Mark T. Dunbar Disclosures. Hot Topics in Retina. The Challenge. Where is the Fluid? 4/12/2016

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Cuthbert Francis
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1 A PANEL DISCUSSION: RAPID-FIRE POSTERIOR SEGMENT UPDATE! Steve Ferrucci, OD Chief, Optometry Sepulveda VA Plummer St #112e Sepulveda CA, Mark T. Dunbar, OD Bascom Palmer Eye Institute Miami, FL Mark T. Dunbar Disclosures Mark T. Dunbar, OD is on the Advisory Boards for Carl Zeiss Meditec, Allergan, Regeneron, Reed exhibitions. I have received honorarium from some but not all of these companies I do not own stock in any of the companies/technologies discussed today Please silence all mobile devices Hot Topics in Retina OCT Angiography (OCT-A) Has OCT emerged as standard of care? Are all VEGF drugs created equal? Protocol T DRCR.net are we seeing a paradigm shift in the treatment of diabetic retinopathy? Protocol S Are we doing harm to our patients by prescribing AREDS supplements? Evolving treatments of dry AMD The Challenge Being able to correlate what you are seeing clinicallywith what is happening anatomically and then making the correct diagnosis Is there fluid or retinal thickening? Where is the fluid? Being able to diagnose conditions that may not be seen with traditional ophthalmoscopy Where is the Fluid? 1

42 y/o Hispanic Female: Burred Vision LE PED involving fovea Advances in

Depth Map Normal Eye CNV Color Depth Map combines superficial, deepand

Superficial Retina Deep Retina Avascular Retina Color Depth Retina Map

2 42 y/o Hispanic Female: Burred Vision LE PED involving fovea Advances in Diagnostic Technology can Help Establish a Diagnosis AngioPlex Color Depth Map Normal Eye CNV Color Depth Map combines superficial, deepand avascularmaps and allows for depth visualization of blood flow Superficial Retina Deep Retina Avascular Retina Color Depth Retina Map AngioPlex Maps are flattened 2D representations vasculature. Color Represents Depth in Tissue 2

Structure - Retina OCT Imaging in Eye Care Has it evolved to be considered Standard of Care? MD vs.

3 Angiography Analysis : Angiography 3x3 mm AngioPlex - Retina Depth Encoded Structure - Retina OD OS Ischemia near the FAZ Slice: 164 Tracked during scan Macula Angio Scan Angiography Analysis : Angiography 3x3 mm OD OS AngioPlex - Retina Structure - Retina OCT Imaging in Eye Care Has it evolved to be considered Standard of Care? MD vs. OD SDOCT Does it matter which one? Don t be intimidated by the technology Diabetes and Retinal Vascular Disease They want to give me a great deal on a Stratus? 3

4 The ABC s of DME DRCR.net Protocol I Protocol T RISE RIDE READ VISTA VIVID Are All Anti-VEGF Drugs Created Equal? Avastin (Bevacizumab) Lucentis (ranibizumab) Eylea(Aflibercept) Upregulation of VEGF-A 1-39 The Diabetic Retinopathy Clinical Research Network Protocol T Comparative Effectiveness Study of Aflibercept, Bevacizumab and Ranibizumab for DME 22 *Controls in these studies included patients with cataract, macular hole, or epiretinalmembrane in the absence of any retinal vascular disease. DRCR.net: Protocol T At 1 yr Aflibercept(Eylea) group gained 13.3 letters, Ranibiumab(Lucentis) group gained 11.2 letters Bevacizumab(Avastin) group gained 9.7 letters There were no statistically significant differences among subgroups of patients starting the trial with visual acuity between 20/32 and 20/40 Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumabfor diabetic macular edema [published online ahead of print February 18, 2015]. N EnglJ Med. doi: /nejmoa

5 Mean Change in Visual Acuity Letter Score Mean Change in Visual Acuity Letter Score, Full Cohort Week Treatment Group Comparison*: Aflibercept vs. Bevacizumab P<0.001 Afliberceptvs. RanibizumabP= Ranibizumab vs. Bevacizumab P = Weeks DRCR.net If VA was 20/50 or worse Afliberceptgained 18.9 letter Ranibizumab gained 14.2 letters Bevacizumabgained 11.8 letters Aflibercept Bevacizumab Ranibizumab * P-values adjusted for baseline visual acuity and multiple comparisons Mean Change in Visual Acuity Letter Score Mean Change in Visual Acuity Letter Score Baseline Visual Acuity 20/50 or Worse ~ 50% of Cohort 1-Year Treatment Group Comparison*: Aflibercept vs. Bevacizumab P<0.001 Aflibercept vs. Ranibizumab P = Ranibizumab vs. Bevacizumab P = Weeks Aflibercept Bevacizumab Ranibizumab * P-values adjusted for baseline visual acuity and multiple comparisons Mean Change in Visual Acuity Letter Score Mean Change in Visual Acuity Letter Score Baseline Visual Acuity 20/32 to 20/40 ~50% of Cohort Weeks Aflibercept Bevacizumab Ranibizumab ~+8 Mean Change in Visual Acuity Letter Score Mean Change in Visual Acuity Over 2 Years Full Cohort Week Treatment Group Comparison*: Aflibercept vs. Bevacizumab P = 0.02 Aflibercept vs. Ranibizumab P= 0.47 Ranibizumab vs. Bevacizumab P = Weeks Aflibercept Bevacizumab Ranibizumab Mean Change in Visual Acuity Letter Score Mean Change in Visual Acuity Over 2 Years Baseline Visual Acuity 20/50 or Worse ~50% of Cohort Week Treatment Group Comparison*: Aflibercept vs. Bevacizumab P = 0.02 Aflibercept vs. Ranibizumab P= 0.18 Ranibizumab vs. Bevacizumab P = * P-values adjusted for baseline visual acuity and multiple comparisons Weeks Aflibercept Bevacizumab Ranibizumab * P-values adjusted for baseline visual acuity and multiple comparisons 5

1 st Exam: 7/22 Are We Seeing A Paradigm Shift in the Treatment of Diabetic Retinopathy? 5 ½ yrs after Initial exam 20/20 OU DRCR.

5 mg intravitreousranibizumabat baseline and as frequently as every 4 weeks (based on a structured re-treatment protocol) Primary endpoint: mean change in VA letter score from baseline

8 letters from baseline in the ranibizumabgroup vs. improvement of 0.

6 1 st Exam: 7/22 Are We Seeing A Paradigm Shift in the Treatment of Diabetic Retinopathy? 5 ½ yrs after Initial exam 20/20 OU DRCR.net: Protocol S Is Lucentisas good (noninferior) as traditional PRP for patients with PDR? 55 U.S. clinical sites 203eyes were randomly assigned to receive PRP (completed in 1 to 3 visits) and 191 eyes received 0.5 mg intravitreousranibizumabat baseline and as frequently as every 4 weeks (based on a structured re-treatment protocol) Primary endpoint: mean change in VA letter score from baseline to 2 years. JAMA. 2015; 314(20): doi: /jama (Published). DRCR.net: Protocol S At 2 years, VA improved by 2.8 letters from baseline in the ranibizumabgroup vs. improvement of 0.2 letters from baseline in the PRP group There was more peripheral VF loss and more vitrectomy s in the PRP group vs. Lucentis VF Loss: 213 db in the ranibizumabgroup vs. 531 db in the PRP group PPV: 15% with PRP vs. 4% with Lucentis When DME present, Lucentisdid a better job treating Macular Edema JAMA. 2015; 314(20): doi: /jama (Published). 6

Prevalence of DME in the US Approximately 8 million (21%) of people with diabetes have DR 1 5.8 million are diagnosed 1-3 2.3 million have DME 3 8.

3MM 1 800K Undiagnosed 1 2.3MM 3 1.5MM 3 1.5MM Diagnosed 1 ~1.

NHANES 2005-2008, projected to 2012 US population. 2. Centers for Disease Control and Prevention. www.cdc.gov.accessed June 9, 2014.Saaddine JB, et al. Arch Ophthalmol. 2008;126(12):1740-1747. 3.

7 Prevalence of DME in the US Approximately 8 million (21%) of people with diabetes have DR million are diagnosed million have DME 3 8.0MM 1 DME in the US Nearly 800,000 Americans suffer from DME but remain undiagnosed 1 Another 1.1 million are diagnosed with DME but are not receiving treatment 1,2 5.8MM MM 1 800K Undiagnosed 1 2.3MM 3 1.5MM 3 1.5MM Diagnosed 1 ~1.1MM Diagnosed, Untreated 1,2 400K 4 240K 4 ~400K Treated 2 DR Prevalence DR Diagnosed DME Prevalence DME Diagnosed DME Treated DME Anti-VEGF Treated 1. NHANES , projected to 2012 US population. 2. Centers for Disease Control and Prevention. June 9, 2014.Saaddine JB, et al. Arch Ophthalmol. 2008;126(12): BioTrends Research Group. TreatmentTrends : Diabetic Retinopathy/Diabetic Macular Edema (US) Proprietary Quantitative Market Research (n=103 retina specialists, n=23,994 DME eyes with central involvement); fielded November Prevalence Diagnosis Rate Treatment Rate 1.BioTrends Research Group. TreatmentTrends : Diabetic Retinopathy/Diabetic Macular Edema (US) Proprietary Quantitative Market Research (n=103 retina specialists, n=23,994 DME eyes with central involvement); fielded November Are We Harming Our Patients By Prescribing Nutritional Supplements in AMD? Macular Degeneration Association 7

8 Is there a conflict of interest between the NEI and B&L? Independent Group Analyzed AREDS Data Estimated Probability 40% 30% Rates to Advanced AMD AMD Categories 3 and 4 by Treatment Group Placebo Antioxidants Zinc Antioxidants + Zinc 28% AREDS2 Inclusion Criteria Bilateral Large Drusen or Late AMD in One Eye 20% 20% 10% 0% 0 25% Risk Reduction P vs. A+Z p<0.01 P vs. Z p< Years Large Drusen GA NV AMD Study Design NOT Really A Control Control 1012 No AREDS 19 Lutein and Zeaxanthin 1044 Randomized Participants n=4203 AREDS 3036 DHA and EPA 1068 AREDS 1148 Lutein/Zeaxanthin + DHA/EPA 1079 The Age-Related Eye Disease Study 2 (AREDS2) Research Group Lutein + Zeaxanthin and Omega-3 Fatty Acids for Age-Related Macular Degeneration: The Age- Related Eye Disease Study 2 (AREDS2) Randomized Clinical Trial Published online May 5, 2013 AREDS 659 AREDS minus ß-Carotene 863 AREDS + Low Zinc 689 AREDS minus ß-Carotene + Low Zinc 825 Available at jamanetwork.com 8

Estimated Probability 40% 30% 20% 10% 0% 0 Probability of Progression to AAMD Placebo - AREDS L/Z DHA/EPA L/Z & DHA/EPA 31% 31% 30% 29% 1 2 3 4 5 Years The Answer: AREDS 2 The data did not

Formulation Vitamin C (500 mg) Vitamin E (400 IU) Beta Carotene (15 mg) Lutein (10 mg)/zeaxanthin (2 mg) Zinc (80 mg zinc oxide) Copper (2 mg cupric oxide) Omega-3 fatty acids (DHA/EPA) Genetic

LIPC COL8A1 TIMP3 ARMS2 APOE CETP ABCA1 C3 C2 CFB CFI CFH CFH CFI CFB C2 C3 ARMS2 TIMP3 COL8A1 LIPC APOE CETP ABCA1 Complement Oxygen Metabolism Extracellular Matrix Cholesterol Metabolism

9 Estimated Probability 40% 30% 20% 10% 0% 0 Probability of Progression to AAMD Placebo - AREDS L/Z DHA/EPA L/Z & DHA/EPA 31% 31% 30% 29% Years The Answer: AREDS 2 The data did not demonstrate a significant reduction in progression to advanced AMD in any of the three treatment arms as compared to the control group So ARED 1 supplement just as good as AREDS 2 But AREDS2 Formulation Vitamin C (500 mg) Vitamin E (400 IU) Beta Carotene (15 mg) Lutein (10 mg)/zeaxanthin (2 mg) Zinc (80 mg zinc oxide) Copper (2 mg cupric oxide) Omega-3 fatty acids (DHA/EPA) Genetic Testing in AMD Macula Risk (Atic Dx) Retnagene Purchased by Nicox: Relaunched in June 2014 Nicox purchased by Valeant Key Genes Involved in the Development of AMD Clinical Assessment + Genetics LIPC COL8A1 TIMP3 ARMS2 APOE CETP ABCA1 C3 C2 CFB CFI CFH CFH CFI CFB C2 C3 ARMS2 TIMP3 COL8A1 LIPC APOE CETP ABCA1 Complement Oxygen Metabolism Extracellular Matrix Cholesterol Metabolism Smoking BMI Age AMD status Complete set of Risk factors Non-Genetic Factors 40% Genetic Factors 60% 1. CFH 2. CFI 3. C2 4. CFB 5. C3 6. ARMS2 7. TIMP3* 8. COL8A1* 9. LIPC* 10. CETP* 11. ABCA1* 12. APOE 9

10 What is the Relationship between Genetics, AMD and AREDS Supplement? Genetic analysis of 995 patients with intermediate (moderate) AMD who were in the original AREDS 1 study Followed for 12 years Evaluated the interaction of genetics and type of nutritional supplement on progression from moderate to advanced AMD 49% derive more benefit from treatment other than AREDS Patients with genetically determined CFH high risk alleles, zinc was associated with increased progression to advanced AMD Patients with ARMS2 high risk alleles, zinc was associated with DECREASED progression to advanced AMD antioxidants worsened the outcome Patients with CFH risk alleles benefit from antioxidants without zinc but patients with ARMS2 risk alleles benefit from zinc without antioxidant Genetic Testing and Recommending Nutritional Supplements Of the estimated 15 million Americans taking the AREDS formula, more than ten million should not be on either zinc or antioxidants Only about 23% of patients taking AREDS formula should be while the vast majority should not Genotype-directed therapy of the study population would have more than doubled the reduction in AMD progression rate compared to treatment with the AREDS formulation 10

June 26, 2014 Epub Sept 4, 2014 Wait - But that s Not All This Week Treatment Responses to Antioxidants and Zinc based on Genetic Profiles Conclusions: The benefit of

11 June 26, 2014 Epub Sept 4, 2014 Wait - But that s Not All This Week Treatment Responses to Antioxidants and Zinc based on Genetic Profiles Conclusions: The benefit of the AREDS formulation seems the result of a favorable response by patients in only 1 genotype group, balanced by neutral or unfavorable responses in 3 genotype groups 11

Heterogeneous response to zinc/antioxidants within AREDS Category 3 patients Take Home Message Genotype Group 1 2 3 4 Better Average -> Worse

specific treatment or surveillance strategies have been shown in one or more published clinical trials to be of benefit to individuals with

12 Heterogeneous response to zinc/antioxidants within AREDS Category 3 patients Take Home Message Genotype Group Better Average -> Worse American Academy of Ophthalmology Avoid routine genetic testing for genetically complex disorders like age-related maculardegeneration until specific treatment or surveillance strategies have been shown in one or more published clinical trials to be of benefit to individuals with specific disease-associated genotypes. In the meantime, ophthalmologists should confine the genotyping of such patients to research studies. 12

13 So Now What? Should we even do Genetic Testing? I think the value is in assessing risk and determing appropriate follow up 61 y/o White Male CC of new onset flashes followed by a central floater RE X 3-4 days Seen by OD 20/30 Dilates with Neo 2.5%, examines with BIO and takes optos photo Diagnosis vitreous syneresis No tobacco dust or Schaeffer s sign Explains Si/Sx of RD Asked to return in 1 mo 61 y/o White Male The pt returns 3 weeks later 20/30 blob not as dark, many little specs Is having trouble reading and working on computer Dilated with 2.5% neo Evaluated with Superfield 90, BIO, Optos Diagnosed with vitreous floaters RTC 1 mo 61 y/o White Male Pt calls office 2 weeks later says vision is getting worse Referred to retinal specialist (2 weeks since last exam) Diagnosed with macula-off RD Surgery including ultimately, MP for ERM, CE/IOL 13

14 PVD 65% of individuals > 65 have PVD More common in women More common following intraocular surgery More common following inflammation More common in aphakes PVD Retinal tears occur 8-15% of eyes with symptomatic PVD 90% are superior VH occurs in 13-19% of symptomatic PVD s VH + PVD -> 70% will have a retinal break PVD No VH -> 2-4% will have retinal break Exam of a Pt with Symptomatic PVD Should have a high suspicion of detecting Weis ring Should have a high index of suspicion of a possible retinal break Clinical exam should be conducted with these suspicions Clinical Exam of a Patient with A Symptomatic PVD All the testing and procedures that you would normally do with any patient Dilated fundus exam Look specifically at the anterior vitreous Note presence or absence of pigment or cells in the anterior vitreous -> tobacco dust, schafer s sign Peripheral extended ophthalmoscopy including scleral depression Symptoms of Flashes PVD NOT Seen What is your management? Return with in 3-4 weeks Symptoms of Flashes PVD is Seen What is your management? Do you bring him back for follow up? 14

Management of Acute PVD With Symptoms Educate about the Si/Sx of RD Return in 4-6 weeks, then 3-4 months, then annually Lattice Degeneration as a Routine Finding? Is this any cause for concern?

26 y/o Black Female Lattice Degeneration Present 5-20% of the general population Localized area of retinal thinning associated with a fluid pocket in the overlying cortical vitreous Wants to know if

15 Management of Acute PVD With Symptoms Educate about the Si/Sx of RD Return in 4-6 weeks, then 3-4 months, then annually Lattice Degeneration as a Routine Finding? Is this any cause for concern? How do you manage it? 26 y/o Black Female Lattice Degeneration Present 5-20% of the general population Localized area of retinal thinning associated with a fluid pocket in the overlying cortical vitreous Wants to know if her astigmatism has changed? Lattice Degeneration and Risk of RD Indications for Prophylactic Treatment of Peripheral Retinal Tears and Holes in Symptomatic Patients RD develop in 0.7% of eyes with lattice degeneration followed for 10.8 yrs Eyes with lattice that developed tractional retinal tears 40% occurred in areas not associated with lattice normal-appearing retina Horseshoe tears Operculated holes Atrophic holes Treat Yes Rarely No Byer NE. Ophthalmology. 1989; 96:

Indications for Prophylactic Treatment of Peripheral Retinal Tears and Holes in Asymptomatic Patients Phakic

Holes No Rarely Rarely No Rarely Sometimes Flap Tears Sometimes Sometimes Usually 48 y/o Asymptomatic Pilot

Unremarkable Fundus 44 y/o Hisp Female 20/20 44 y/o Hisp Female What is Correct Diagnosis? 1.

16 Indications for Prophylactic Treatment of Peripheral Retinal Tears and Holes in Asymptomatic Patients Phakic Highly Myopic Fellow Eye (RD in other) Atrophic Holes No No Rarely Operculated Holes Lattice with or without Holes No Rarely Rarely No Rarely Sometimes Flap Tears Sometimes Sometimes Usually 48 y/o Asymptomatic Pilot VA 20/15 OU Anterior Segment: Unremarkable Fundus 48 y/o Pilot No Sx VA 20/15 OU Anterior Segment: Unremarkable Fundus 44 y/o Hisp Female 20/20 44 y/o Hisp Female What is Correct Diagnosis? 1. Choroidal nevus 2. Choroidal melanoma 3. Melanocytoma 4. I don t really care, I am going to refer it regardless of what the diagnosis is? 16

Growth over 7 ½ months < 3 mm elevation < 3 DD in size 95% are less than 2

Features Suggesting Nevi Drusen Overlying neurosensory detachment

Zones of RPE atrophy Choroidal Melanoma >3 mm elevation Variable pigment

$American Radiologist Presented on Monday for a refraction Blurry vision OU$

17 Growth over 7 ½ months < 3 mm elevation < 3 DD in size 95% are less than 2 DD Slate gray Drusen SRF associated with drusen CNVM Choroidal Nevi Features Suggesting Nevi Drusen Overlying neurosensory detachment Choroidal neovascular membrane Circinate exudate Bony pigment spiculing Zones of RPE atrophy Choroidal Melanoma >3 mm elevation Variable pigment Multiple areas of orange pigment (lipofuscin) Serous fluid (detachment) in absence of drusen Unequivocal evidence of growth 37 y/o Middle Eastern American Radiologist Presented on Monday for a refraction Blurry vision OU RE: 20/50 LE: 20/20 17

18 18

The Age-Related Eye Disease Study

What have the Age-Related Eye Disease Study (AREDS) and AREDS2 Taught Us? Emily Y. Chew, MD National Eye Institute/National Institutes of Health On Behalf of the AREDS and AREDS2 Research Groups Presenter