Faruque Ghanchi

Defining response to anti-VEGF therapies in neovascular AMD

The introduction of anti-vascular endothelial growth factor (anti-VEGF) has made significant impact on the reduction of the visual loss due to neovascular age-related macular degeneration (n-AMD). There are significant inter-individual differences in response to an anti-VEGF agent, made more complex by the availability of multiple anti-VEGF agents with different molecular configurations. The response to anti-VEGF therapy have been found to be dependent on a variety of factors including patient’s age, lesion characteristics, lesion duration, baseline visual acuity (VA) and the presence of particular genotype risk alleles. Furthermore, a proportion of eyes with n-AMD show a decline in acuity or morphology, despite therapy or require very frequent re-treatment. There is currently no consensus as to how to classify optimal response, or lack of it, with these therapies. There is, in particular, confusion over terms such as ‘responder status’ after treatment for n-AMD, ‘tachyphylaxis’ and ‘recalcitrant’ n-AMD. This document aims to provide a consensus on definition/categorisation of the response of n-AMD to anti-VEGF therapies and on the time points at which response to treatment should be determined. Primary response is best determined at 1 month following the last initiation dose, while maintained treatment (secondary) response is determined any time after the 4th visit. In a particular eye, secondary responses do not mirror and cannot be predicted from that in the primary phase. Morphological and functional responses to anti-VEGF treatments, do not necessarily correlate, and may be dissociated in an individual eye. Furthermore, there is a ceiling effect that can negate the currently used functional metrics such as >5 letters improvement when the baseline VA is good (ETDRS>70 letters). It is therefore important to use a combination of both the parameters in determining the response.The following are proposed definitions: optimal (good) response is defined as when there is resolution of fluid (intraretinal fluid; IRF, subretinal fluid; SRF and retinal thickening), and/or improvement of >5 letters, subject to the ceiling effect of good starting VA. Poor response is defined as <25% reduction from the baseline in the central retinal thickness (CRT), with persistent or new IRF, SRF or minimal or change in VA (that is, change in VA of 0+4 letters). Non-response is defined as an increase in fluid (IRF, SRF and CRT), or increasing haemorrhage compared with the baseline and/or loss of >5 letters compared with the baseline or best corrected vision subsequently. Poor or non-response to anti-VEGF may be due to clinical factors including suboptimal dosing than that required by a particular patient, increased dosing intervals, treatment initiation when disease is already at an advanced or chronic stage), cellular mechanisms, lesion type, genetic variation and potential tachyphylaxis); non-clinical factors including poor access to clinics or delayed appointments may also result in poor treatment outcomes. In eyes classified as good responders, treatment should be continued with the same agent when disease activity is present or reactivation occurs following temporary dose holding. In eyes that show partial response, treatment may be continued, although re-evaluation with further imaging may be required to exclude confounding factors. Where there is persistent, unchanging accumulated fluid following three consecutive injections at monthly intervals, treatment may be withheld temporarily, but recommenced with the same or alternative anti-VEGF if the fluid subsequently increases (lesion considered active). Poor or non-response to anti-VEGF treatments requires re-evaluation of diagnosis and if necessary switch to alternative therapies including other anti-VEGF agents and/or with photodynamic therapy (PDT). Idiopathic polypoidal choroidopathy may require treatment with PDT monotherapy or combination with anti-VEGF. A committee comprised of retinal specialists with experience of managing patients with n-AMD similar to that which developed the Royal College of Ophthalmologists Guidelines to Ranibizumab was assembled. Individual aspects of the guidelines were proposed by the committee lead (WMA) based on relevant reference to published evidence base following a search of Medline and circulated to all committee members for discussion before approval or modification. Each draft was modified according to feedback from committee members until unanimous approval was obtained in the final draft. A system for categorising the range of responsiveness of n-AMD lesions to anti-VEGF therapy is proposed. The proposal is based primarily on morphological criteria but functional criteria have been included. Recommendations have been made on when to consider discontinuation of therapy either because of success or futility. These guidelines should help clinical decision-making and may prevent over and/or undertreatment with anti-VEGF therapy.

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 0.2 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.

Erratum: Defining response to anti-VEGF therapies in neovascular AMD

Correction to: Eye (2015) 29, 721–731; doi:10.1038/eye.2015.48; published online 17 April 2015 Since the online publication of the above article, the authors have noted that the name of the ninth author was published incorrectly. The correct name is SP Kelly. The authors have also noted that the conflict of interest statements were not complete.

The introduction of verteporfin photodynamic therapy in the UK: PDT users group (PDTUG) surveillance programme report 1

AimsTo report overall patient recruitment characteristics and visual acuity (VA) outcome related to baseline lesion characteristics for patients with choroidal neovascularisation (CNV) treated with verteporfin photodynamic therapy (PDT) during its introduction into routine National Health Service practice.MethodsThirteen treatment centres prospectively submitted data on patients undergoing verteporfin PDT for CNV of mixed aetiology between November 1999 and May 2004 into the PDT Users Group (PDTUG) surveillance database. The primary outcome was the proportion of eyes losing <15 letters of VA at 12 and 24 months, follow-up compared with the baseline examination.ResultsOne thousand eight hundred and ninety-four eyes of 1755 patients were analysed. Lesion characteristics at baseline were: classic no occult 1152 (67.4%), predominantly classic with occult 531 (31.1%). Recruitment rate rose steadily from 13 in the first to 188 in the final quarter. Data were available at 12 months on 1010 (53.3%) and at 24 months on 310 (16.4%) eyes. The proportion of eyes losing <15 letters was 71% (716/1010) at 12 months and 70% (217/310) at 24 months. At 12 months 91% (917/1010) of patients lost <30 letters. The mean number of PDT treatments for the cohort was 2.4 in the first 12 months. An adverse reaction or event was reported in 8.1% (364/4515) of treatments. Non-visual adverse events were infrequent.ConclusionsEfficacy and safety of verteporfin PDT in reducing vision loss in macular degeneration can be reproduced in routine clinical practice. Compared to the TAP study, the fewer treatments needed in the PDTUG cohort indicate the potential for better cost-effectiveness.

Changes in intraocular pressure in study and fellow eyes in the IVAN trial

Purpose To describe changes in intraocular pressure (IOP) in the ‘alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN)’ trial (registered as ISRCTN92166560). Design Randomised controlled clinical trial with factorial design. Participants Patients (n=610) with treatment naïve neovascular age-related macular degeneration were enrolled and randomly assigned to receive either ranibizumab or bevacizumab and to two regimens, namely monthly (continuous) or as needed (discontinuous) treatment. Methods At monthly visits, IOP was measured preinjection in both eyes, and postinjection in the study eye. Outcome measures The effects of 10 prespecified covariates on preinjection IOP, change in IOP (postinjection minus preinjection) and the difference in preinjection IOP between the two eyes were examined. Results For every month in trial, there was a statistically significant rise in both the preinjection IOP and the change in IOP postinjection during the time in the trial (estimate 0.02 mm Hg, 95% CI 0.01 to 0.03, p<0.001 and 0.03 mm Hg, 95% CI 0.01 to 0.04, p=0.002, respectively). There was also a small but significant increase during the time in trial in the difference in IOP between the two eyes (estimate 0.01 mm Hg, 95% CI 0.005 to 0.02, p<0.001). There were no differences between bevacizumab and ranibizumab for any of the three outcomes (p=0.93, p=0.22 and p=0.87, respectively). Conclusions Anti-vascular endothelial growth factor agents induce increases in IOP of small and uncertain clinical significance. Trial registration number ISRCTN92166560.

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 &mgr;g/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 &mgr;g/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.

Visual Acuity Outcomes in Diabetic Macular Edema With Fluocinolone Acetonide 0.2 μg/Day Versus Ranibizumab Plus Deferred Laser (DRCR Protocol I)

BACKGROUND AND OBJECTIVE Visual outcomes of the FAME study (0.2 μg/day fluocinolone acetonide [FAc]) and Protocol I (0.5 mg ranibizumab plus deferred laser) were compared using the area under the curve (AUC) analysis method. PATIENTS AND METHODS Best-corrected visual acuity (BCVA) data collected during a period of 3 years of follow-up for patients enrolled in FAME or Protocol I were used to calculate AUC of the change in BCVA over a time curve. RESULTS In the overall population, there was a greater treatment effect for ranibizumab plus deferred laser compared with FAc. However, for subgroups of pseudophakic eyes, eyes with chronic diabetic macular edema (DME), and pseudophakic eyes with chronic DME, ranibizumab plus deferred laser and FAc were not found to be significantly different. The ranibizumab group received a median of 14 injections during a 36-month period compared with a mean of 1.3 injections in the FAc group. CONCLUSION In pseudophakic and chronic DME subgroups, FAc was comparable to ranibizumab plus deferred laser with fewer injections. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:698-706.].

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.

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.

Single incision wagon wheel phaco

ABSTRACT Soft-to-semisoft cataracts may be challenging to remove with conventional sculpting and chopping phaco techniques. There are risks to intracameral structures during excessive and prolonged instrumentation. At a paracentesis site, corneal trauma may lead to wound leakage and astigmatism. We describe a technique for soft-to-semisoft lens extraction that minimises the mechanical stresses within the eye and utilises low phaco energy during surgery. The endonucleus is positioned in the vertical plane at the level of the capsulorhexis, and then removed in a centrifugal manner. Our single site wagon wheel technique uses the flow dynamics associated with high vacuum and burst phaco to safely remove soft-to-semisoft cataracts. ▸ To view the full report and accompanying video please go to: http://bjo.bmj.com/cgi/content/full/92/9/1205/DC1 ▸ All videos from the BJO video report collection are available from: http://bjo.bmj.com/video/collection.dtl