A safety evaluation of ranibizumab in the treatment of age-related macular degeneration

Introduction: The use of intravitreal ranibizumab has transformed the outcomes for thousands of patients with wet age related macular degeneration (AMD), which is the leading cause of blindness in developed countries. Prior to its introduction, most patients with wet AMD would rapidly lose central vision. The use of intravitreal ranibizumab has been shown to reduce certifiable visual loss by about a half. Current treatment regimens with ranibizumab in wet AMD require multiple injections over several years and so it is highly relevant to review the safety record of this important drug.Areas covered: This review considers the important ocular and systemic adverse events (AE) that have been reported in the literature, particularly in the context of the pivotal clinical trials that have been performed. It also reviews the safety of other anti-VEGF drugs that are used in wet AMD, namely bevacizumab and aflibercept, and compares these drugs with ranibizumab.Expert opinion: Overall, intravitreal ranibizumab can be considered a safe and highly effective drug for patients with wet AMD. However recent concerns about retinal thinning following ranibizumab therapy, possible systemic AE associated with all anti-VEGF drugs and the occurrence of complications relating to drug preparation and delivery must be considered. © 2014 Informa UK, Ltd.

The effects of coloured light filter overlays on reading rates in age-related macular degeneration

Purpose: To determine the effect of coloured light filter overlays on reading rates for people with age-related macular degeneration (AMD). Method: Using a prospective clinical trial design, we examined the null hypothesis that coloured light filter overlays do not improve reading rates in AMD when compared to a clear filter. Reading rates for 12 subjects with non-exudative AMD, associated with a relative scotoma and central fixation (mean age 81 years, SD 5.07 years) were determined using the Rate of Reading Test® (printed, nonsense, lower case sans serif, stationary text) with 10 different, coloured light filter overlays (Intuitive Overlays®; figures in brackets are percentage transmission values); rose (78%), pink (78%), purple (67%), aqua (81%), blue (74%), lime-green (86%), mint-green (85%), yellow (93%), orange (83%) and grey (71%). A clear overlay (Roscolene # 00) (360 cdm-2) with 100% transmittance was used as a control. Results: ANOVA indicated that there was no statistically significant difference in reading rates with the coloured light filter overlays compared to the clear filter. Furthermore, chi-squared analysis indicated that the rose, purple and blue filters had a significantly poorer overall ranking in terms of reading rates compared to the other coloured and clear light filters. Conclusion: Coloured light filter overlays are unlikely to provide a clinically significant improvement in reading rates for people with non-exudative AMD associated with a relative scotoma and central fixation. Copyright © Acta Ophthalmol Scand 2004.

Benefit of coloured lenses for age-related macular degeneration

Purpose: To evaluate and compare the functional and perceived benefits of wearing coloured lenses by patients with age-related macular degeneration (ARMD). Method: Ten subjects with early ARMD and five elderly controls wore a selection of NoIR wrap-around coloured lenses (yellow 29.7% light transmission, orange 22.9%, red 16.8% and grey 10.3%), each for a duration of 7 days. Contrast sensitivity, colour vision, visual acuity, the effect of glare and peripheral sensitivity were measured for each lens and compared with a control (no lens) condition. Subjective ratings of visual performance were also scored. Results: Compared with the no filter condition, red and grey lenses reduced contrast sensitivity whereas yellow and orange lenses increased contrast sensitivity. These objective changes were supported by subjective ratings in subjects with ARMD. Grey lenses reduced the loss of contrast sensitivity usually suffered in the presence of glare, whereas visual acuity and peripheral sensitivity decreased with red lenses. Colour vision became distorted with red lenses in control subjects, but was relatively unaffected by the use of coloured lenses in subjects with ARMD. Conclusions: The subjective benefit of coloured lenses appears to be due to a minor enhancement of contrast sensitivity. © 2002 The College of Optometrists.

Age-related macular degeneration patients' awareness of nutritional factors

Age-related macular degeneration (AMD) is the leading cause of visual impairment in older adults in the United Kingdom. This study sought to characterise AMD patients who seek the services of the Macular Society, and determine the level and source of their dietary knowledge. A questionnaire was designed, validated, and administered to 158 participants. The questions covered demographic data and knowledge of nutrition and supplementation. The mean age of participants was 79 years; 61% of them were female, and 27% were registered visually impaired. Only 55% of the participants thought diet was important for eye health, 63% felt that they had not received enough information about AMD. The participants reported that their information mainly came from non-professional support groups. Most participants identified healthy food, but could not say why, and were not able to identify carotenoid rich foods. The results of the study will inform design of education and dissemination methods regarding dietary information. © The Author(s) 2014.

Exploring attitudes towards dietary modification and nutritional supplementation in people with and without age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause for visual impairment and blindness registration in the developed world. Due to the large amounts of conflicting AMD research on the role of nutrition and antioxidant intake, it is difficult for patients and practitioners to determine which measures can be taken to slow down the disease progression. The aim of this research was to determine the beliefs and knowledge that patients with AMD have about nutrition, to identify whether their condition is preventing them from eating a healthy diet, and to discover what their diet consists of. For the initial study, 158 participants with AMD (mean age 79 ± 7.8 years) and 50 participants without AMD (mean age 67 ± 8 years) were recruited from the Macular Society helpline, or from optometric practice. Participants had a 25 minute telephone interview where a 36-question survey was completed. The survey elicited demographic information, and questions covered the knowledge that participants had on nutrition and their current diet. The results from this survey uncovered three major findings: 1) 100% of AMD participants felt that they do not have enough information and support from eye-care practitioners regarding nutrition, 2) AMD patients are confused over, and display a lack of knowledge of, which foods are beneficial for eye health and when and what nutritional supplements to take, evidenced by 65% of participants not taking the correct dosage 3) AMD patients are not eating enough nutrients that would be beneficial for their condition - consuming an average of 1.4mg of lutein and zeaxanthin rather than the recommended 10mg. A clinical decision-making aid was created as an intervention based upon these findings. The aim of the aid was to help eye-care practitioners give the correct nutritional advice to their patients. Founded on the AREDS 2 inclusion and exclusion criteria, practitioners are able to identify which patients could benefit from a nutritional supplement, and which patients could benefit from dietary modification. An evaluation of the aid with 72 qualified eye-care practitioners exhibited a statistically significant increase in confidence after using the aid for two weeks. An evaluation using 51 student optometrists showed a statistically significant increase in confidence and a statistically significant increase in appropriate management of patients after using the aid. This project has elicited findings that are significant for AMD patient education. It is hoped that through these studies, patients will receive consistent advice about the risk factors for AMD, the link between AMD and nutrition, and the importance of maintaining a healthy, well-balanced diet.

Bilateral visual outcomes and service utilization of patients treated for 3 years with ranibizumab for neovascular age-related macular degeneration

Background: The aim of this study was to describe bilateral visual outcomes and the effect of incomplete follow-up after 3 years of ranibizumab therapy for neovascular age-related macular degeneration. Secondarily, the demands on service provision over a 3-year period were described. Methods: Data on visual acuity, hospital visits, and injections were collected over 36 months on consecutive patients commencing treatment over a 9-month period. Visual outcome was determined for 1) all patients, using last observation carried forward for missed visits due to early discontinuation and 2) only those patients completing full 36-month follow-up. Results: Over 3 years, 120 patients cumulatively attended hospital for 1,823 noninjection visits and 1,365 injection visits. A visual acuity loss of <15 letters (L) was experienced by 78.2% of patients. For all patients (n=120), there was a mean loss of 1.68 L using last observation carried forward for missing values. Excluding five patients who died and 30 who discontinued follow-up, mean gain was 1.47 L. In bilateral cases, final acuity was on average 9 L better in second eyes compared to first eyes. Also, 91% of better-seeing eyes continued to be the better-seeing eye. Conclusion: We have demonstrated our approach to describing the long-term service provision and visual outcomes of ranibizumab therapy for neovascular age-related macular degeneration in a consecutive cohort of patients. Although there was a heavy burden with very frequent injections and clinic visits, patients can expect a good level of visual stability and a very high chance of maintaining their better-seeing eye for up to 3 years. © 2014 Chavan et al. This work is published by Dove Medical Press Limited.

Dietary analysis and nutritional behaviour in people with and without age-related macular disease

Background and Aims: Consumption of antioxidant nutrients can reduce the risk of progression of age-related macular degeneration (AMD) - the leading cause of visual impairment in adults over the age of 50 years in the UK. Lutein and zeaxanthin (L&Z) are of particular interest because they are selectively absorbed by the central retina. The objectives of this study were to analyse the dietary intake of a group of AMD patients, assess their ability to prepare and cook healthy food, and to make comparisons with people not affected by AMD. Methods: 158 participants with AMD were recruited via the UK charity The Macular Society, and fifty participants without AMD were recruited from optometric practice. A telephone interview was conducted by trained workers where participants completed a 24 hour food diary, and answered questions about cooking and shopping capabilities. Results: In the AMD group, the average L&Z intake was low in for both males and females. Those able to cook a hot meal consumed significantly more L&Z than those who were not able. Most participants were not consuming the recommended dietary allowance of fibre, calcium, vitamin D and E, and calorific intake was also lower than recommendations for their age-group. The non-AMD group consumed more kilocalories and more nutrients than the AMD group, but the L&Z intake was similar to those with AMD. The main factor that influenced participant’s food choices was personal preference. Conclusion: For an ‘informed’ population, many AMD participants were under-consuming nutrients considered to be useful for their condition. Participants without AMD were more likely to reach recommended daily allowance values for energy and a range of nutrients. It is therefore essential to design more effective dietary education and dissemination methods for people with, and at risk of, AMD.

Understanding the IT-related attitudes and needs of persons with age-related macular degeneration:a case study

In the UK, 20 per cent of people aged 75 years and over are living with sight loss; this percentage is expected to increase as the population ages (RNIB, 2011). Age-Related Macular Degeneration (AMD) is the UK’s leading cause of severe visual impairment amongst the elderly. It accounts for 16,000 blind/partial sight registrations per year and is the leading cause of blindness among people aged 55 years and older in western countries (Bressler, 2004). Our ultimate goal is to develop an assistive mobile application to support accurate and convenient diet data collection on which basis to then provide customised dietary advice and recommendations in order to help support individuals with AMD to mitigate their ongoing risk and retard the progression of the disease. In this paper, we focus on our knowledge elicitation activities conducted to help us achieve a deep and relevant understanding of our target user group. We report on qualitative findings from focus groups and observational studies with persons with AMD and interviews with domain experts which enable us to fully appreciate the impact that technology may have on our intended users as well as to inform the design and structure of our proposed mobile assistive application.

Effect of initial retinal thickness on outcome of intravitreal bevacizumab therapy for diabetic macular edema

Purpose: To investigate whether eyes with diabetic macular edema (DME) and central retinal thickness (CRT) >400 μm had better visual and anatomical outcomes compared to eyes with a CRT <400 μm when treated with intravitreal bevacizumab in a real-world setting. Patients and methods: Patients undergoing intravitreal bevacizumab therapy for DME were identified from the departmental database of a tertiary referral unit. Following the initial injection, a retreatment was performed for any persistent macular edema, unless there had been no previous response to repeated doses. Recorded parameters included visual acuity, CRT on optical coherence tomography (spectral domain optical coherence tomography [SD-OCT]), and SD-OCT characteristics. Comparisons were made between data at baseline and 12 months after the first injection, and differences were tested for statistical significance using the Student's t-test. Results: In all, 175 eyes of 142 patients were analyzed. Patients in group 2 (CRT >400 μm) had significantly more injections than group 1 (CRT <400 μm) (4.0 versus 3.3; P=0.003). Both groups had similar numbers of eyes with preexisting epiretinal membrane and/or vitreomacular traction at baseline. The reduction in CRT was significantly greater in group 2 when compared to group 1 (P<0.0001). In terms of visual gain between baseline and month 12, each gained significantly by a mean of 0.12 logarithm of the minimum angle of resolution units (P=0.0001), but there was no difference between groups 1 and 2 (P=0.99). Conclusion: These results do not support a 400 μm baseline CRT cut-off for treating DME with bevacizumab, in contrast to published data on ranibizumab. Our results also indicate that patients with a thicker CRT require more bevacizumab injections, making treatment less cost-effective for these patients. Our results could be used by practitioners to support the use of bevacizumab in DME without applying a CRT cut-off. © 2014 Mushtaq et al.

The effect of ocular nutritional supplements on macular pigment optical density

This thesis describes the investigation of the effects of ocular supplements with different levels of nutrients on the macular pigment optical density (MPOD) in participants with healthy eyes. Abstract A review of the literature highlighted that ocular supplements are produced in various combinations of nutrients and concentrations. The ideal concentrations of nutrients such as lutein (L) have not been established. It was unclear whether different stages of eye disease require different concentrations of key nutrients, leading to the design of this study. The primary aim was to determine the effects of ocular supplements with different concentrations of nutrients on the MPOD of healthy participants. The secondary aim was to determine L and zeaxanthin (Z) intake at the start and end of the study through completion of food diaries. The primary study was split into two experiments. Experiment 1 was an exploratory study to determine sample size and experiment 2 the main study. Statistical power was calculated and a sample size of 38 was specified. Block stratification for age, gender and smoking habit was applied and from 101 volunteers 42 completed the study, 31 with both sets of food diaries. Four confounders were accounted for in the design of the study; gender, smoking habit, age and diet. Further factors that could affect comparability of results between studies were identified during the study and were not monitored; ethnicity, gastro-intestinal health, alcohol intake, body mass index and genetics. Comparisons were made between the sample population and the Sheffield general population according to recent demographic results in the public domain. Food diaries were analysed and shown to have no statistical difference when comparing baseline to final results. The average L and Z intake for the 31 participants who returned both sets of food diaries was initially 1.96mg and 1.51mg for the final food diaries. The effect of the two ocular supplements with different levels of xanthophyll (6mg lutein/zeaxanthin and 10mg lutein only) on MPOD was not significantly different over a four-month period.

Improving the cost-effectiveness of photographic screening for diabetic macular oedema:a prospective, multi-centre, UK study

Background/aims: Retinal screening programmes in England and Scotland have similar photographic grading schemes for background (non-proliferative) and proliferative diabetic retinopathy, but diverge over maculopathy. We looked for the most cost-effective method of identifying diabetic macular oedema from retinal photographs including the role of automated grading and optical coherence tomography, a technology that directly visualises oedema. Methods: Patients from seven UK centres were recruited. The following features in at least one eye were required for enrolment: microaneurysms/dot haemorrhages or blot haemorrhages within one disc diameter, or exudates within one or two disc diameters of the centre of the macula. Subjects had optical coherence tomography and digital photography. Manual and automated grading schemes were evaluated. Costs and QALYs were modelled using microsimulation techniques. Results: 3540 patients were recruited, 3170 were analysed. For diabetic macular oedema, England's scheme had a sensitivity of 72.6% and specificity of 66.8%; Scotland 's had a sensitivity of 59.5% and specificity of 79.0%. When applying a ceiling ratio of £30 000 per quality adjusted life years (QALY) gained, Scotland's scheme was preferred. Assuming automated grading could be implemented without increasing grading costs, automation produced a greater number of QALYS for a lower cost than England's scheme, but was not cost effective, at the study's operating point, compared with Scotland's. The addition of optical coherence tomography, to each scheme, resulted in cost savings without reducing health benefits. Conclusions: Retinal screening programmes in the UK should reconsider the screening pathway to make best use of existing and new technologies.

Ranibizumab 0.5 mg for diabetic macular edema with bimonthly monitoring after a phase of initial treatment:18-month, multicenter, phase IIIB RELIGHT study

Abstract PURPOSE: To evaluate ranibizumab 0.5 mg using bimonthly monitoring and individualized re-treatment after monthly follow-up for 6 months in patients with visual impairment due to diabetic macular edema (DME). DESIGN: A phase IIIb, 18-month, prospective, open-label, multicenter, single-arm study in the United Kingdom. PARTICIPANTS: Participants (N = 109) with visual impairment due to DME. METHODS: Participants received 3 initial monthly ranibizumab 0.5 mg injections (day 0 to month 2), followed by individualized best-corrected visual acuity (BCVA) and optical coherence tomography-guided re-treatment with monthly (months 3-5) and subsequent bimonthly follow-up (months 6-18). Laser was allowed after month 6. MAIN OUTCOME MEASURES: Mean change in BCVA from baseline to month 12 (primary end point), mean change in BCVA and central retinal thickness (CRT) from baseline to month 18, gain of ≥10 and ≥15 letters, treatment exposure, and incidence of adverse events over 18 months. RESULTS: Of 109 participants, 100 (91.7%) and 99 (90.8%) completed the 12 and 18 months of the study, respectively. The mean age was 63.7 years, the mean duration of DME was 40 months, and 77.1% of the participants had received prior laser treatment (study eye). At baseline, mean BCVA was 62.9 letters, 20% of patients had a baseline BCVA of >73 letters, and mean baseline CRT was 418.1 μm, with 32% of patients having a baseline CRT <300 μm. The mean change in BCVA from baseline to month 6 was +6.6 letters (95% confidence interval [CI], 4.9-8.3), and after institution of bimonthly treatment the mean change in BCVA at month 12 was +4.8 letters (95% CI, 2.9-6.7; P < 0.001) and +6.5 letters (95% CI, 4.2-8.8) at month 18. The proportion of participants gaining ≥10 and ≥15 letters was 24.8% and 13.8% at month 12 and 34.9% and 19.3% at month 18, respectively. Participants received a mean of 6.8 and 8.5 injections over 12 and 18 months, respectively. No new ocular or nonocular safety findings were observed during the study. CONCLUSIONS: The BCVA gain achieved in the initial 6-month treatment period was maintained with an additional 12 months of bimonthly ranibizumab PRN treatment.

One-year outcome of bevacizumab therapy for chronic macular edema in central and branch retinal vein occlusions in real-world clinical practice in the UK

Background: The purpose of this study was to investigate the 12-month outcome of macular edema secondary to both chronic and new central and branch retinal vein occlusions treated with intravitreal bevacizumab in the real-life clinical setting in the UK. Methods: Retrospective case notes analysis of consecutive patients with retinal vein occlusions treated with bevacizumab in 2010 to 2012. Outcome measures were visual acuity (measured with Snellen, converted into logMAR [logarithm of the minimum angle of resolution] for statistical calculation) and central retinal thickness at baseline, 4 weeks post-loading phase, and at 1 year. Results: There were 56 and 100 patients with central and branch retinal vein occlusions, respectively, of whom 62% had chronic edema and received prior therapies and another 32% required additional laser treatments post-baseline bevacizumab. Baseline median visual acuity was 0.78 (interquartile range [IQR] 0.48–1.22) in the central group and 0.6 (IQR 0.3–0.78) in the branch group. In both groups, visual improvement was statistically significant from baseline compared to post-loading (P,0.001 and P=0.03, respectively), but was not significant by month 12 (P=0.058 and P=0.166, respectively); 30% improved by at least three lines and 44% improved by at least one line by month 12. Baseline median central retinal thickness was 449 μm (IQR 388–553) in the central group and 441 µm (IQR 357–501) in the branch group. However, the mean reduction in thickness was statistically significant at post-loading (P,0.001) and at the 12-month time point (P,0.001) for both groups. The average number of injections in 1 year was 4.2 in the central group and 3.3 in the branch group. Conclusion: Our large real-world cohort results indicate that bevacizumab introduced to patients with either new or chronic edema due to retinal vein occlusion can result in resolution of edema and stabilization of vision in the first year.

Improving the economic value of photographic screening for optical coherence tomography-detectable macular oedema:a prospective, multicentre, UK study

Objectives: To determine the best photographic surrogate markers for detecting sight-threatening macular oedema (MO) in people with diabetes attending UK national screening programmes. Design: A multicentre, prospective, observational cohort study of 3170 patients with photographic signs of diabetic retinopathy visible within the macular region [exudates within two disc diameters, microaneurysms/dot haemorrhages (M/DHs) and blot haemorrhages (BHs)] who were recruited from seven study centres. Setting: All patients were recruited and imaged at one of seven study centres in Aberdeen, Birmingham, Dundee, Dunfermline, Edinburgh, Liverpool and Oxford. Participants: Subjects with features of diabetic retinopathy visible within the macular region attending one of seven diabetic retinal screening programmes. Interventions: Alternative referral criteria for suspected MO based on photographic surrogate markers; an optical coherence tomographic examination in addition to the standard digital retinal photograph. Main outcome measures: (1) To determine the best method to detect sight-threatening MO in people with diabetes using photographic surrogate markers. (2) Sensitivity and specificity estimates to assess the costs and consequences of using alternative strategies. (3) Modelled long-term costs and quality-adjusted life-years (QALYs). Results: Prevalence of MO was strongly related to the presence of lesions and was roughly five times higher in subjects with exudates or BHs or more than two M/DHs within one disc diameter. Having worse visual acuity was associated with about a fivefold higher prevalence of MO. Current manual screening grading schemes that ignore visual acuity or the presence of M/DHs could be improved by taking these into account. Health service costs increase substantially with more sensitive/less specific strategies. A fully automated strategy, using the automated detection of patterns of photographic surrogate markers, is superior to all current manual grading schemes for detecting MO in people with diabetes. The addition of optical coherence tomography (OCT) to each strategy, prior to referral, results in a reduction in costs to the health service with no decrement in the number of MO cases detected. Conclusions: Compared with all current manual grading schemes, for the same sensitivity, a fully automated strategy, using the automated detection of patterns of photographic surrogate markers, achieves a higher specificity for detecting MO in people with diabetes, especially if visual acuity is included in the automated strategy. Overall, costs to the health service are likely to increase if more sensitive referral strategies are adopted over more specific screening strategies for MO, for only very small gains in QALYs. The addition of OCT to each screening strategy, prior to referral, results in a reduction in costs to the health service with no decrement in the number of MO cases detected. © Queen's Printer and Controller of HMSO 2013.