Associations with baseline visual acuity in 12,414 eyes starting treatment for neovascular AMD.

AIMS: To determine baseline visual acuity before the start of treatment for neovascular age-related macular degeneration (AMD), compare median and visual acuity states between treatment sites and investigate the association of socio-demographic and clinical characteristics with baseline acuity. METHODS: Anonymised demographic and clinical data, collected as part of routine clinical care, were extracted from electronic medical records at treating National Health Service (NHS) Trusts. Analyses were restricted to eyes with baseline visual acuity recorded at treatment initiation. Associations with baseline acuity were investigated using multivariate linear regression. RESULTS: Analysis included 12,414 eyes of 9116 patients at 13 NHS Trusts. Median baseline acuity was LogMAR 0.46 (interquartile range = 0.26-0.80) and 34.5% of eyes had good acuity, defined as LogMAR ≤0.3. Baseline acuity was positively associated with second-treated eye status, younger age, lower socio-economic deprivation, independent living, and female sex. There was little evidence of association between baseline acuity and distance to the nearest treatment centre, systemic or ocular co-morbidity. Despite case-mix adjustments, there was evidence of significant variation of baseline visual acuity between sites. CONCLUSIONS: Despite access to publicly funded treatment within the NHS, variation in visual acuity at the start of neovascular AMD treatment persists. Identifying the characteristics associated with poor baseline acuity, targeted health awareness campaigns, professional education, and pathway re-design may help to improve baseline acuity, the first eye gap, and visual acuity outcomes.

Aflibercept in clinical practice; visual acuity, injection numbers and adherence to treatment, for diabetic macular oedema in 21 UK hospitals over 3 years.

INTRODUCTION: Randomised controlled trials provide evidence that a treatment works. Real world evidence is required to assess if proven treatments are effective in practice. METHOD: Retrospective data collection on patients given aflibercept for diabetic macular oedema over 3 years from 21 UK hospitals: visual acuity (VA); Index of multiple deprivation score (IMD); injection numbers; protocols used, compared as a cohort and between sites. RESULTS: Complete data: 1742 patients (from 2196 eligible) at 1 year, 860 (from 1270) at 2, 305 (from 506) at 3 years. The median VA improved from 65 to 71, 70, 70 (ETDRS letters) at 1, 2 and 3 years with 6, 9 and 12 injections, respectively. Loss to follow-up: 10% 1 year, 28.8% at 3. Centres varied: baseline: mean age 61-71 years (p < 0.0001); mean IMD score 15-37 (p < 0.0001); mean VA 49-68 (p < 0.0001). Only four centres provided a loading course of five injections at monthly intervals and one 6. This did not alter VA outcome at 1 year. Higher IMD was associated with younger age (p = 0.0023) and worse VA at baseline (p < 0.0001) not total number of injections or change in VA. Lower starting VA, higher IMD and older age were associated with lower adherence (p = 0.0010). CONCLUSIONS: The data showed significant variation between treatment centres for starting age, VA and IMD which influenced adherence and chances of good VA. Once treatment was started IMD did not alter likelihood of improvement. Loading dose intensity did not alter outcome at one year.

The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade.

Age-related macular degeneration (AMD) is a complex neurodegenerative eye disease with behavioral and genetic etiology and is the leading cause of irreversible vision loss among elderly Caucasians. Functionally significant genetic variants in the alternative pathway of complement have been strongly linked to disease. More recently, a rare variant in the terminal pathway of complement has been associated with increased risk, Complement component 9 (C9) P167S. To assess the functional consequence of this variant, C9 levels were measured in two independent cohorts of AMD patients. In both cohorts, it was demonstrated that the P167S variant was associated with low C9 plasma levels. Further analysis showed that patients with advanced AMD had elevated sC5b-9 compared to those with non-advanced AMD, although this was not associated with the P167S polymorphism. Electron microscopy of membrane attack complexes (MACs) generated using recombinantly produced wild type or P167S C9 demonstrated identical MAC ring structures. In functional assays, the P167S variant displayed a higher propensity to polymerize and a small increase in its ability to induce hemolysis of sheep erythrocytes when added to C9-depleted serum. The demonstration that this C9 P167S AMD risk polymorphism displays increased polymerization and functional activity provides a rationale for the gene therapy trials of sCD59 to inhibit the terminal pathway of complement in AMD that are underway.

Epigenetics in age-related macular degeneration: new discoveries and future perspectives.

The study of epigenetics has explained some of the 'missing heritability' of age-related macular degeneration (AMD). The epigenome also provides a substantial contribution to the organisation of the functional retina. There is emerging evidence of specific epigenetic mechanisms associated with AMD. This 'AMD epigenome' may offer the chance to develop novel AMD treatments.

Genetics and genetic testing for age-related macular degeneration.

Considerable advances have been made in our understanding of age-related macular degeneration (AMD) genetics over the past decade. The genetic associations discovered to date are estimated to account for approximately half of AMD heritability, and functional studies of these variants have revealed new insights into disease pathogenesis, leading to the development of potential novel therapies. There is furthermore growing interest in genetic testing for predicting an individual's risk of AMD and offering personalised preventive or therapeutic treatments. We review the progress made so far in AMD genetics and discuss the possible applications for genetic testing.

Real-world experience with 0.2 µg/day fluocinolone acetonide intravitreal implant (ILUVIEN) in the United Kingdom.

AimsTo compare safety outcomes and visual function data acquired in the real-world setting with FAME study results in eyes treated with 0.2 µg/day fluocinolone acetonide (FAc).MethodsFourteen UK clinical sites contributed to pseudoanonymised data collected using the same electronic medical record system. Data pertaining to eyes treated with FAc implant for diabetic macular oedema (DMO) was extracted. Intraocular pressure (IOP)-related adverse events were defined as use of IOP-lowering medication, any rise in IOP>30 mm Hg, or glaucoma surgery. Other measured outcomes included visual acuity, central subfield thickness (CSFT) changes and use of concomitant medications.ResultsIn total, 345 eyes had a mean follow-up of 428 days. Overall, 13.9% of patients required IOP-lowering drops (included initiation, addition and switching of current drops), 7.2% had IOP elevation >30 mm Hg and 0.3% required glaucoma surgery. In patients with prior steroid exposure and no prior IOP-related event, there were no new IOP-related events. In patients without prior steroid use and without prior IOP-related events, 10.3% of eyes required IOP-lowering medication and 4.3% exhibited IOP >30 mm Hg at some point during follow-up. At 24 months, mean best-recorded visual acuity increased from 51.9 to 57.2 letters and 20.8% achieved ≥15-letter improvement. Mean CSFT reduced from 451.2 to 355.5 µm.ConclusionsWhile overall IOP-related emergent events were observed in similar frequency to FAME, no adverse events were seen in the subgroup with prior steroid exposure and no prior IOP events. Efficacy findings confirm that the FAc implant is a useful treatment option for chronic DMO.

Real-world visual acuity outcomes between ranibizumab and aflibercept in treatment of neovascular AMD in a large US data set.

PurposeTo examine 12-month real-world visual acuity outcomes and treatment patterns in neovascular age-related macular degeneration (nAMD) eyes, including those with pigment epithelial detachment (PED), receiving ranibizumab or aflibercept.Patients and methodsElectronic medical records were used to identify ranibizumab or aflibercept-treated nAMD eyes with 12 months follow-up from first prescription. The primary objective was to compare mean change in visual acuity (VA) between index and month 12, in eyes treated with ranibizumab and aflibercept to assess the non-inferiority of ranibizumab vs aflibercept using a -5 letter non-inferiority margin. The number of injections and non-injection visits during follow-up were key secondary objectives.ResultsA total of 3350 ranibizumab and 4300 aflibercept treatment-naive eyes were included. At month 12, mean change from index in VA letter score was -0.30 for ranibizumab and -0.19 for aflibercept (P=0.81). The adjusted difference of mean change was -0.14 (-0.79 to 0.51) (P=0.67) (generalized estimating equations method) confirming the non-inferiority of ranibizumab. Eyes received a similar number of injections during follow-up. The mean (±SD) number of ranibizumab and aflibercept injections were 6.70 (±2.54) and 7.00 (±2.40), respectively (P<0.0001). In PED eyes, the mean (±SD) change between baseline to month 12 was 1.25 (±11.3) for ranibizumab and -0.39 (±13.3) for aflibercept (adjusted between-group difference 1.80 (-0.71 to 4.30; P=0.16)) achieved with a mean (±SD) 7.85 (±2.68) ranibizumab and 7.47 (±2.45) aflibercept injections, (P=0.11).ConclusionsRanibizumab and aflibercept treatment yielded comparable VA outcomes in nAMD eyes, including those with PED, with similar treatment patterns over 12 months in real-world clinical practice.

Second-year visual acuity outcomes of nAMD patients treated with aflibercept: data analysis from the UK Aflibercept Users Group.

PurposeTo audit the visual acuity (VA) outcomes achieved at the end of year two in 17 UK centres, which followed the year 1 VIEW protocol in year 1, but a variable approach in year 2 for aflibercept for neovascular macular degeneration (nAMD).Patients and methodsRetrospective data analysis, from an electronic medical record, of a consecutive series of treatment-naive nAMD patients who received aflibercept for 2 consecutive years, having followed the VIEW protocol in year one, defined as eyes having received 7 or 8 injections from baseline.ResultsThe mean number of intravitreal injections (IVI)s during year 2 was 3.7 in 1180 eyes (1083 patients). The mean baseline VA of the whole cohort was 56.3 ETDRS letters, improving to 61.3 at 1 year (+5) and 59.1 (+2.8) at the end of year 2. The mean VA letter score at the end of year 2, stratified by number of IVIs into three groups was as follows: group A, 57.3 (gain of +1.7) (44% of eyes (/=6 IVIs)). Even though there were VA gains in the three groups over the 2-years, there was a drop in VA in year one to two. Eyes that received >/=6 IVIs (group C) had a smaller reduction of VA during year 2 than those which received

A systematic review to assess the 'treat-and-extend' dosing regimen for neovascular age-related macular degeneration using ranibizumab.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. Monthly or as-needed (PRN) dosing strategies of intravitreal ranibizumab have been established as efficacious treatment options for neovascular AMD. More recently, the 'treat-and-extend' dosing regimen (TREX) is being adopted in clinical practice as it represents a patient-centric and economical option, reducing treatment burden by extending injection intervals when possible. However, the efficacy of TREX using ranibizumab monotherapy remains to be defined. Therefore, we performed a systematic review to assess the current evidence for TREX using ranibizumab by searching MEDLINE, Embase and PubMed. Of the 1733 articles identified, nine TREX studies were included in our analysis (n=748 eyes). Average patient age was 79.25 (range: 77.34-82.00; SD: 7.27). Baseline BCVA ranged from 48.5-68.9 ETDRS letters. BCVA improvement was 8.92 letters at 1 year (range: 6.5-11.5; SD: 7.54), as a weighted mean accounting for numbers of study eyes. The weighted mean number of injections at one year was 8.60 (range: 7.3-12.0; SD: 1.73). Previously, the landmark ANCHOR and MARINA trials reported gains of 11.3 and 7.2 letters, respectively, using monthly ranibizumab. Chin-Yee et al reported a gain of 3.5 ETDRS letters with 5.3 (S.D. 0.66) PRN ranibizumab injections as weighted means at 1 year in their recent systematic review. Our analysis suggests that TREX delivers visual outcomes superior to PRN and approaches similar efficacy to monthly injections. Further RCTs are needed to fully evaluate the efficacy and economy of TREX in the long-term.

Fundus autofluorescence imaging: systematic review of test accuracy for the diagnosis and monitoring of retinal conditions.

We conducted a systematic review of the accuracy of fundus autofluorescence (FAF) imaging for diagnosing and monitoring retinal conditions. Searches in November 2014 identified English language references. Sources included MEDLINE, EMBASE, the Cochrane Library, Web of Science, and MEDION databases; reference lists of retrieved studies; and internet pages of relevant organisations, meetings, and trial registries. For inclusion, studies had to report FAF imaging accuracy quantitatively. Studies were critically appraised using QUADAS risk of bias criteria. Two reviewers conducted all review steps. From 2240 unique references identified, eight primary research studies met the inclusion criteria. These investigated diagnostic accuracy of FAF imaging for choroidal neovascularisation (one study), reticular pseudodrusen (three studies), cystoid macular oedema (two studies), and diabetic macular oedema (two studies). Diagnostic sensitivity of FAF imaging ranged from 32 to 100% and specificity from 34 to 100%. However, owing to methodological limitations, including high and/or unclear risks of bias, none of these studies provides conclusive evidence of the diagnostic accuracy of FAF imaging. Study heterogeneity precluded meta-analysis. In most studies, the patient spectrum was not reflective of those who would present in clinical practice and no studies adequately reported whether FAF images were interpreted consistently. No studies of monitoring accuracy were identified. An update in October 2016, based on MEDLINE and internet searches, identified four new studies but did not alter our conclusions. Robust quantitative evidence on the accuracy of FAF imaging and how FAF images are interpreted is lacking. We provide recommendations to address this.

One-year real-world outcomes in patients receiving fixed-dosing aflibercept for neovascular age-related macular degeneration.

PurposeTo investigate 1-year visual and anatomic outcomes of intravitreal aflibercept for neovascular age-related macular degeneration (nAMD) given at a fixed 8-weekly interval.MethodsRetrospective, single-practice data analysis from an electronic medical record system of 255 eyes (223 patients) with treatment-naïve nAMD receiving 8-weekly aflibercept.ResultsMean logarithm of the minimum angle of resolution best-corrected visual acuity (BCVA) improved from 0.66 at baseline to 0.50 at month 11 (P<0.0001). Mean central retinal thickness (CRT) decreased from 311 µm at baseline to 211 µm at month 11 (P<0.0001). Our mean VA gain of eight ETDRS letters was comparable to the VIEW 1 and VIEW 2 Trials' results at the end of year 1. After loading at month 5, mean BCVA was 0.48 (P<0.0001), and mean CRT was 235 µm. At month 5, 143 eyes (56%) were inactive defined by the absence of macular haemorrhage and intraretinal fluid (IRF) and subretinal fluid (SRF) on optical coherence tomography, and 112 eyes (44%) remained active. At month 11, 136 eyes (53%) were inactive, and 119 eyes (47%) remained active. At month 11, 77% of inactive eyes after loading remained inactive, and 77% of the active eyes after loading remained active. At month 11, mean BCVA of the inactive group was 0.51, and mean BCVA of the active group was 0.48 (P=0.54).ConclusionsAflibercept administered by fixed dosing over 1 year improved VA and macular morphology in treatment-naïve eyes. Active lesions at month 11 do not have worse VA outcomes compared with inactive lesions. The macular status after loading is a reliable indicator of disease activity at the end of year 1.

Multicolor imaging in the diagnosis and follow up of type 2 acute macular neuroretinopathy.

PurposeTo study the usefulness of multicolor imaging (MC) photographs in addition to near infrared reflectance (NIR) and spectral domain optical coherence tomography (SD-OCT) in the detection and follow up of acute macular neuroretinopathy (AMN).Patients and methodsSix patients with a complaint of paracentral scotomas in at least one eye due to AMN were included. They underwent full ophthalmic examination and multimodal imaging including color fundus photographs, (SD-OCT), NIR, and MC at baseline and follow up.ResultsFour females and two males, aged 19-64 years, and eight eyes affected by AMN, were included. Acute phase SD-OCT in all patients confirmed the diagnosis of type 2 AMN with partial recovery of the outer retina in the convalescent phase. NIR and MC elicited in all cases hypo-reflective AMN lesions pointing toward the fovea. MC exhibited a higher contrast between the affected and the physiologic retina that slowly attenuated during the follow up showing a decrease in the hypo-reflectance of the lesions.ConclusionMC imaging was more detailed than fundus color photographs and as detailed as NIR in the detection of AMN. When available, MC imaging should complement SD-OCT and NIR in the diagnosis and follow up of this rare inflammatory condition that may be underdiagnosed.

Risk of geographic atrophy in age-related macular degeneration patients treated with intravitreal anti-VEGF agents.

Anti-vascular endothelial growth factor (VEGF) intravitreal agents are the only successful treatment for wet age-related macular degeneration (AMD). However, there are emerging signals that anti-VEGF treatment can potentially increase development of geographic atrophy (GA). Histopathologic, animal, and clinical studies support this hypothesis although direct proof of a relationship between GA and use of anti-VEGF agents in neovascular AMD is not yet established. This review presents current evidence supporting an association between anti-VEGF therapy and progression of geographic atrophy. The need of exploring alternative methods of treating AMD is indirectly but clearly emphasized.