA gain of ≥ 10 ETDRS letters at 6 months, mean ETDRS BCVA, Radner maximum reading speed, National Eye Institute 25-item Visual Function Questionnaire composite score, EQ-5D-5L with vision bolt-on score, Short Warwick and Edinburgh Mental Wellbeing score, scotoma size on Humphrey field analyser, and presence/absence of subfoveal fibrosis and/or atrophy and area of fibrosis/atrophy using independent reading centre multimodal image analysis (12 months only). Key safety outcomes are adverse events, serious adverse events, and important medical events, coded using the Medical Dictionary for Regulatory Activities Preferred Terms. DISCUSSION: The best management of SMH is unknown. TIGER aims to establish if the benefits of SMH surgery outweigh the risks, relative to aflibercept monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT04663750 ; EudraCT: 2020-004917-10.

Association between vision impairment and mortality: a systematic review and meta-analysis.

BACKGROUND: The number of individuals with vision impairment worldwide is increasing because of an ageing population. We aimed to systematically identify studies describing the association between vision impairment and mortality, and to assess the association between vision impairment and all-cause mortality. METHODS: For this systematic review and meta-analysis, we searched MEDLINE (Ovid), Embase, and Global Health database on Feb 1, 2020, for studies published in English between database inception and Feb 1, 2020. We included prospective and retrospective cohort studies that measured the association between vision impairment and all-cause mortality in people aged 40 years or older who were followed up for 1 year or more. In a protocol amendment, we also included randomised controlled trials that met the same criteria as for cohort studies, in which the association between visual impairment and mortality was independent of the study intervention. Studies that did not report age-adjusted mortality data, or that focused only on populations with specific health conditions were excluded. Two reviewers independently assessed study eligibility, extracted the data, and assessed risk of bias. We graded the overall certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations framework. We did a random-effects meta-analysis to calculate pooled maximally adjusted hazard ratios (HRs) for all-cause mortality for individuals with a visual acuity of <6/12 versus those with ≥6/12; <6/18 versus those with ≥6/18; <6/60 versus those with ≥6/18; and <6/60 versus those with ≥6/60. FINDINGS: Our searches identified 3845 articles, of which 28 studies, representing 30 cohorts (446 088 participants) from 12 countries, were included in the systematic review. The meta-analysis included 17 studies, representing 18 cohorts (47 998 participants). There was variability in the methods used to assess and report vision impairment. Pooled HRs for all-cause mortality were 1·29 (95% CI 1·20-1·39) for visual acuity <6/12 versus ≥6/12, with low heterogeneity between studies (n=15; τ2=0·01, I2=31·46%); 1·43 (1·22-1·68) for visual acuity <6/18 versus ≥6/18, with low heterogeneity between studies (n=2; τ2=0·0, I2=0·0%); 1·89 (1·45-2·47) for visual acuity <6/60 versus ≥6/18 (n=1); and 1·02 (0·79-1·32) for visual acuity <6/60 versus ≥6/60 (n=2; τ2=0·02, I2=25·04%). Three studies received an assessment of low risk of bias across all six domains, and six studies had a high risk of bias in one or more domains. Effect sizes were greater for studies that used best-corrected visual acuity compared with those that used presenting visual acuity as the vision assessment method (p=0·0055), but the effect sizes did not vary in terms of risk of bias, study design, or participant-level factors (ie, age). We judged the evidence to be of moderate certainty. INTERPRETATION: The hazard for all-cause mortality was higher in people with vision impairment compared with those that had normal vision or mild vision impairment, and the magnitude of this effect increased with more severe vision impairment. These findings have implications for promoting healthy longevity and achieving the Sustainable Development Goals. FUNDING: Wellcome Trust, Commonwealth Scholarship Commission, National Institutes of Health, Research to Prevent Blindness, the Queen Elizabeth Diamond Jubilee Trust, Moorfields Eye Charity, National Institute for Health Research, Moorfields Biomedical Research Centre, Sightsavers, the Fred Hollows Foundation, the Seva Foundation, the British Council for the Prevention of Blindness, and Christian Blind Mission.

Are we advancing universal health coverage through cataract services? Protocol for a scoping review.

INTRODUCTION: Universal health coverage (UHC) includes the dimensions of equity in access, quality services that improve health and protection against financial hardship. Cataract continues to be the leading cause of blindness globally, despite cataract surgery being an efficacious intervention. The aim of this scoping review is to map the nature, extent and global distribution of data on cataract services for UHC in terms of equity, access, quality and financial protection. METHODS AND ANALYSIS: The search will be constructed by an Information Specialist and undertaken in MEDLINE, Embase and Global Health databases. We will include all published non-interventional primary research studies and systematic reviews that report a quantitative assessment of access, equity, quality or financial protection of cataract surgical services for adults at the subnational, national, regional or global level from population-based surveys or routinely collected health service data since 1 January 2000 and published through to February 2020.Screening and data charting will be undertaken using Covidence systematic review software. Titles and abstracts of identified studies will be screened by two authors independently. Full-text articles of potentially relevant studies will be obtained and reviewed independently by two authors against the inclusion criteria. Any discrepancies between the authors will be resolved by discussion, and with a third author as necessary. A data charting form will be developed and piloted on three studies by three authors and amendments made as necessary. Data will be extracted by two reviewers independently and summarised narratively and using maps. ETHICS AND DISSEMINATION: Ethical approval was not sought as the scoping review will only use published and publicly accessible data. The review will be published in an open access peer-reviewed journal. A summary of the results will be developed for website posting, stakeholder meetings and inclusion in the ongoing Lancet Global Health Commission on Global Eye Health.

Association between vision impairment and mortality: protocol for a systematic review and meta-analysis.

INTRODUCTION: Due to growth and ageing of the world's population, the number of individuals worldwide with vision impairment (VI) and blindness is projected to increase rapidly over the coming decades. VI and blindness are an important cause of years lived with disability. However, the association of VI and blindness with mortality, including the risk of bias in published studies and certainty of the evidence, has not been adequately studied in an up-to-date systematic review and meta-analysis. METHODS AND ANALYSIS: The planned systematic review and meta-analysis will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Databases, including MEDLINE Ovid, Embase Ovid and Global Health, will be searched for relevant studies. Two reviewers will then screen studies and review full texts to identify studies for inclusion. Data extraction will be performed, and for included studies, the risk of bias and certainty of the evidence will be assessed using the Grades of Recommendation, Assessment, Development and Evaluation approach. The prognostic factor in this study is visual function, which must have been measured using a standard objective ophthalmic clinical or research instrument. We will use standard criteria from WHO to categorise VI and blindness. All-cause mortality may be assessed by any method one or more years after baseline assessment of vision. Results from included studies will be meta-analysed according to relevant sections of the Meta-analysis Of Observational Studies in Epidemiology checklist. ETHICS AND DISSEMINATION: This review will only include published data; therefore, ethics approval will not be sought. The findings of this review and meta-analysis will be published in an open-access, peer-reviewed journal and will be included in the ongoing Lancet Global Health Commission on Global Eye Health.

Changes in quality of life shortly after routine cataract surgery.

OBJECTIVE: To perform a pilot study to explore use of a generic patient-reported outcome measure to assess patient-perceived improvements in quality of life within 2-4 weeks of routine cataract surgery and to explore differences after first or second eye surgery. Secondary analysis explored effects of gender and ethnicity. DESIGN: Prospective observational study. PARTICIPANTS: Consecutive patients attending a weekly nurse-led postoperative clinic. METHODS: The Glasgow Benefit Inventory (GBI), a validated, postinterventional questionnaire (not specific to one particular medical or surgical intervention), was administered. Mean scores were calculated. Scores were compared when patients were grouped by first or second eye, and by gender or ethnicity (unpaired t test). Scores potentially range from +100 (maximum benefit) to -100 (maximum detriment). RESULTS: The GBI was administered 113 times to 109 patients (4 patients were seen after both first and second eye surgery). Mean overall score was +22.8 (median +19.4; SD 19.7; 95% CI +19.2 to +26.4). Mean (SD) subscores were +30.5 (25.3), +17.8 (26.7), and -3.1 (19.9) for general, social support, and physical health subdomains, respectively. Total benefit scores were not significantly different for first or second eye surgery, or across gender (p > 0.3). Scores for patients of African (including African Caribbean) ethnicity were significantly higher than those obtained from European patients (p = 0.002). CONCLUSIONS: Patients reported significant improvements in quality of life even a few weeks after cataract surgery, as assessed by the GBI. Second eye surgery appeared to confer similar benefit to first eye surgery. The significant difference in scores between ethnic groups invites further investigation.