FROM OUTDATED TO UPDATED Eminence-Based Medicine Evidence-Based Medicine A REVIEW OF KEY CLINICAL TRIALS Anthony DeWilde, OD FAAO 1 EMINENCE BASED MEDICINE 2 EVIDENCE BASED MEDICINE 3 4
CLINICAL TRIALS Help us to Better diagnose Guide special testing Make treatment decisions Educate patients 5 6 DIAGNOSIS TESTING DRS/ETDRS Anti-VEGF trials show benefit of testing Defined CSME and High Risk NV Find treatable macular edema 7 8
TREATMENT TREATMENT Many trials highlight effectiveness of treatment ONTT, HEDS Some may be counterintuitive CVOS 9 10 TREATMENT EDUCATION What to expect when treated Side effects 50% of ODs surveyed knew how to tx Herpes Simples Keratitis Outcomes Course of treatment Natural history 11 12
GOALS GOALS Diabetes Mellitus Understand Studies Learn what to look for in diagnosis Develop plan for referral/patient education AMD Glaucoma Herpes Simplex Optic Neuritis 13 14 DIABETES MELLITUS DIABETES MELLITUS Threats to Vision Proliferative NVG Traction RD Threats to Vision Macula Edema Ischemia V-Heme 15 16
DIABETIC RETINOPATHY STUDY (DRS) DIABETIC RETINOPATHY STUDY Benefit found for High Risk NV Does PRP reduce the rate of profound vision loss from PDR Profound vision loss = < 20/800 NVD 1/4 Disc Area NVD or NVE with pre-retinal/v-heme If not high risk, not enough benefit to justify treatment 17 18 DIABETIC RETINOPATHY STUDY DIABETIC RETINOPATHY STUDY Benefit = prevent profound vision loss Profound Vision Loss Risk = peripheral vision loss 10% develop macular edema 25% Untreated 12.5% Treated 50% Relative Risk Reduction 19 20
DIABETIC RETINOPATHY STUDY RISK REDUCTION Profound Vision Loss 12.5% Absolute Risk Reduction (ARR) ARR = Untreated - Treated NNT = 100/ARR Number Needed to Treat (NNT) = 8 21 22 RISK REDUCTION RISK REDUCTION 50% Relative Risk Reduction 100% -> 50% 40% -> 20% 2/million -> 1/million 23 24
RISK REDUCTION EARLY TREATMENT DIABETIC RETINOPATHY STUDY (ETDRS) Does focal/grid laser help patients with diabetic macular edema? 25 26 EARLY TREATMENT DIABETIC RETINOPATHY STUDY (ETDRS) Found benefit if Clinically Significant Macular Edema (CSME) Retinal thickening 1 disc area any part within 1 disc diameter of center of fovea Hard exudates within 1/3 disc diameter of center of fovea with adjacent thickening Retinal thickening within 1/3 disc diameter of center of fovea 27 28
EARLY TREATMENT DIABETIC RETINOPATHY STUDY (ETDRS) EARLY TREATMENT DIABETIC RETINOPATHY STUDY (ETDRS) If CSME If CSME Loss of < 2 lines 25% untreated ARR = 12.5% NNT = 8 12.5% treated 29 30 DIABETIC MACULAR EDEMA STUDIES Treatment Criteria - Anti-VEGF Central retinal thickening <20/30 BOLT RESTORE RISE/RIDE DRCR 31 32
STUDIES STUDIES 100% lost < 3 lines with Avastin Compared to 86% with laser 40% gained > 3 lines with Lucentis Compared to 22% with laser (deferred Lucentis) 33 34 STUDIES STUDIES 60% achieved 20/40 with Lucentis Compared to 42% with laser (deferred Lucentis) At 5 years Lucentis + Laser 75% achieved 20/40 35 36
DRCR STUDIES 1% rate of endophthalmitis Could Eylea be given less frequently? 0.06% per injection rate (out of 3176 injections) 37 38 VISTA/VIVID VISTA/VIVID Gain 3 lines 2 Year Results Aflibercept (Monthly or Bi-monthly) vs. Laser Monthly 38% Bi-monthly 33% Laser 13% Ophthalmology 2015;122:2044-2052 39 40
VISTA/VIVID LUCENTIS FOR PDR Average injections Monthly - 22 Bi-monthly - 14 Is Lucentis as good as PRP for PDR? 41 42 LUCENTIS FOR PDR LUCENTIS FOR PDR PRP group lost 3 letters Lucentis group lost no letters VF loss -23 db Lucentis -422 db PRP 43 44
LUCENTIS FOR PDR DME ANTI-VEGF - SUMMARY Lucentis and Avastin effective for DME Macular Edema 9% Lucentis 28% PRP 60-75% reading acuity at 5 years Can be combined with laser **10% developed macular edema with PRP in DRS 45 46 DME ANTI-VEGF - SUMMARY DIABETIC RETINOPATHY Application Aflibercept may be given less often When can we stop? Treatment indicated if High risk PDR CSME Central macular thickening with < 20/30 47 48
AGE-RELATED MACULAR DEGENERATION AGE-RELATED MACULAR DEGENERATION Threats to Vision Atrophy Threats to Vision Atrophy Neovascularization 49 50 AGE-RELATED MACULAR DEGENERATION AGE-RELATED MACULAR DEGENERATION Threats to Vision Neovascularization Atrophic AREDS Exudative Anti-VEGF (Lucentis, Avastin, Eyelea) 51 52
AGE-RELATED MACULAR DEGENERATION AGE-RELATED EYE DISEASE STUDY (AREDS) Atrophic AREDS Exudative Are high-dose multivitamins with A, C, E, and Zinc able to reduce progression of dry AMD? Anti-VEGF (Lucentis, Avastin, Eyelea) 53 54 AGE-RELATED EYE DISEASE STUDY (AREDS) AGE-RELATED EYE DISEASE STUDY (AREDS) 4 Categories No benefit found for Categories 1 and 2 1. No AMD - few small or no drusen 2. Early AMD - several small drusen or few medium sized 3. Intermediate AMD - many medium drusen or large drusen 4. Advanced AMD When Categories 3 and 4 were combined, benefit found Reduction of acuity of 3 lines 29% untreated 23% treated 55 56
AGE-RELATED EYE DISEASE STUDY (AREDS) AGE-RELATED EYE DISEASE STUDY (AREDS) Categories 3 and 4 No complications from vitamins found ARR 6% NNT = 17 Other trials have found Increased lung cancer in smokers on Vitamin A Increased prostate cancer with Zinc Worse heart disease with Vitamin E 57 58 AGE-RELATED EYE DISEASE STUDY (AREDS) AGE-RELATED EYE DISEASE STUDY (AREDS) AREDS 10 year AREDS 2 found no difference between AREDS 1 by adding Lutein and Zeaxanthin Moderate vision loss 53% untreated 46% treated 59 60
AGE-RELATED EYE DISEASE STUDY (AREDS) AGE-RELATED EYE DISEASE STUDY (AREDS) AREDS 10 year AREDS 10 year Moderate vision loss ARR 7% NNT = 14 Still no benefit for Categories 1 and 2 Most benefit observed in Category 4 No benefit for Central Geographic Atrophy 61 62 STUDIES - ANTI-VEGF STUDIES MARINA/ANCHOR VIEW CATT/GEFAL 90% maintain acuity with treatment Only 50% untreated maintain Treat and Extend 63 64
STUDIES STUDIES 41% gained 3 lines of acuity with treatment Only 6% untreated gained 33-42% achieve 20/40 or better treated Only 6% untreated reach 20/40 65 66 STUDIES TREAT AND EXTEND Avastin = Lucentis = Eylea Fewer injections with Eylea 11 vs 16 at 2 years Treat every month for 3 months If stable, extend out 67 68
TREAT AND EXTEND TREAT AND EXTEND 90% had stability at 2 years 45% had 20/40 acuity Fewer injections (13 versus 17) Fewer Visits Less $$ Ophthalmology 2015;122:1212-1219 69 70 AMD GLAUCOMA Evidence from pre-glaucoma (OHTS) to advanced glaucoma (AGIS) Application Evidence for low tension (CNTGS) Evidence for surgery vs. medicine (CIGTS) Still no treatment for Dry AMD Vitamins can slow progression in small group of patients Wet AMD helped by Anti-VEGF Next frontier is less frequent administration 71 72
OCULAR HYPERTENSION TREATMENT STUDY (OHTS) OCULAR HYPERTENSION TREATMENT STUDY (OHTS) Evaluate the benefit of treating ocular hypertension to reduce development of glaucoma Patients with IOP 24-32 Treated with medication to lower IOP to < 24 Minimum of 20% reduction 73 74 OCULAR HYPERTENSION TREATMENT STUDY (OHTS) OCULAR HYPERTENSION TREATMENT STUDY (OHTS) Outcome Reproducible VF loss 9.5% untreated 4.4% treated Clinically significant optic disc deterioration 75 76
OCULAR HYPERTENSION TREATMENT STUDY (OHTS) OCULAR HYPERTENSION TREATMENT STUDY (OHTS) ARR 5.1% Application NNT = 20 We can prevent Glaucoma by treating Ocular Hypertension Most people with Ocular Hypertension don t develop Glaucoma 77 78 OCULAR HYPERTENSION TREATMENT STUDY (OHTS) OCULAR HYPERTENSION TREATMENT STUDY (OHTS) What else did we learn? What else did we learn? 86% of patients with VF loss returned to normal after 1 repeat Patients with IOP 24-32 with thinner corneas had higher risk Does this mean that all patients with thinner corneas are at risk?? 79 80
EARLY MANAGEMENT GLAUCOMA TRIAL (EMGT) EARLY MANAGEMENT GLAUCOMA TRIAL (EMGT) Determine benefit of treating patients with early Glaucoma Outcomes VF progression ONH progression 81 82 EARLY MANAGEMENT GLAUCOMA TRIAL (EMGT) EARLY MANAGEMENT GLAUCOMA TRIAL (EMGT) 62% Untreated 45% Treated ARR 17% NNT = 6 83 84
EARLY MANAGEMENT GLAUCOMA TRIAL (EMGT) EARLY MANAGEMENT GLAUCOMA TRIAL (EMGT) What else did we find out? Application 50% of patients with VF loss reverted to normal upon retesting There is evidence that treating early glaucoma is beneficial 85 86 COLLABORATIVE NORMAL TENSION GLAUCOMA STUDY (CNTGS) COLLABORATIVE NORMAL TENSION GLAUCOMA STUDY (CNTGS) Treatment goal = lowering IOP by 30% from baseline Establish whether there is a benefit to treating NTG with medication Measure VF progression ONH progression 87 88
COLLABORATIVE NORMAL TENSION GLAUCOMA STUDY (CNTGS) COLLABORATIVE NORMAL TENSION GLAUCOMA STUDY (CNTGS) Results If not fixation threatened, 2/3 did not progress 89 90 COLLABORATIVE NORMAL TENSION GLAUCOMA STUDY (CNTGS) COLLABORATIVE NORMAL TENSION GLAUCOMA STUDY (CNTGS) Application Results If fixation threatened, should treat Of the 1/3 that did progress, added to fixation threatened group 12% treated progressed If non-fixation threatened, may be ok to watch carefully 35% untreated progressed 91 92
COLLABORATIVE INITIAL GLAUCOMA TREATMENT STUDY (CIGTS) COLLABORATIVE INITIAL GLAUCOMA TREATMENT STUDY (CIGTS) To evaluate whether patients do better with Trabeculectomy followed by medication Medication followed by trabeculectomy Outcomes VF progression VA loss IOP goal met 93 94 COLLABORATIVE INITIAL GLAUCOMA TREATMENT STUDY (CIGTS) COLLABORATIVE INITIAL GLAUCOMA TREATMENT STUDY (CIGTS) Surgical complications 17% needed cataract surgery (compared to 6% of medicine group) No substantial difference in VF progression 13% flat AC 12% ptosis 11% risk of choroidal detachment 7% of surgical lost > 3 lines of acuity 4% in medicine arm 10% AC bleed 6% wound leak 1% hypotony 95 96
ADVANCED GLAUCOMA INTERVENTION STUDY (AGIS) ADVANCED GLAUCOMA INTERVENTION STUDY (AGIS) Evaluated benefit of treatment for patients with advanced Glaucoma Often stated outcomes deal with whether to do Trabeculectomy or Laser Trabeculoplasty first These results have little clinical application 97 98 ADVANCED GLAUCOMA INTERVENTION STUDY (AGIS) GLAUCOMA Application Biggest messages are We can slow progression of even advanced glaucoma The lower the IOP the better <18 was good, <14 was even better No matter what stage, we can intervene with IOP lowering Medication and surgery are effective Medication is safer VF loss should be confirmed 99 100
HERPETIC EYE DISEASE STUDY (HEDS) HERPETIC EYE DISEASE STUDY (HEDS) Herpes Ocular Complications Epithelial typically resolves without complication Epithelial Disease NO steroid! Stromal Disease Uveitis 101 102 HERPETIC EYE DISEASE STUDY (HEDS) HERPETIC EYE DISEASE STUDY (HEDS) Stromal is COMPLEX! Consider herpetic uveitis if Often worst outcomes Older age Triad Uveitis Corneal edema Increased IOP 103 104
HERPETIC EYE DISEASE STUDY (HEDS) HERPETIC EYE DISEASE STUDY (HEDS) HEDS 1 When using topical antiviral, are topical steroids beneficial in treating stromal keratitis? HEDS 1 For patients with stromal keratitis, on topical steroid and anti-viral, is it beneficial to add oral acyclovir? More failure during first 10 weeks on placebo 73% vs 26% No statistically significant difference 105 106 HERPETIC EYE DISEASE STUDY (HEDS) HERPETIC EYE DISEASE STUDY (HEDS) HEDS 1 For patients with HSV uveitis, is there benefit to adding oral acyclovir? HEDS 2 Does oral acyclovir used early in treatment of acute HSV keratitis reduce risk of developing stromal keratitis or uveitis later? Not enough patients enrolled No 107 108
HERPETIC EYE DISEASE STUDY (HEDS) HERPETIC EYE DISEASE STUDY (HEDS) HEDS 2 HEDS 2 Does low dose oral acyclovir reduce likelihood or recurrence? Does low dose oral acyclovir reduce likelihood or recurrence? Yes! 400 mg BID reduced from 32% to 19% 109 110 HERPETIC EYE DISEASE STUDY (HEDS) HERPETIC EYE DISEASE STUDY (HEDS) HEDS 2 HEDS helped inform us how to treat Herpes Simplex Does UV, stress, or corneal trauma influence recurrence rate? If epithelial disease, treat with topical antiviral No 111 112
HERPETIC EYE DISEASE STUDY (HEDS) HERPETIC EYE DISEASE STUDY (HEDS) If stromal, treat with topical steroid with antiviral cover If stromal with overlying epithelial defect, must treat epithelium first Consider oral antiviral for preventing recurrence 113 114 HERPETIC EYE DISEASE STUDY (HEDS) OPTIC NEURITIS TREATMENT TRIAL (ONTT) Not enough patients to know for HSV uveitis Evaluated use of steroids in treating acute optic neuritis Consider if also have elevated IOP, corneal edema Consider if first uveitis in older patient 115 116
OPTIC NEURITIS OPTIC NEURITIS TREATMENT TRIAL (ONTT) Inflammation of optic nerve Patients randomized into 3 groups Consider in younger patients (20-40) Oral pred (1 mg/kg/day) x 14 days IV steroid x 3 days then oral pred x 11 days Oral placebo x 14 days 117 118 OPTIC NEURITIS TREATMENT TRIAL (ONTT) OPTIC NEURITIS TREATMENT TRIAL (ONTT) For decades patients treated with Oral Steroid Based on Anecdote 93% of all patients recovered to at least 20/40 at 1 year ONTT sought to answer benefit 119 120
OPTIC NEURITIS TREATMENT TRIAL (ONTT) OPTIC NEURITIS TREATMENT TRIAL (ONTT) IV steroid with oral taper sped recovery 4 days compared to 15 days 1/3 of patients had recurrence Oral prednisone group had 44% recurrence rate 121 122 OPTIC NEURITIS TREATMENT TRIAL (ONTT) OPTIC NEURITIS TREATMENT TRIAL (ONTT) At 15 years Oral prednisone group Did not improved visual acuity outcomes Increased rate of new attack of optic neuritis 69% were 20/20 Overall rate of developing MS was 50% 123 124
OPTIC NEURITIS TREATMENT TRIAL (ONTT) OPTIC NEURITIS TREATMENT TRIAL (ONTT) What else did we learn? At 15 years 90% of patients had pain on eye movement If no lesions on MRI, risk of MS was 25% If 1 or more MRI lesions, risk was 72% 1/3 of optic neuritis is papillitis 2/3 of optic neuritis is retrobulbar optic neuritis Look for APD 125 126 OPTIC NEURITIS TREATMENT TRIAL (ONTT) Application Most patients with Optic Neuritis recover acuity Oral steroids don t help and might harm Consider MRI findings when educating about risk of MS Look for signs/symptoms Pain on eye movement, APD, possible ONH edema 127