Evolution in Screening: Benefits of identifying and managing disease earlier

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Robyn Ramsey
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1 Evolution in Screening: Benefits of identifying and managing disease earlier Bora Eldem, Prof.,MD.,FEBO, Professor of Ophthalmology, Faculty of Medicine, Hacettepe University, Turkey

2 Survey methodology 1 Qualitative study Eight countries: Argentina, Bangladesh, Germany, Japan, Mexico, Romania, Saudi Arabia and Uganda Interviews to examine the experience of people with diabetes (n=73) as well as providers (n=48) 2 Quantitative study Forty-one countries across Europe, the Americas, Africa, Middle East, Asia and Oceania Purposeful sample of people with diabetes (n=3,590) and/or healthcare professionals (n=1,451)

complications patients are most aware of 1. Vision loss (40%) 2. Cardiovascular disease/stroke (17%) 3.

3 Awareness of diabetes complications Diabetes patients are more aware of vision loss as a complication of diabetes than any other complication Top 5 complications patients are most concerned about Top 5 complications patients are most aware of 1. Vision loss (40%) 2. Cardiovascular disease/stroke (17%) 3. Amputation (16%) 4. Kidney disease (13%) 5. Neuropathy (4%) Vision loss Amputation Neuropathy Kidney disease Foot ulcers

4 Discussions with the healthcare provider Over a quarter of patients are not having conversations about potential eye complications with healthcare providers as early or as regularly as they should Frequency of discussions with health care professionals about eye complications Never Around 1 in 6 patients only discuss symptoms once they have already arisen Every visit Nearly 1 in 8 patients never discuss eye complications with their physicians Once per year Multiple times per year

Education and prevention summary 1 2 Patients are aware and concerned

their diabetes well and not doing everything they can to prevent

health care providers as early or regularly as they should 3 There is

5 Education and prevention summary 1 2 Patients are aware and concerned about vision loss as a complication of diabetes but are not managing their diabetes well and not doing everything they can to prevent vision loss Many patients are not discussing eye complications with health care providers as early or regularly as they should 3 There is a lack of patient educational resources to support prevention and early diagnosis

Symptom presentation to health provider Providers say nearly two-thirds of patients come for screening only when visual problems have already occurred Less than 1 in 3 patients screened in time

6 Symptom presentation to health provider Providers say nearly two-thirds of patients come for screening only when visual problems have already occurred Less than 1 in 3 patients screened in time Timing of presentation for eye screening Too late for effective treatment More than one-quarter of patients say they have not had an eye exam in the past two years (26%) When visual problems have already occurred In time for screening

Diagnosis and management summary 1 2 3 The majority of patients

Lack of understanding of diabetes-related eye complications as

from being screened as early or as often as they should Poor

insufficient resources for both patients and providers is

7 Diagnosis and management summary The majority of patients present for screening after vision loss has already occurred Lack of understanding of diabetes-related eye complications as well as long wait times and high costs are preventing patients from being screened as early or as often as they should Poor referral pathways, lack of multidisciplinary integration and insufficient resources for both patients and providers is leading to late diagnosis and limiting specialists ability to improve patient outcomes

manage diabetes and its complications Vision

perform work-related tasks, which can lead

8 Impact of vision loss summary Eye complications impact a patient s ability to manage diabetes and its complications Vision loss can impact a patient s ability to perform work-related tasks, which can lead to significant economic consequences DR and vision loss not only have a tremendous personal impact, but also affects families and entire countries

9 Early diagnosis and initiation of anti-vegf treatment is of crucial importance

10 Baseline VA is associated with VA outcomes at Year 1 Patients with VA of 20/32 or better at Year 1 (%) The relationships between various baseline characteristics and VA outcomes at Year 1 after treatment with ranibizumab were analyzed in a DRCR.net study Patients with VA of 20/32 or better at Year Eyes with lower VA at baseline were more likely to achieve larger gains in VA but less likely to reach near-normal VA 0 20/320-20/100 20/80-20/63 20/50 20/40 Baseline VA Change in VA from baseline (letters) DRCR.net, Diabetic Retinopathy Clinical Research Network; VA, visual acuity. Bressler SB et al. Arch Ophthalmol 2012; 130 (9): supplementary table 2.

Delaying anti-vegf treatment may lead to irreversible vision loss Mean change in BCVA from baseline (ETDRS letters) From Week 100, patients in the laser group were eligible to receive PRN aflibercept

11 Delaying anti-vegf treatment may lead to irreversible vision loss Mean change in BCVA from baseline (ETDRS letters) From Week 100, patients in the laser group were eligible to receive PRN aflibercept treatment if they met predefined vision loss and OCT criteria Patients in the laser group who received aflibercept treatment after Week 100 achieved only modest vision gains, suggesting that irreversible vision loss may have occurred when access to aflibercept treatment was delayed VIVID: Mean change in BCVA through Week 148 Measurements censored after rescue treatment was given * * +9.4* Week +11.4* Includes patients who received aflibercept PRN *P< vs. laser. Any one of the following: (a) >50 µm increase in CST compared with the lowest previous measurement; (b) new or persistent cystic retinal changes or subretinal fluid on OCT, or persistent diffuse edema in the central subfield on OCT; (c) loss of 5 letters from the best previous measurement in conjunction with any increase in CST; or (d) increase of 5 letters between the current and the most recent visit. Full analysis set; last observation carried forward. 2q4, 2 mg every 4 weeks; 2q8, 2 mg every 8 weeks, after 5 initial monthly doses; BCVA, best corrected visual acuity; CST, central subfield thickness; ETDRS, Early Treatment Diabetic Retinopathy Study; OCT, optical coherence tomography; PRN, pro re nata (as needed); VEGF, vascular endothelial growth factor. Heier JS et al. Ophthalmology 2016; 123 (11): * +10.3* Laser (n=132) Aflibercept 2q4 (n=136) Aflibercept 2q8 (n=135)

12 Screening has the potential to reduce the prevalence of DR-related blindness DR, diabetic retinopathy.

13 In England and Wales, DR is no longer the leading cause of certifiable blindness DR has been the leading cause of certifiable blindness among working-age adults in England and Wales for many years Top three causes of certifiable blindness* among working-age adults (16 64 years) in England and Wales: Optic atrophy 10.1[ 10.1% Hereditary retinal disorders 15.8[ 15.8% DR 17.7[ 17.7% Leading cause: DR Proportion of certifications (%) *Blindness was certified if the following criteria were met in the better-seeing eye: BCVA <3/60; BCVA <6/60 and very contracted; BCVA 6/60 and very contracted, especially in the lower part of the field. BCVA, best corrected visual acuity; DR, diabetic retinopathy. Bunce C et al. Eye (Lond) 2008; 22 (7):

14 In England and Wales, DR is no longer the leading cause of certifiable blindness DR screening programs were introduced in England and Wales between 2003 and 2008 By 2010, DR was no longer the leading cause of certifiable blindness Top three causes of certifiable blindness* among working-age adults (16 64 years) in England and Wales: Optic atrophy 14.1[ 14.1% Hereditary retinal disorders 20.2[ 20.2% Leading cause: Hereditary disorders DR 14.4[ 14.4% Proportion of certifications (%) *Blindness was certified if the following criteria were met in the better-seeing eye: BCVA <3/60; BCVA <6/60 and very contracted; BCVA 6/60 and very contracted, especially in the lower part of the field. BCVA, best corrected visual acuity; DR, diabetic retinopathy. Bunce C et al. Eye (Lond) 2008; 22 (7):

15 The NHS diabetic eye screening pathway Eligible patients are invited for screening Digital retinal photographs are obtained Images are graded Referral to retinal specialist Further surveillance (annual rescreening) NHS, National Health Service. Public Health England. Diabetic eye screening care pathway. Available at Accessed July 2017.

16 Graded images receive annual rescreening or are referred for further investigation Low risk eyes No disease (R0 M0) Mild non-proliferative retinopathy (R1 M0) Higher risk eyes Pre-proliferative DR (R2) Proliferative retinopathy (R3) Maculopathy (M1); Ungradable (U) Annual rescreen Referred to hospital eye service DR, diabetic retinopathy. Tufail A et al. Ophthalmology 2017; 124 (3):

17 Image grading is a multistep process Retinal images may undergo multiple analyses by image graders before referral The speed of referral depends on the grade of disease R0 R1 R2 R3 M0 M1 U Retinal image grading No retinopathy Background retinopathy Pre-proliferative retinopathy Proliferative retinopathy No maculopathy Maculopathy Ungradable 90% of R0 Level 1 grader Agreed R0, R1 Annual rescreen Level 2 grader Urgent referral (R3) R3, R2, M1, U, R1, and 10% of R0 Level 3 grader All R3, U Agreed R2, M1 Disagreements over grade R0, R1 R3, R2, M1, U Referral to hospital eye service Tufail A et al. Ophthalmology 2017; 124 (3):

18 Implementing DR screening programs can be challenging DR, diabetic retinopathy.

19 Manual grading is labor and capital intensive, requiring trained human graders

The global incidence of diabetes has more than doubled since 1980 415 million adults were diagnosed

million Diabetes is a leading cause of vision loss among working-age adults 3 Ogurtsova K et al.

who.int/diabetes/publications/grd-2016/en. Accessed September 2017.

20 The global incidence of diabetes has more than doubled since million adults were diagnosed with the disease in This is predicted to rise to 642 million by million Diabetes is a leading cause of vision loss among working-age adults 3 Ogurtsova K et al. Diabetes Res Clin Pract 2017; 128: Global report on diabetes; Available at: Accessed September Diabetic retinopathy Asia Pacific. Available at: Accessed September 2017.

Automated retinal image analysis has the potential to reduce the burden of DR screening Automated retinal image analysis systems (ARIAS) allow the detection of DR without requiring a human grader 1

21 Automated retinal image analysis has the potential to reduce the burden of DR screening Automated retinal image analysis systems (ARIAS) allow the detection of DR without requiring a human grader 1 The diagnostic accuracy of these systems has been reported to be comparable to that of a human grader, with a high degree of sensitivity 1 ARIA systems have the potential to increase efficiency, reproducibility and coverage of screening programs 2 To be implemented, an ARIA system should be: Independently validated Able to perform in a reallife, high-volume setting Safe Cost-effective ARIA, automated retinal image analysis; DR, diabetic retinopathy. Tufail A et al. Ophthalmology 2017; 124 (3): Gulshan V et al. JAMA 2016; 316 (22):

22 The diagnostic accuracy of several ARIA systems was tested in a UK Health Technology Assessment ARIA, automated retinal image analysis. Tufail A et al. Health Technol Assess 2016; 20 (92): 1 72.

23 Key features of the study population Patients presenting for routine DR screening in central London 20,258 consecutive patients (102,856 images) Multiple camera types Multiple photographers Multiple graders Multiple ethnicities: White: 41% Asian: 35% Black: 20% DR, diabetic retinopathy. Tufail A et al. Health Technol Assess 2016; 20 (92): 1 72.

24 Investigating the accuracy and costeffectiveness of ARIA systems Aim: To determine the effectiveness/cost-effectiveness of CE-marked ARIA systems that were available at the time of study initiation: The ability of each ARIAS to correctly identify patients with DR was compared against trained human graders A health-economic analysis was performed to investigate the cost-effectiveness of each ARIAS compared with purely manual grading ARIAS igradingm Retmarker EyeArt IDx-DR* Version and manufacturer Version 1.1, Medalytix (Manchester, UK) / Digital Healthcare (Cambridge, UK) Version /02/10, Critical Health (Coimbra, Portugal) Eyenuk Inc. (California, USA) IDx (Iowa, USA) *IDx-DR withdrew from the study because of commercial reasons. ARIA, automated retinal image analysis; ARIAS, automated retinal image analysis system; CE, Conformité Européenne; DR, diabetic retinopathy. Tufail A et al. Health Technol Assess 2016; 20 (92): 1 72.

25 Results Retmarker and EyeArt achieved acceptable sensitivity and false positive rates for referable retinopathy igradingm classified all images as being disease present or ungradable No patients were filtered out as having no disease Disease classification Sensitivity point estimate, % (95% CI) Retmarker EyeArt Any retinopathy 73.0 ( ) 94.7 ( ) Referable retinopathy 85.0 ( ) 93.8 ( ) This was because the software was unable to process disc-centered images Proliferative retinopathy 97.9 ( ) 99.6 ( ) CI, confidence interval. Tufail A et al. Health Technol Assess 2016; 20 (92): 1 72.

ARIA systems may improve the cost-effectiveness of DR screening The specificities of Retmarker and EyeArt were sufficient to be cost saving 1 In a UK cost-effectiveness analysis, ARIA systems were

26 ARIA systems may improve the cost-effectiveness of DR screening The specificities of Retmarker and EyeArt were sufficient to be cost saving 1 In a UK cost-effectiveness analysis, ARIA systems were deemed cost-saving when replacing Level 1 graders, or as a filter prior to Level 1 human grading* 1 For a program of about 20,000 patients, use of ARIA systems was predicted to save between 80,000 and 100,000 1 *Cost information comprised data obtained from manufacturers, Persona Social Services Research Unit costs, NHS tariff payment system national prices, hospital costs data, existing literature, and expert opinion. ARIA, automated retinal image analysis; ARIAS, automated retinal image analysis system; D +, disease present; D, disease absent; DR, diabetic retinopathy; M1, maculopathy; NHS, National Health Service; R0, no retinopathy; R1, background retinopathy; R2, pre-proliferative retinopathy; R3, proliferative retinopathy; TF, technical failure; U, ungradable. Tufail A et al. Ophthalmology 2017; 124 (3):

Burden relative to purely manual analysis (%) In Portugal, the use of an ARIAS has reduced the burden of screening by almost 50% The Retmarker automated screening system was introduced in central

27 Burden relative to purely manual analysis (%) In Portugal, the use of an ARIAS has reduced the burden of screening by almost 50% The Retmarker automated screening system was introduced in central Portugal in July 2011 Since its implementation, the ARIAS has reportedly reduced the burden of grading by 48% compared with manual grading alone DR image grading in central Portugal Burden of No automated analysis Automated analysis 100% 78% 52% ARIAS, automated retinal image analysis system; DR, diabetic retinopathy. Ribeiro L et al. Ophthalmologica 2015; 233 (2):

28 Emerging ARIA systems for detecting DR are likely to have better sensitivity/specificity but need independent validation Emerging ARIA systems and deep learning algorithms may report better sensitivities and specificities than those that have been previously tested There is a need for independent assessment and validation of these systems and algorithms 1,2 1. AI, artificial intelligence; ARIA, automated retinal image analysis; DR, diabetic retinopathy. 2. Tufail A et al. Health Technol Assess 2016; 20 (92): Gulshan V et al. JAMA. 2016; 316 (22):

29 In conclusion In patients with diabetes, irreversible vision loss may occur if the initiation of anti-vegf treatment is delayed, but regular screening can facilitate timely intervention 1,2 Since the introduction of nationwide screening in England and Wales, DR is no longer the leading cause of blindness in working-age adults 2 Implementing a screening system can be challenging, and the image grading process is cost and labor intensive 3 ARIA systems, such as Retmarker and EyeArt could replace human graders in the early steps of image grading 3 By doing so, they may reduce the cost and manpower required for DR screening and improve access for patients, facilitating earlier diagnosis and intervention 3,4 1. ARIA, automated retinal image analysis; DR, diabetic retinopathy; VEGF, vascular endothelial growth factor.heier JS et al. Ophthalmology 2016; 123 (11): Liew G et al. BMJ Open 2014; 4 (2): e Tufail A et al. Ophthalmology 2017; 124 (3): Gulshan V et al. JAMA 2016; 316 (22):

Diabetic Retinopathy: Recent Advances in Treatment and Treatment Approaches

Diabetic Retinopathy: Recent Advances in Treatment and Treatment Approaches Dr. David Wong Associate Professor Retina Specialist, Department of Ophthalmology & Vision Sciences, University of Toronto, Canada