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AMD: A Common Sense Approach

AMD: A Common Sense Approach. Kyle Dohm, OD Naval Medical Center San Diego, CA Andrew Franken, OD Reifschneider Eye Center Leavenworth, KS. Definition.

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AMD: A Common Sense Approach

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  1. AMD: A Common Sense Approach Kyle Dohm, OD Naval Medical Center San Diego, CA Andrew Franken, OD Reifschneider Eye Center Leavenworth, KS

  2. Definition • A chronic degenerative disorder of the macula (including the choroid, retinal pigment epithelium and photoreceptors) that features RPE (geographic) atrophy, serous detachment of the RPE and choroidal neovascularization -- ultimately degrading central vision, typically in those patients 50 years and older.

  3. Does this patient have AMD?(two pics because could be viewed w/ a stereo viewer)

  4. OS

  5. MaybeMaybe Not • Can you really know for sure? • Possibly just normal aging changes. • Drusen/RPE changes common in those 45 years old and above. • If it was early AMD, can you help the patient? • NO. More to come. • Our assessment of the macula: “RPE changes w/o net”

  6. Another patient • 68 WM • HTN controlled c Lisinopril • Low refractive error c presbyopia 20/20 OD/OS • All exam findings unremarkable except the next slide

  7. OS

  8. AMD? Norm age changes?

  9. Pretty similar to first patient. Very common in the older population (some form of drusen and/or RPE changes almost universal). Both of these patients were 20/20 and have been stable (no change in photos or VA) for many years with these pigmentary changes.

  10. Threats to Vision • 2 threats to vision from AMD • (1) RPE atrophy for which there is no Tx • RPE dies and thus photoreceptors die too • (2) CNVM (net) for which there is Tx, but is not always successful • Some might argue #1 above. The possible benefit of eye vitamins is a modest retarding of progression in a small number of patients with advanced retinal abnormalities; they are certainly not a cure.

  11. Wet AMD • 4 things to look for in your fundus exam • Sub-RPE net (looks grey/green/brown); located btn RPE and Bruch’s membrane of choroid. • Sub-Retinal net (looks red); located btn sensory retina and RPE. • Sub-RPE Detachment (PED) (looks like a large soft drusen—yellow/gray) • Sub-Retinal Detachment (looks clear and elevated) • Hard to see! Why? • clear fluid under clear tissue

  12. In a nutshell • Looking for blood and/or fluid (clear plasma) under the sensory retina and/or the RPE • Indicates Wet AMD and possible Tx • For Dry AMD, be cautious of the diagnosis, especially if VA is unaffected. • Could possibly do more harm than good if you discuss the Dx of this sight-threatening disease with the patient, when in fact the patient has normal aging changes. • A 50 year old who has 35 more years to live might have a reduced quality of life if worried about going blind.

  13. What did you see? • Wet AMD • Subsensory (retinal) net: blood btn RPE and sensory retina • Subsensory detachment: can’t really see elevation here since it is not in stereo • Sub RPE net and sub RPE detachment (again, hard to appreciate w/out stereo) • Order a Fluorescein Angiogram (FA) • Refer to retinal specialist for possible Tx

  14. Nets in GARPE (Geographic Atrophy of the RPE)? • Yes or no and why? • Not usually since RPE dies and eventually choriocapillaris, which is the source of nets, dies too. • Watch for nets around the borders of GARPE, however.

  15. An example of how Dry AMD can progress. • Dry AMD w/ many drusen and RPE changes w/o net • Slow reduction in VA over the years. • Progressed to Geographic atrophy and even more reduction in VA

  16. You do some stats • What is the risk reduction for a given Tx vs. placebo in these examples? • 90% vs. 45% • 10% vs. 5% • 2 out of 1000 vs. 1 out of 1000 • All of these have a relative risk reduction (RRR) of 50% • Most studies give RRR

  17. 3 stats to look for in a study • Relative Risk (RR): ratio of risk of conversion in Txed pts vs Untxed pts • Absolute Risk (AR): % of Untxed minus % of Txed • Number Needed to Treat (NNT): inverse of ARR (# of pts needed to undergo tx in order to help 1) • Ex. 10% placebo vs 5% Txed • RRR: 5%/10%= 50% • ARR: 10%-5%= 5% • NNT: 1/5%= 20

  18. More Statistics • P-value: usually p<0.5 = statistically significant, which doesn’t necessarily mean clinically significant • Confidence Interval: describes magnitude and range of the true Tx effect; so 95% CI describes range of values that the true effect occurred at least 95% of the time, 5% chance • NNT: # of pts that would have to be treated for one pt to benefit • Bayesian Analysis: used for Dx not Tx • See the following website (write down and view later) from the Medical College of Wisconsin for a helpful online tool • http://www.intmed.mcw.edu/clincalc/bayes.html

  19. Must always know the power of the study being read/analyzed. • Prospective, randomized, masked (double-blind is best), controlled (placebo/sham), long-term clinical trial (multicenter) is most powerful. • We don’t still Tx MS w/ only oral steroids, contrary to 40+ years of experience and “literature” claiming its usefulness and success. • It’s good to analyze a study’s data and draw your own conclusions. These may not always be exactly in step with the authors’ conclusions. • Read. Interpret. Think. Analyze. (RITA)

  20. AREDS (Age-Related Eye Disease Study) • Purpose- evaluate effect of high-dose antioxidants (vitamins C and E and beta carotene) and zinc supplements on AMD progression and VA • 3,640 patients followed for an average of 6.3 years • All patients began with 20/32 vision in at least one eye

  21. 4 Groups • Category 1: essentially AMD free= <5 small drusen • Category 2= mild/borderline AMD: >5 small drusen, and/or RPE changes • Category 3: mod AMD= at least 1 large drusen, extensive intermediate drusen, non-central geographic atrophy (GA) or any combo • Category 4: advanced AMD (central GA or CNV) or <20/32 in non-study eye; no advanced AMD and > 20/32 in study eye

  22. Results • Statistical significance could not be found in any of the categories; only when groups 3 and 4 were combined was there a statistical significant finding • At 5 years, probability of 15 letter decrease (3 lines on ETDRS chart) was 29% placebo vs 23% antioxidants + zinc (in groups 3 & 4 combined)

  23. What does this really mean? • 29%-23%= 6% ARR; NNT = 17 • So 6 out of 100 people in groups 3 & 4 (combined) on AREDS formulation will not lose 3 lines of VA in 5 years [6 can be found by ARR or by taking 77 AREDS pts not losing 3 lines minus 71 placebo pts not losing 3 lines] • 71 out of 100 placebo (not taking AREDS vitamins) will not lose 3 lines of VA in 5 years either • What should we tell patients when they ask “Will vitamins slow progression and/or prevent me from getting AMD?”

  24. Response • Eye vitamins have been shown to slow progression in 1 out of 17 (6%) patients with advanced dry AMD • There is no evidence eye vitamins prevent AMD or slow progression in those with mild/moderate AMD • However, there is currently ongoing research in this area (AREDS II) and we are hopeful for positive results • We should be honest about the benefit or lack thereof • Simply tell your patient with mild/moderate changes that the eye vitamins that are so commonly advertised are not necessary for the current stage of his/her condition

  25. Quotes from the study (AREDS Report # 8) • “The treatment benefit is modest and participants in all treatment arms continue to progress to advanced AMD and lose vision over time.” • “The results of AREDS to date demonstrate no benefit of the study formulations for persons in Categories 1 or 2.” • “In AREDS, persons in these categories (1 or 2) had low rates of progression to advanced AMD and therefore the study has very low power to assess the effect of these treatments on the development of advanced AMD. With these low rates it seems reasonable to defer consideration of supplementation until the risk of progression is higher, especially because analyses to date do not show that treatment is effective in slowing the progression of AMD from Category 2 to Categories 3 or 4. Whether supplementation benefits persons who already have advanced neovascular AMD in both eyes is not clear and this study was not designed to address this question.”

  26. Any harm from high dose Antioxidants and Zinc?? • High dose = many times (5-15) above Recommended Dietary Allowance (RDA) • Increased risk of UTI requiring hospitalization • Increased lung cancer risk for smokers (on beta carotene) • Increased risk of yellowing of skin • Possible increased risk for anemia and prostate cancer • Possible increased risk of cholesterol med becoming less effective • Possible increased bleeding time/blood thinning (more so than expected) while on anti-coag med • Not bad to take a multivitamin and eat plenty of fruits and veggies!

  27. Switch Gears Wet AMD Treatments

  28. Visudyne (verteporfin) • Photochemical (administered via IV) that has an affinity for new, leaky blood vessels (nets) • Laser is delivered on the net; the Vertoporfin is stimulated; the leaky vessels are occluded • Treatment is for predominantly classic nets (no benefit was shown w/ occult lesions)

  29. Study Results: Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study • Results @ 1 year (avg 3.4 treatments) • Loss of 15 letters or less: 61% Tx vs 46% placebo • 20/40 or better: 4.7% vs 1% • Results @ 2 years (avg 2.2 treatments) • Loss of 15 letters or less: 53% Tx vs 38% placebo • 20/40 or better: 5.5% vs 2.4% • ARR: 15% NNT: 7

  30. Macugen (pegaptanib) • Intravitreal injection that binds a domain on VEGF-A, thus blocking VEGF 165 from the receptors • VEGF is the chemical released which stimulates new blood vessel growth • So this can be used on occult lesions • FDA approved in December 2004

  31. Study Results: VEGF Inhibition Study in Ocular Neovascularization (VISION) (2 concurrent studies) • 1186 pts with VA of 20/40-20/320 • All types of CNV membranes allowed in the study • Loss of 15 letters or less: 70% Tx vs 55% controls • ARR: 15% NNT: 7 • Maintained or gained vision: 33% Tx vs 23% controls

  32. Lucentis (ranibizumab) • Also an intravitreal injection; binds/blocks VEGF-A • Monoclonal antibody fragment given every month • Unlike Macugen, Lucentis binds to and inhibits all forms of VEGF-A and its active degradation products • FDA approved for Wet AMD on June 30, 2006

  33. Study Results • Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) • 95% Lucentis pts vs 62% sham-treated pts showed visual improvement or stabilization after 12 months • Lucentis-Txed pts: 3 times as many pts with 20/40 compared to baseline • Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) • Maintained (less than 15 letters lost) or improved vision after 12 mo: • 0.3 mg Lucentis: 94% • [VA improved by 15 letters or more: 35.7%] • 0.5 mg Lucentis: 96% • [VA improved by 15 letters or more: 40.3%] • PDT (verteporfin): 64% • [VA improved by 15 letters or more: 5.6%]

  34. Avastin (bevacizumab) • Also an intravitreal injection that blocks VEGF-A • Used off-label for AMD • Parent molecule from which Lucentis comes from • Full length monoclonal antibody given every 2-4 weeks (possibly longer in future) • Avastin has 2 antigen-binding domains; Lucentis has one • FDA approved in Feb. 2004 for metastatic colorectal cancer

  35. Study Results • National Eye Institute plans to fund prospective, multicenter trial directly comparing Lucentis to Avastin for ocular neovascularization • Small uncontrolled studies and anecdotal evidence suggests that it is similarly efficacious and as safe as Lucentis, but much less expensive • Anecdotal evidence from case studies suggest that it may be efficacious for macular edema as well • Current studies on safety and efficacy are ongoing

  36. Cost of Treatments • Visudyne • $1400 per treatment x 5.6 treatments = approx. $7840 over 2 years ($3920 1 yr) • Macugen • $1000 per treatment x 8.5 treatments = approx. $8500 over 54 weeks • Lucentis • $1950 per treatment x 12 treatments = approx. $23,400 for one year • Avastin • About $75 per treatment x 12 treatments = approx. $900 for one year • Potentially more promising and far less expensive

  37. AMD, new perimetry techniques, VEGF, neovascularization are all hot areas of research • AREDS II (lutein, zeaxanthin, omega-3 fatty acids) • More VEGF therapies • Avastin (systemic use as well as intravitreal for AMD, CRVO, DR, CME, other macular edemas) • VEGF Trap (another intravitreal med) • Small interfering RNA-based therapies • Receptor tyrosine kinase inhibitors • Combo approaches • Macular Computerized Psychophysical Test (MCPT) • Preferential Hyperacuity Perimetry (PHP) • Gene therapy • Macular translocation surgery • Etc.

  38. Home Amsler Grids (HAG) • HAGs are not sensitive at detecting CNVM in pts w/ AMD • 3 theories why that is the case • HAGs do not force fixation (unnatural to observe with non-foveal points) • HAGs do not overcome cortical completion (brain can “fill in” distortion, rendering them unrecognizable) • Detection reduced by crowding effects of neighboring lines (isolating distortions compromised)

  39. The West London Survey • “The Amsler chart is of doubtful value in retinal screening for early laser therapy of subretinal membranes.” • AMD patients instructed and given Home Amsler Grids • 100 patients who develop net (confirmed by FA) • 29 Responders from HAG • 11 of 29 treatable w/ PDT • 71 non-responders of HAG found by routine exam or came back due to other Sxs, of which 26 were treatable • 25 pts returned because of Sxs other than HAG

  40. Granted • The survey was a pilot (small sample of patients) to a larger study, so not high powered • Improved therapies (Lucentis, Avastin) became available after publication • Compliance is an issue with HAG • HAG itself is very subjective • Many normals will describe photopsias, which can occur with normal vision

  41. Oh yeah • The 29 responders to HAG had a mean age of 61, and the 71 non-responders to HAG had a mean age of 77 • Who is at most risk for vision loss w/ AMD? • So most of the older cohort of pts who indeed had wet AMD did not even notice on HAG • If you find a wavy in-office grid, and see absolutely no other signs funduscopically and no loss in VA, do you order an FA? • We say not. Therefore why do a test if you are going to ignore its results. Don’t let it confound you.

  42. You’re the doctor • Person who has lost vision in one eye from AMD • Advanced form of AMD • FHx of someone who has lost vision and pt is inquiring about home monitoring • Above are some cases (related to AMD) that we believe are acceptable for Home Amsler Grid monitoring • Our concern: handing these out like candy to pts w/ normal aging changes

  43. Emotional and Scary • “Patient, your eyes look like they have some early pigmentary changes/aging changes that are typically normal for people your age. BUT, take home this grid and monitor your sight daily/weekly and call us/return immediately if you notice any changes in the lines.” • Patient hears I could possibly lose some of my sight at any time, any day. • Pretty scary thought! • Caution on what you say to patients and on just starting a plan/treatment with little thought. • It is a very emotional process to find out that you may/do have a sight threatening disease.

  44. References • Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins c and e, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119:1417-1436. • Bressler NM. New detection technologies important in management of AMD [monograph on the Internet]. Ocular Surgery News. Mar 2006 [cited 2006 Oct 13]. Available: http://www.vindicomeded.com/osn/view.asp?rID=16442&uid=73310. • Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al. for the ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355(14):1432-1444. • Celia, F. A rivalry between two AMD drugs. Rev Optom 2006;143(10):41-46. • Cheatham KM. Personal communication. Kansas City Veterans Administration Medical Center, Kansas City, MO. Aug-Dec 2005. • Ferris FL. A new treatment for ocular neovascularization. N Engl J Med 2004;351(27):2863-2865.

  45. References cont. • Freeman WR, Falkenstein I. Avastin and new treatments for AMD: where are we? (Editorial). Retina 2006;26(8):853-858. • Gragoudas ES, Adamis AP, Cunningham ET, Feinsod M, Guyer DR for the VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351(27):2805-2816. • Harkins TJ. Personal communication. Kansas City Veterans Administration Medical Center, Kansas City, MO. Aug-Dec 2005. • Harkins TJ. Treating choroidal neovascular membranes in age-related macular degeneration. Clin Eye Vision Care 1994;6(4):213-216. • Hu C, Kneusel R, Barnas G. Bayesian analysis model: online clinical calculator. [on the Internet]. Medical College of Wisconsin. [cited 2006 Jan 22]. Available: http://www.intmed.mcw.edu/clincalc/bayes.html. • Kaiser PK. Antivascular endothelial growth factor agents and their development: therapeutic implications in ocular diseases. Am J Ophthalmol 2006;142(4):660-668.e1. • Kanski JJ. Clinical ophthalmology: a systematic approach. 5th ed. London: Butterworth Heinemann; 2003.

  46. References cont. • Kogan BA. AREDS 2 continues study of AMD and nutrition. Optom Management 2006;41(9):12. • Pulido JS, Blake CR. Special considerations in the guidelines for high-dose vitamin supplementation in patients with age-related macular degeneration (Correspondence). Arch Ophthalmol 2004;122:662. • Rosenfeld PJ. Intravitreal avastin: the low cost alternative to lucentis? Am J Opthalmol 2006;142(1):141-143. • Steinbrook, R. The price of sight – ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med 2006;355(14):1409-1412. • Sternberg P, Lewis H. Photodynamic therapy for age-related macular degeneration: a candid appraisal. Am J Ophthalmol 2004;137(3):483-485. • Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials---TAP report 1. Arch Ophthalmol 1999;117:1329-1345.

  47. References cont. • Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials---TAP report 2. Arch Ophthalmol 2001;119:198-207. • Willett WC, Stampfer MJ. What vitamins should I be taking, doctor? N Engl J Med 2001;345(25):1819-1824. • Zaidi FH, Cheong-Leen R, Gair EJ, Weir R, Sharkawi E, Lee N, et al. The amsler chart is of doubtful value in retinal screening for early laser therapy of subretinal membranes. The west london survey. Eye 2004;18:503-508.

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