Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial

Background: Treatments for open-angle glaucoma aim to prevent vision loss through lowering of intraocular pressure, but to our knowledge no placebo-controlled trials have assessed visual function preservation, and the observation periods of previous (unmasked) trials have typically been at least 5 years. We assessed vision preservation in patients given latanoprost compared with those given placebo. Methods: In this randomised, triple-masked, placebo-controlled trial, we enrolled patients with newly diagnosed open-angle glaucoma at ten UK centres (tertiary referral centres, teaching hospitals, and district general hospitals). Eligible patients were randomly allocated (1:1) with a website-generated randomisation schedule, stratified by centre and with a permuted block design, to receive either latanoprost 0·005% (intervention group) or placebo (control group) eye drops. Drops were administered from identical bottles, once a day, to both eyes. The primary outcome was time to visual field deterioration within 24 months. Analyses were done in all individuals with follow-up data. The Data and Safety Monitoring Committee (DSMC) recommended stopping the trial on Jan 6, 2011 (last patient visit July, 2011), after an interim analysis, and suggested a change in primary outcome from the difference in proportions of patients with incident progression between groups to time to visual field deterioration within 24 months. This trial is registered, number ISRCTN96423140. Findings: We enrolled 516 individuals between Dec 1, 2006, and March 16, 2010. Baseline mean intraocular pressure was 19·6 mm Hg (SD 4·6) in 258 patients in the latanoprost group and 20·1 mm Hg (4·8) in 258 controls. At 24 months, mean reduction in intraocular pressure was 3·8 mm Hg (4·0) in 231 patients assessed in the latanoprost group and 0·9 mm Hg (3·8) in 230 patients assessed in the placebo group. Visual field preservation was significantly longer in the latanoprost group than in the placebo group: adjusted hazard ratio (HR) 0·44 (95% CI 0·28–0·69; p=0·0003). We noted 18 serious adverse events, none attributable to the study drug. Interpretation: This is the first randomised placebo-controlled trial to show preservation of the visual field with an intraocular-pressure-lowering drug in patients with open-angle glaucoma. The study design enabled significant differences in vision to be assessed in a relatively short observation period

Light path-length distributions within the retina

A Monte Carlo simulation of light propagation through the retina has been developed to understand the path-length distributions within the retinal vessel. For full-field illumination, the path-length distribution within the vessel comprises directly backscattered light and light that has passed once or twice through the vessel. The origins of these light path-length distributions can be better understood by investigating different combinations of single-point illumination and detection positions. Perhaps the most significant observation is that illumination at the edges of the vessel, rather than over the whole field of view, and detection directly above the vessel capture only the light that has taken a single pass through the vessel. This path-length distribution is tightly constrained around the diameter of the vessel and can potentially provide enhancements for oxygen saturation imaging. The method could be practically implemented using an offset-pinhole confocal imaging system or structured light illumination

Combining Structural and Vascular Parameters to Discriminate Among Glaucoma Patients, Glaucoma Suspects, and Healthy Subjects.

PurposeCompare the ability of peripapillary and macular structural parameters, vascular parameters, and their integration to discriminate among glaucoma, suspected glaucoma (GS), and healthy controls (HCs).MethodsIn this study, 196 eyes of 119 patients with glaucoma (n = 81), patients with GS (n = 48), and HCs (n = 67) underwent optical coherence tomography (OCT) and OCT angiography to measure peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell-inner plexiform layer (mGCIPL) thicknesses, radial peripapillary capillary perfusion density (RPC-PD), and macular GCIPL perfusion density (GCIPL-PD). Parameters were integrated regionally with logistic regression and globally with machine learning algorithms. Diagnostic performances were evaluated with area under the receiver operating characteristic (AUROC) curves.ResultsPatients with glaucoma had mild to moderate damage (median, -3.3 dB; interquartile range, -6.5 to -1.4). In discriminating between patients with glaucoma and the HCs, pRNFL thickness had higher AUROC curve values than RPC-PD for average (0.87 vs. 0.62; P < 0.001), superior (0.86 vs. 0.54; P < 0.001), inferior (0.90 vs. 0.71; P < 0.001), and temporal (0.65 vs. 0.51; P = 0.02) quadrants. mGCIPL thickness had higher AUROC curve values than GCIPL-PD for average (0.84 vs. 0.68; P < 0.001), superotemporal (0.76 vs. 0.65; P = 0.016), superior (0.72 vs. 0.57; P = 0.004), superonasal (0.70 vs. 0.56; P = 0.01), inferotemporal (0.90 vs. 0.72; P < 0.001), inferior (0.87 vs. 0.69; P < 0.001), and inferonasal (0.78 vs. 0.65, P = 0.012) sectors. All structural multisector indices had higher diagnostic ability than vascular ones (P < 0.001). Combined structural-vascular indices did not outperform structural indices. Similar results were found to discriminate glaucoma from GS.ConclusionsCombining structural and vascular parameters in a structural-vascular index does not improve diagnostic ability over structural parameters alone.Translational relevanceOCT angiography does not add additional benefit to structural OCT in early to moderate glaucoma diagnosis

Real-World Outcomes of Selective Laser Trabeculoplasty in the United Kingdom

Purpose: Selective laser trabeculoplasty (SLT) is a common treatment option for managing glaucoma and ocular hypertension. We assessed the real-world effectiveness of SLT and baseline factors associated with treatment success in the United Kingdom. Design: Retrospective observational study of de-identified electronic medical records (Medisoft Glaucoma module [Medisoft Ltd, Leeds, UK]) from 5 UK ophthalmology teaching centers. Participants: Adult patients undergoing their first recorded SLT. For bilateral SLT (same day), analyses included 1 randomly selected eye. Methods: Patient demographics, procedure details, and clinical outcomes data were extracted. Factors associated with treatment success were assessed using multivariable Cox regression. Main Outcome Measures: Change from baseline in intraocular pressure (IOP) and glaucoma medication use at 12 to 18 and 24 to 36 months post-SLT. A Kaplan–Meier survival analysis was also conducted. Failure of SLT was defined as any further glaucoma procedure post-SLT or any of the following at 2 consecutive visits: IOP >21 mmHg, IOP reduction <20% from baseline, or increase in glaucoma medications from baseline. Results: A total of 831 SLT-treated eyes (mean baseline IOP 22.0 mmHg) of 831 patients were analyzed. At 12 to 18 and 24 to 36 months post-SLT, respectively, significant reductions in IOP (−4.2 [95% confidence interval {CI}, −4.7 to −3.7] and −3.4 [95% CI, −4.1 to −2.7] mmHg; both P 21 mmHg vs. ≤21 mmHg, 95% CI, 0.57–0.80; P < 0.001). Selective laser trabeculoplasty success was not significantly associated with age (P = 0.78), baseline visual field mean deviation (P = 1.00), or concurrent use of IOP-lowering medication (P = 0.52). Conclusions: Most patients initially responded to SLT, but the majority failed within 1 year. Efficacy of SLT was better in patients with higher baseline IOP but did not differ by glaucoma severity or concurrent use of IOP-lowering medication. These findings may help inform which patients are suitable for SLT therapy

Frequency of visual field testing when monitoring patients newly diagnosed with glaucoma: mixed methods and modelling

Background: Visual field (VF) tests are the benchmark for detecting and monitoring the eye disease glaucoma. Measurements from VF tests are variable, which means that frequent monitoring, perhaps over a long period of time, is required to accurately detect true glaucomatous progression. In 2009, guidelines for the diagnosis and management of glaucoma issued by the National Institute for Health and Care Excellence revealed an absence of research evidence about the clinical effectiveness and cost-effectiveness of using different monitoring intervals to detect disease progression. However, the European Glaucoma Society (EGS) guidelines on patient examination recommend that newly diagnosed glaucoma patients should undergo VF testing three times per year in the first 2 years after initial diagnosis. Objectives: The primary objective of this project was to explore the clinical effectiveness and cost-effectiveness of using different monitoring intervals to detect VF progression in newly diagnosed glaucoma patients. Other objectives sought to (1) explore glaucoma patients’ views and experiences of monitoring using focus groups; and (2) establish glaucoma subspecialists’ attitudes regarding frequency of VF testing using a five-item questionnaire. Design: These questions were investigated using a multicentre audit of current practice and existing NHS data (VF records from almost 90,000 patients). New research knowledge was provided through statistical and health economic modelling of these and additional published data. Results: The multicentre audit showed that VF monitoring is, on average, carried out annually. Patient focus groups indicated that, although patients do not like VF testing, they accept it as a critical part of their care. Patients raised concerns regarding distracting testing environments, quality of instructions, explanation of results and excessive waiting times. Questionnaires revealed that clinicians’ attitudes towards the frequency of VF testing varied considerably, and many glaucoma specialists believed that current recommendations are impractical. Statistical modelling suggested that EGS recommendations could be clinically effective as progression can be identified sooner than is possible with annual testing. Health economic modelling suggested that increased VF monitoring may also be cost-effective [incremental cost-effectiveness ratio (ICER) was equal to £21,679]. Conclusions: Statistical modelling of VF data suggests there is strong rationale for following EGS recommendations with the primary benefit of providing better information about fast-progressing patients. Our health economic model suggested that increasing VF testing may be cost-effective (ICER was equal to £21,679), especially when accounting for gains to society. Nevertheless, many clinicians consider increased VF testing of patients impossible with current resources. In addition, patient focus groups raised concerns about the practicalities of delivery of VF tests. Future work: Results from this study could inform the design of a prospective randomised comparative trial of different VF monitoring intervals in glaucoma linked to stratifying patients according to risk factors for progression. The statistical model for VF data can be further developed to be used as a practical tool for optimising individualised follow-up. The views of clinicians and patients indicate that service delivery of VF testing is an important issue and worthy of further investigation. Ensuring the confidence and co-operation of the patient should be at the centre of future research into the most efficient strategies for glaucoma monitoring. Funding: This work was funded by the National Institute for Health Research Health Services and Delivery Research programme

OCT Signal Enhancement with Deep Learning

Purpose- To establish whether deep learning methods are able to improve the signal-to-noise ratio of time-domain (TD) OCT images to approach that of spectral-domain (SD) OCT images. Design- Method agreement study and progression detection in a randomized, double-masked, placebo-controlled, multicenter trial for open-angle glaucoma (OAG), the United Kingdom Glaucoma Treatment Study (UKGTS). Participants- The training and validation cohort comprised 77 stable OAG participants with TD OCT and SD OCT imaging at up to 11 visits within 3 months. The testing cohort comprised 284 newly diagnosed OAG patients with TD OCT images from a cohort of 516 recruited at 10 United Kingdom centers between 2007 and 2010. Methods- An ensemble of generative adversarial networks (GANs) was trained on TD OCT and SD OCT image pairs from the training dataset and applied to TD OCT images from the testing dataset. Time-domain OCT images were converted to synthesized SD OCT images and segmented via Bayesian fusion on the output of the GANs. Main Outcome Measures- Bland-Altman analysis assessed agreement between TD OCT and synthesized SD OCT average retinal nerve fiber layer thickness (RNFLT) measurements and the SD OCT RNFLT. Analysis of the distribution of the rates of RNFLT change in TD OCT and synthesized SD OCT in the two treatment arms of the UKGTS was compared. A Cox model for predictors of time-to-incident visual field (VF) progression was computed with the TD OCT and the synthesized SD OCT images. Results- The 95% limits of agreement were between TD OCT and SD OCT were 26.64 to –22.95; between synthesized SD OCT and SD OCT were 8.11 to –6.73; and between SD OCT and SD OCT were 4.16 to –4.04. The mean difference in the rate of RNFLT change between UKGTS treatment and placebo arms with TD OCT was 0.24 (P = 0.11) and with synthesized SD OCT was 0.43 (P = 0.0017). The hazard ratio for RNFLT slope in Cox regression modeling for time to incident VF progression was 1.09 (95% confidence interval [CI], 1.02–1.21; P = 0.035) for TD OCT and 1.24 (95% CI, 1.08–1.39; P = 0.011) for synthesized SD OCT. Conclusions- Image enhancement significantly improved the agreement of TD OCT RNFLT measurements with SD OCT RNFLT measurements. The difference, and its significance, in rates of RNFLT change in the UKGTS treatment arms was enhanced and RNFLT change became a stronger predictor of VF progression