James Talks

Macular ischaemia: a contraindication for anti-VEGF treatment in retinal vascular disease?

Anti-vascular endothelial growth factor (anti-VEGF) therapy has been shown to be effective at improving vision in patients with macular oedema due to diabetic retinopathy and vein occlusions, but blocking VEGF at least in theory could be detrimental to vascular integrity. For this reason, some patients with macular ischaemia were excluded from studies showing the effectiveness of therapy. A considerable number of patients present with mixed pathology of macular oedema and macular ischaemia and it is often impossible to determine the degree to which ischaemia accounts for decreased vision. In this review, the authors have dealt with the specific question of whether or not there is evidence to support potential worsening of the macular perfusion and visual function after anti-VEGF treatment with bevacizumab or ranibizumab for macular oedema secondary to diabetic retinopathy or retinal vein occlusions, especially if there is coexisting macular ischaemia. The authors conclude that anti-VEGF therapy rarely seems to further compromise the retinal circulation; however, worsening of macular ischaemia in the long term cannot be definitely excluded, particularly in eyes with significant ischaemia at baseline and after repeated intraocular anti-VEGF injections. The decision to offer prolonged anti-VEGF treatment in cases of significant coexisting macular ischaemia should not be based only on measurements of macular thickness; instead repeat fluorescein angiograms should be performed.

Use of optical coherence tomography, fluorescein angiography and indocyanine green angiography in a screening clinic for wet age-related macular degeneration

Aims: To assess the utility of optical coherence tomography (OCT) in a nurse-led, fast-track clinic for new age-related macular degeneration (AMD) referrals, and to see how often indocyanine green angiography (ICGA) led to an additional diagnosis to that provided by fundus fluorescein angiography (FFA). Method: Retrospective audit of a consecutive series of 134 new patients referred with suspected wet AMD. When visual acuity was ⩾6/60 an OCT was performed. If the OCT was consistent with “wet” AMD, the patient underwent simultaneous FFA/ICGA. The sensitivity and specificity of this clinic was calculated. The number of additional diagnoses made using ICGA was recorded. Results: 23/134 (17.16%) patients had OCT only and were not subsequently found to have wet AMD. FFA/ICGA was performed in 111 patients, showing wet AMD in 90 (81%) patients. OCT as used in our clinic had a sensitivity of 1 and a specificity of 0.65 for detecting wet AMD. ICGA provided additional diagnoses in 19 (14.17%) patients. ICGA detected a specific vascular abnormality in 58% of the occult lesions. Conclusions: OCT proved to be an effective screening tool for wet AMD in this clinic, with excellent sensitivity and reasonable specificity. ICGA provided an additional diagnosis in a significant number of cases, but did not define a vascular abnormality in all occult cases.

Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial

BACKGROUNDnProliferative diabetic retinopathy is the most common cause of severe sight impairment in people with diabetes. Proliferative diabetic retinopathy has been managed by panretinal laser photocoagulation (PRP) for the past 40 years. We report the 1 year safety and efficacy of intravitreal aflibercept.nnnMETHODSnIn this phase 2b, single-blind, non-inferiority trial (CLARITY), adults (aged ≥18 years) with type 1 or 2 diabetes and previously untreated or post-laser treated active proliferative diabetic retinopathy were recruited from 22 UK ophthalmic centres. Patients were randomly assigned (1:1) to repeated intravitreal aflibercept (2 mg/0·05 mL at baseline, 4 weeks, and 8 weeks, and from week 12 patients were reviewed every 4 weeks and aflibercept injections were given as needed) or PRP standard care (single spot or mutlispot laser at baseline, fractionated fortnightly thereafter, and from week 12 patients were assessed every 8 weeks and treated with PRP as needed) for 52 weeks. Randomisation was by minimisation with a web-based computer generated system. Primary outcome assessors were masked optometrists. The treating ophthalmologists and participants were not masked. The primary outcome was defined as a change in best-corrected visual acuity at 52 weeks with a linear mixed-effect model that estimated adjusted treatment effects at both 12 weeks and 52 weeks, having excluded fluctuations in best corrected visual acuity owing to vitreous haemorrhage. This modified intention-to-treat analysis was reapplied to the per protocol participants. The non-inferiority margin was prespecified as -5 Early Treatment Diabetic Retinopathy Study letters. Safety was assessed in all participants. This trial is registered with ISRCTN registry, number 32207582.nnnFINDINGSnWe recruited 232 participants (116 per group) between Aug 22, 2014 and Nov 30, 2015. 221 participants (112 in aflibercept group, 109 in PRP group) contributed to the modified intention-to-treat model, and 210 participants (104 in aflibercept group and 106 in PRP group) within per protocol. Aflibercept was non-inferior and superior to PRP in both the modified intention-to-treat population (mean best corrected visual acuity difference 3·9 letters [95% CI 2·3-5·6], p<0·0001) and the per-protocol population (4·0 letters [2·4-5·7], p<0·0001). There were no safety concerns. The 95% CI adjusted difference between groups was more than the prespecified acceptable margin of -5 letters at both 12 weeks and 52 weeks.nnnINTERPRETATIONnPatients with proliferative diabetic retinopathy who were treated with intravitreal aflibercept had an improved outcome at 1 year compared with those treated with PRP standard care.nnnFUNDINGnThe Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

Real-world experience with 0.2 μ g/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 0.2u2009μg/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>30u2009mmu2009Hg, 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 >30u2009mmu2009Hg 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 >30u2009mmu2009Hg 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 355.5u2009μm.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.

Information used to decide on retreatment of exudative age-related macular degeneration with anti-VEGF in clinical practice.

Purpose. To record the information used in order to make a retreatment decision in patients with exudative age-related macular degeneration (AMD) and to assess if an optical coherence tomography (OCT)–only follow-up clinic would suffice. Methods. Two hundred patients under treatment with intravitreal anti–vascular endothelial growth factor injections (anti-VEGF) for exudative AMD were included. Each patient had previously received at least 3 intravitreal anti-VEGF injections (loading dose) (range 3–24 injections). Clinicians seeing the patients beyond the third injection were asked to document the criteria used to make a retreatment decision. Results. Overall, in 171 (85.5%) cases the retreatment decision was based on OCT findings of intraretinal or subretinal fluid alone. Diagnosis of recurrence requiring treatment would have been missed in 12 cases (6%), if OCT-only data had been used and funduscopy or visual function criteria had been omitted. Decision was based solely on functional criteria in only 2% of the cases. The retreatment decision was based on evaluation of morphologic funduscopic or OCT criteria in 187 (93.5%) cases. Conclusions. With the increasing number of patients having follow-up after anti- VEGF treatment, efficient systems of follow-up are required. Although most retreatment decisions could have been made by qualitative assessment of OCT images alone, the examination has considerable limitations. Optical coherence tomography in combination with color fundus photography could serve as screening tools for a rational implementation of other invasive imaging techniques such as fundus fluorescein angiography and indocyanine green angiography in decision-making.

Two week, OCT-based follow-up as guidance for retreatment with ranibizumab for CNV apparently refractory to therapy.

Purpose To assess the value of 2-week optical coherence tomography (OCT) follow-up for re-treatment decision-making in patients receiving monthly ranibizumab injections for choroidal neovascular membrane (CNV), which was apparently refractory to treatment. Methods A total of 25 eyes of 25 consecutive patients with refractory CNV were included. Patients were classified as having refractory disease if no visual acuity (VA) change and no change in the pattern of macular fluid was noticed on OCT after at least 3 consecutive monthly injections, excluding the loading doses. Repeat injection was given and reassessment with VA and OCT was undertaken at 2, 4, 8, and 12 weeks. Results Complete resolution or marked reduction of macular fluid was noted in 19 patients at 2 weeks (responders). In 18 responders, the fluid increased on 4- and persisted on 8- and 12-week follow-ups, so that further injections were given at these time points. In 6 patients, no significant change was noted at 2 weeks (nonresponders). In all of them, VA and OCT were stable on 4-, 8-, and 12-week follow-ups, without further injections. Conclusions As some patients are responding for at least part of the month, injections may be worth continuing or possibly more frequent injections, tailored to the individuals response, may need to be considered. Alternative therapies such as aflibercept may also need to be considered. In nonresponding eyes, other cytokines except for vascular endothelial growth factor are probably involved in the pathogenesis or such cases may have structural damage that will not respond to therapy.

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 (</=3 IVIs)); group B, 59.8 (+3.8) (34% of eyes (4–5 IVIs)); group C, 61.7 (+3.7) (22% 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 </=3 IVIs (group A) (P=0.0014).ConclusionsProviding a higher number of injections after a Q8 regime in year 1 results in higher VA gains in year 2 of treatment.

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 79u2009775 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=0.48u2009and 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.

Appropriateness of quality standards for meaningful intercentre comparisons of aflibercept service provision for neovascular age-related macular degeneration

PurposeReal-world data give different information on health-care delivery compared with randomised controlled trials. We aimed to evaluate the appropriateness of possible quality standards for intersite comparisons of outcomes of providing Aflibercept for neovascular age-related macular degeneration (nAMD) in clinical practice.Patients and methodsRetrospective data analysis from an electronic medical record. A consecutive series of treatment-naive patients initiated on aflibercept for nAMD, in the UK from March 2013 to October 2015. Age, visual acuity (VA) at baseline and 1 year, and injection episodes were remotely extracted in an anonymised format.ResultsThe mean baseline VA was 54.3 letters, ranging from 51.3 to 58.1 between different centres, in 5620 eyes taken from 12 centres. Out of these, 3360 were initiated on treatment more than a year before. The percentage with <35 letters at baseline was 19.9–3% and that with >70 letters was 24.8–10.7%. Eyes with ≥70 letters at 1 year ranged from 20.2 to 42.9% and those with <35 ranged from 4.5 to 21.6% across different sites. Injection rates in 1 year varied from 5.5 to 8.6, and data available at 1 year also varied from 82.3 to 46.4%.ConclusionsSignificant variation was found between sites attempting to provide the same therapeutic regime. For fair comparisons between sites, we recommend that both VA measures and process measures, such as injection numbers, retention rates, and discharge policies, are used. More work is required to explain the differences. Such real-world data are not generated in the same way as a randomised clinical trial, and maybe best used to help improve service provision.