Current Clinical Evidence in Ophthalmology [1 ed.] 9789062992515, 9789062998838

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ISBN 978-90-6299-251-5

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Copyright © 2017. Kugler Publications. All rights reserved.

CURRENT CLINICAL EVIDENCE IN OPHTHALMOLOGY

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CURRENT CLINICAL EVIDENCE IN OPHTHALMOLOGY Harry W. Roberts Jesse Gale Keith R. Martin Section Editors: Prof. Harminder Dua (Cornea), Prof. Keith Martin (Glaucoma), Prof. Paul Mitchell (Retina), Prof. Alfredo Sadun (Neuroophthalmology), Prof. Anthony Moore (Paediatrics)

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With additional Retinal Section author Dr. Neil Avery and contributions from Dr. Neil Sharma

Kugler Publications/Amsterdam/The Netherlands

ISBN 978-90-6299-251-5

Copyright © 2017. Kugler Publications. All rights reserved.

Kugler Publications P.O. Box 20538 1001 NM Amsterdam, The Netherlands www.kuglerpublications.com © 2017 Kugler Publications, Amsterdam, The Netherlands All rights reserved. No part of this book may be translated or reproduced in any form by print, photoprint, microfilm, or any other means without prior written permission from the publisher. Kugler Publications is an imprint of SPB Academic Publishing bv, P.O. Box 20538, 1001 NM Amsterdam, The Netherlands Cover design by Willem Driebergen, Rijnsburg, The Netherlands

Table of Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii About the authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii Section 1: Anterior Segment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Herpetic Eye Disease Study - 1 (HEDS - 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Herpetic Eye Disease Study - 2 (HEDS - 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Endophthalmitis Vitrectomy Study (EVS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 European Society for Cataract and Refractive Surgeons (ESCRS Study) . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Collaborative Longitudinal Evaluation of Keratoconus (CLEK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

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Corneal collagen cross-linking in progressive keratoconus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Section 2: Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Ocular Hypertension Treatment Study (OHTS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 European Glaucoma Prevention Study (EGPS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Early Manifest Glaucoma Trial (EMGT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 vii

United Kingdom Glaucoma Treatment Study (UKGTS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Advanced Glaucoma Intervention Study (AGIS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Collaborative Initial Glaucoma Treatment Study (CIGTS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Collaborative Normal-Tension Glaucoma Study (CNTGS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Low-Tension Glaucoma Treatment Study (LoGTS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Glaucoma Laser Trial (GLT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 5-Fluorouracil Filtering Surgery Study (FFSS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Tube Versus Trabeculectomy (TVT) study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Ahmed Baerveldt Comparison (ABC) and Ahmed Versus Baerveldt (AVB) Studies . . . . . . . . . . . . . . . . . 38 Effectiveness in Angle-closure Glaucoma of Lens Extraction (EAGLE) Study . . . . . . . . . . . . . . . . . . . . . . . 40

Section 3: Retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Diabetic Control and Complication Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 United Kingdom Prospective Diabetes Study (UKPDS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Diabetic Retinopathy Study (DRS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Early Treatment of Diabetic Retinopathy Study (ETDRS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

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DRCR.NET Protocol I – Macular Laser Combined with Ranibizumab or Triamcinalone vs. Macular Laser Alone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 DRCR.NET Protocol T - Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema . . . . . 54 DRCR.NET Protocol S - Panretinal Photocoagulation vs. Intravitreal Ranibizumab for Proliferative Diabetic Retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Diabetic Retinopathy Vitrectomy Study (DRVS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Ranibizumab for Diabetic Macular Oedema (RISE & RIDE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 viii

Ranibizumab Monotherapy or Combined with Laser versus Laser Monotherapy for Diabetic Macular Edema (RESTORE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Intravitreal Aflibercept for Diabetic Macular Edema (DA VINCI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Intravitreal Aflibercept for Diabetic Macular Edema (VIVID & VISTA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema (BOLT) . . . . . . . . . . . . 70 Fluocinolone Acetonide Vitreous Inserts for Diabetic Macular Edema (FAME A & B) . . . . . . . . . . . . . . . . 72 The Age-Related Eye Disease Study (AREDS I) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Lutein, Zeaxanthin and Omega-3 Fatty Acids for Age-Related Macular Degeneration: The Age-Related Eye Disease Study 2 (AREDS-2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Ranibizumab vs. Verteporfin for Predominantly Classic Choroidal Neovascularisation in Age-Related Macular Degeneration (ANCHOR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 Ranibizumab for Minimally Classic or Occult Neovascular Age-Related Macular Degeneration (MARINA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 Randomised, Double-Masked, Sham-Controlled Trial of Ranibizumab for Neovascular Age-related Macular Degeneration (PIER) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 Safety and Efficacy of a Flexible Dosing Regimen of Ranibizumab in Neovascular Age-Related Macular Degeneration (SUSTAIN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 PrONTO Studies: An Optical Coherence Tomography-Guided Variable Dosing Regimen with Intravitreal Ranibizumab (Lucentis) for Neovascular Age-related Macular Degeneration . . . . . . . . 86 Efficacy and Safety of Monthly versus Quarterly Ranibizumab Treatment in Neovascular Age-related Macular Degeneration (EXCITE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

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SAILOR Study: Safety Assessment of Intravitreal Lucentis for AMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Ranibizumab vs. Bevacizumab for Neovascular Age-Related Macular Degeneration Inhibition of VEGF in Age-related Neovascularisation (IVAN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Ranibizumab vs. Bevacizumab for Neovascular Age-related Macular Degeneration Comparison of Age-related macular degeneration Treatments Trial (CATT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Intravitreal Afliberept (VEGF Trap-Eye) in Wet Age-related Macular Degeneration (VIEW 1&2) . . . . . . . 96 The Central Vein Occlusion Study - CVOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 The Branch Vein Occlusion Study - BVOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 ix

The Standard Care vs. cOrticosteroid for Retinal vEin Occlusion (SCORE) - CRVO . . . . . . . . . . . . . . . . . 102 The Standard Care vs. cOrticosteroid for Retinal vEin Occlusion (SCORE) - BRVO . . . . . . . . . . . . . . . . . 104 Dexamethasone for the treatment of Macular Edema following Retinal Vein Occlusion (GENEVA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 Ranibizumab for the treatment of Macular Edema after Central Retinal Vein Occlusion Study (CRUISE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Ranibizumab for the treatment of Macular Edema following Branch Retinal Vein Occlusion (BRAVO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 Intravitreal Aflibercept for Macular Edema following Central Retinal Vein Occlusion (COPERNICUS & GALILEO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 Intravitreal Aflibercept Injection for Macular Edema following Branch Retinal Vein Occlusion (VIBRANT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Ranibizµmab And Verteporfin Evaluation in Myopic Choroidal Neovascularization (RADIANCE) . . . . 116 Intravitreal Aflibercept in Myopic Choroidal Neovascularization (MYRROR) . . . . . . . . . . . . . . . . . . . . . . 118 Efficacy and Safety of Verteporfin Photodynamic Therapy in Combination with Ranibizumab or Alone Versus Ranibizumab Monotherapy in Patients with Symptomatic Macular Polypoidal Choroidal Vasculopathy (EVEREST) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 Microplasmin for Intravitreous Injection – Traction Release without Surgical Treatment (MIVI-TRUST) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Section 4: Neuro-ophthalmology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

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Optic Neuritis Treatment Trial (ONTT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Interferon-β1a for Optic Neuritis: The Controlled High-risk subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Interferon-β1a for Optic Neuritis: The Early Treatment of Multiple Sclerosis Study (ETOMS) . . . . . . . 130 Interferon-β1b for Optic Neuritis: Betaferon/Betaseron in Newly Emerging Multiple Sclerosis For Initial Treatment (BENEFIT) trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 International Optic Nerve Trauma Study (IONTS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 x

Corticosteroid Randomisation After Significant Head injury trial (CRASH) . . . . . . . . . . . . . . . . . . . . . . . 136 Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 Idebenone for Leber Hereditary Optic Neuropathy – the Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 Idebenone for Leber Hereditary Optic Neuropathy – Carelli retrospective study . . . . . . . . . . . . . . . . . 142 North American Symptomatic Carotid Endarterectomy Trial (NASCET) . . . . . . . . . . . . . . . . . . . . . . . . . . 144

Section 5: Paediatric Ophthalmology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Cryotherapy for Retinopathy of Prematurity (CRYOROP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 Early Treatment for Retinopathy of Prematurity (ETROP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEATROP) . . . . . . . . 152 Pediatric Eye Disease Investigators Group Study (PEDIG) –or– Amblyopia Treatment Study (ATS) . . 154 Infant Aphakia Treatment Study (IATS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 Atropine for the Treatment of Myopia I (ATOM I) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 Atropine for the Treatment of Myopia II (ATOM II) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

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Index of Codes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

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Introduction Clinical ophthalmology, like many other branches of science, is advancing rapidly. With over 230,000 clinical trials registered on ClinicalTrials.gov and more being added every year it becomes increasingly difficult to keep abreast of developments that are relevant to our everyday clinical practice. Major advances such as intravitreal treatments for retinal diseases have led to revolutionary improvements in patient outcomes. Our patients rightly expect that ophthalmologists will deliver the best available care according to solid clinical evidence. Patients also have more access to information and increasingly want to discuss the evidence supporting clinical decisions. Never before has there been such pressure to apply the latest results to our daily clinical practice. With these ideas in mind, we have tried to identify and summarise the key clinical trials that have made the most tangible difference to patient care in ophthalmology. We hope this book will offer a useful portable resource for the practising ophthalmologist and for those preparing for examinations. Our aim is to provide a cogent and useful summary of the evidence that will improve communication and care for our patients.

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Jesse Gale, Keith R. Martin and Harry Roberts

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Preface Modern medicine has become increasingly evidence based, but keeping up to date with the huge amount of information is a challenge for all of us. Few medical specialties have changed as much as ophthalmology over the last 20 years and it is encouraging that many advances in the treatment of eye disease have been based on the strongest type of evidence from randomised clinical trials. It is increasingly difficult for ophthalmologists to keep track of and remember the key lessons from important landmark trials and apply the results to their everyday practice. Thus, “Current Clinical Evidence in Ophthalmology” fills an very important niche and the authors have done a great job in compiling the important trials into such a concise and readable format. The book will be of great value to all of us working in ophthalmology as we strive to use the best available evidence to improve the lives of our patients today and tomorrow. Professor Sir Peng T Khaw PhD FRCS FRCP FRCOphth FRCPath FRSB FCOptom (Hon) DSc FARVO FMedSci Professor of Glaucoma and Ocular Healing, Consultant Ophthalmic Surgeon & Emeritus NIHR Senior Investigator

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Director National Institute for Health Research Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital and UCL Institute of Ophthalmology Eyes and Vision Programme, UCL Partners Academic Health Science Centre Research and Development, Moorfields Eye Hospital

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About the authors Harry Roberts is a specialist registrar ophthalmologist currently working at St Thomas’ Hospital, London, UK. The idea of writing this book came when Harry was preparing to sit his Fellowship of the Royal College of Ophthalmologists (FRCOphth) exams. Subsequently, he was awarded the Harcourt Medal for the top mark in the final FRCOphth exams. He is currently involved in a large randomised controlled trial investigating femtosecond laser assisted cataract surgery compared to conventional phacoemulsification surgery. His subspecialty interests include corneal and cataract surgery.

Dr. Jesse Gale is a consultant ophthalmologist in Wellington, New Zealand. He has subspecialty training in glaucoma and neuro-ophthalmology, and he works in public hospitals and private practice with volunteer work in Pacific countries. Jesse has an interest in ophthalmic education and is a senior clinical lecturer at University of Otago, and visiting lecturer at Australian College of Optometry. His research projects are mostly in the mechanisms of optic nerve disease and community management of glaucoma.

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Keith R. Martin is Professor and Head of Ophthalmology at the University of Cambridge, Deputy Director of the University’s John van Geest Centre for Brain Repair and an Affiliate Principal Investigator at the Wellcome Trust - MRC Cambridge Stem Cell Institute. He is also Academic Lead for Ophthalmology and Lead Clinician for Glaucoma at Cambridge University Hospitals NHS Foundation Trust. Professor Martin established and runs the Glaucoma Research Laboratory at the University of Cambridge, working to develop new treatments for eye disease using stem cells, gene therapy and other techniques. Clinically, he specialises in the medical and surgical management of complex glaucoma in adults and children. He is currently Vice President and President Elect of the World Glaucoma Association.

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List of Abbreviations 5-FU 5-Fluorouracil ADR Adverse drug reaction AL Axial length ALT Argon laser trabeculoplasty AMD/ARMD Age-related macular degeneration ASNV Anterior segment neovascularisation BCVA Best corrected visual acuity BP Blood pressure BRVO Branch retinal vein occlusion c.f. Compared with CCT Central corneal thickness CDR Cup-to-disc ratio CEA Carotid endarterectomy CI Confidence interval CL Contact lens CME/CMO Cystoid macular edema/oedema CMT Central macular thickness CNS Central nervous system Choroidal neovascularisation CNV CNVM Choroidal neovascular membrane CRT Central retinal thickness CRVO Central retinal vein occlusion CSF Cerebrospinal fluid CSLO Confocal scanning laser ophthalmoscopy CSME/CSMO Clinically significant macular edema/oedema CT Computerised tomography CVA Cerebrovascular accident CWS Cotton wool spots D Dioptre DD Disc diameters Docosahexaenoic acid DHA (an omega-3 fatty acid) DM Diabetes mellitus Diabetic macular edema/oedema DME/DMO Diabetic retinopathy DR Eicosapentaenoic acid EPA (an omega-3 fatty acid) Early Treatment of Diabetic ETDRS Retinopathy Study F3T Trifluridine FA/FFA Fundus fluorescein angiogram Fac Fluocinolone acetonide

FBG Fasting blood glucose GA Geographic atrophy GCS Glasgow Coma Scale HbA1C Haemoglobin A1C HM Hand movements HR Hazard ratio HRVO Hemi-retinal vein occlusion HSV Herpes simplex keratitis ICG Indocyanine green IIH Idiopathic intracranial hypertension IOL Intraocular lens IOP Intraocular pressure IRMA Intra-retinal microvascular abnormality IVMP Intravenous methylprednisolone Kmax Maximum keratometry value LHON Leber’s hereditaty optic neuropathy logMAR Logarithm of minimum angle of resolution MD Mean difference MH Macular hole MLT Macular laser therapy MMC Mitomycin C MRI Magnetic resonance imaging MS Multiple sclerosis mtDNA Mitochondrial deoxyribonucleic acid nAMD Neovascular age-related macular degeneration NEI-VFQ National Eye Institute Visual Function Questionnaire NPL No perception of light NSS Not statistically significant NTG Normal-tension glaucoma NV Neovascularisation/new vessels Neovascularisation/new vessels of the NVD disc NVE Neovascularisation/new vessels elsewhere NVI Neovascularisation/new vessels of the iris (Primary) open-angle glaucoma OAG, POAG Optical coherence tomography OCT Ocular hypertension OHT OR Odds ratio PCR Polymerase chain reaction xix

PCV Polypoidal choroidal vasculopathy PDT/vPDT (verteporfin) Photodynamic therapy PFV Persistent fetal vasculature PL Perception of light POHS Presumed ocular histoplasmosis syndrome PRN pro re nata PRP Pan-retinal photocoagulation PSD Pattern standard deviation PVD Posterior vitreous detachment q4 Four weekly q8 Eight weekly RAPD Relative afferent pupillary defect RCT Randomised controlled trial RNFL Retinal nerve fibre layer ROP Retinopathy of prematurity

RPE RR RVO SD SE T1DM T2DM TIA TMVL TON VA VEGF VF VH VMT

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Retinal pigment epithelium Relative risk Retinal vein occlusion Standard deviation Spherical equivalent Type 1 diabetes mellitus Type 2 diabetes mellitus Transient ischaemic attack Transient monocular vision loss Traumatic optic neuropathy Visual acuity Vascular endothelial growth factor Visual field Vitreous haemorrhage Vitreomacular traction

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Anterior Segment Section editor: Prof. Harminder Dua

Herpetic Eye Disease Study - 1 (HEDS - 1) Study design: RCT

Evidence level: 1b

Ophthalmology 1994;1871-1882 | Ophthalmology 1994;1883-1896 | Arch Ophthalmol 1996;1065-1072.

Key questions 1. 2. 3.

What is the role of topical steroids in stromal keratitis associated with HSV? Does oral aciclovir have an additional benefit to topical trifluridine and topical steroids in HSV stromal keratitis? Does oral aciclovir have an additional benefit to topical trifluridine and topical steroids in HSV iridocyclitis?

Aims Epithelial keratitis associated with herpes simplex keratitis (HSV) is known to worsen with topical steroids, so the role of topical steroids in stromal keratitis required formal investigation for efficacy and safety using a randomised trial design. While topical antiviral treatment (trifluridine) was established, the role of oral aciclovir in acute HSV stromal keratitis or HSV iridocyclitis was unknown.

phosphate eight times a day, tapering to ⅛% once a day.

Methods

IRT – Iridocyclitis, receiving topical steroids Fifty patients who were already using topical steroids were randomised to receive aciclovir 400 mg five times daily for a ten-week period, or equivalent routine of placebo. Topical steroid and antiviral therapy was standardised for both groups.

Participants: Three separate randomised controlled trials (RCTs) were conducted at eight centres in the USA.

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Inclusion criteria: • Age > 11 years. Exclusion criteria: • Active HSV epithelial keratitis; • Previous keratoplasty of the affected eye; • Pregnancy. Groups: SKN – Stromal keratitis, not on steroids One hundred and six patients who had not used a topical steroid in the preceding ten days were randomised to receive topical prednisolone phosphate or placebo. A standardised protocol tapered the drops over a ten-week period, commencing with 1% prednisolone 2

SKS – Stromal keratitis, on steroids One hundred and four patients who were already using topical steroids were randomised to receive aciclovir 400 mg five times daily for ten weeks, or equivalent routine of placebo. Topical steroid therapy was standardised for both groups as per the SKN trial.

Primary endpoint: Visual acuity (VA), resolution of active disease, failure of treatment. Follow-up: Patients were evaluated weekly for ten weeks, fortnightly for six more weeks, and at six months.

HEDS-1 Results SKN – Stromal keratitis, not on steroids Seventy-three percent of patients on placebo were withdrawn (and treated with topical steroids at the ophthalmologist’s discretion) within the first ten weeks for treatment failure, compared to 26% of patients on topical steroids (P < 0.001). The group of patients randomised to receive topical prednisolone phosphate were judged to have a resolution of stromal keratitis at a median of 26 days compared to 72 days in the placebo group (P < 0.001). However, there was no difference in VA between the steroid and placebo groups at six months, with 61% compared to 59% improving their VA, and no improvement in 29% and 33% respectively. SKS – Stromal keratitis, on steroids Forty-nine percent of patients on placebo were withdrawn for failure of treatment within the first ten weeks compared to 38% in the oral aciclovir group. Eighteen percent of patients in the aciclovir group were considered a treatment success compared to 20% in the placebo group. Median times to resolution in these patients were 23 days (oral aciclovir) and 19 days (placebo). Median baseline VA was 20/63 in the aciclovir group and 20/40 in the placebo group; VA at six months was 20/40 or better in 58% and 72% ­ respectively.

Overall, there was no apparent additional benefit in the use of oral aciclovir in addition to topical antivirals and steroids. IRT – Iridocyclitis, receiving topical steroids The addition of oral aciclovir to topical trifluridine and prednisolone appeared to be associated with a clinically significant improvement in recovery in HSV iridocyclitis. Treatment failure in the first ten weeks was 68% in the placebo compared to 50% in the oral aciclovir group (P = 0.06). Median number of days to recovery was 16 in the placebo group and 20 in the oral aciclovir group (p = 0.16). Relapse rates were similar between the two groups. Overall, the numbers of patients in this trial were too small, leading to an underpowered study.

Weaknesses Many patients failed to attend the full schedule of follow-up appointments. Topical therapy was standardised rather than titrated to disease activity. Topical acyclovir (aciclovir) is not available (definitely not at the time of the study) in the USA and hence the use of F3T. Modern treatment increasingly involves topical aciclovir or ganciclovir.

Key messages

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1. Topical steroids may be beneficial in speeding resolution of HSV stromal keratitis, but steroids do not affect the VA in the medium term. 2. Systemic aciclovir was not useful for HSV stromal keratitis already receiving topical trifluridine and topical steroids. 3. Potential benefits of oral aciclovir in HSV iridocyclitis did not reach statistical significance.

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Herpetic Eye Disease Study - 2 (HEDS - 2) Study design: RCT

Evidence level: 1b

Arch Ophthalmol 1997;703-712 | N Engl J Med 1998;300-306 | Arch Ophthalmol 2000;1617-1625.

Key questions 1. To determine whether early treatment of HSV-related epithelial keratitis with oral aciclovir prevents progression to the potentially blinding complications of stromal keratitis and iridocyclitis. 2. To determine the efficacy of low-dose oral aciclovir in preventing recurrent HSV eye infection in patients with previous episodes of herpetic eye disease. 3. To determine the role of external factors (such as ultraviolet light or corneal trauma) and behavioural factors (such as life stress) on the induction of ocular recurrences of HSV-related eye disease.

Aims This study focused on oral aciclovir, its use in herpetic corneal epithelial disease and its role in prophylaxis against recurrences. Furthermore, an epidemiological study examined risk factors which may be associated with recurrences of herpetic eye disease.

Methods Participants: Three separate randomised controlled trial RCTs were conducted over eight centres in the USA.

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Inclusion criteria: • Age > 11 years for RCTs, > 17 for epidemiological study. Exclusion criteria: • Immunodeficiency; • Renal insufficiency; • Pregnancy. Groups, Primary outcomes and Follow-up: EKT – Epithelial Keratitis Trial Two hundred and eighty-seven patients were randomised to receive 400 mg aciclovir x5/day or a placebo for three weeks within seven days of onset of an episode of herpetic epithelial keratitis. All patients 4

were treated with trifluridine. Eight follow-up visits were conducted over the following year. The primary outcomes were time until first episode of stromal keratitis or iridocyclitis in the study eye. APT – Aciclovir Prevention Trial Seven hundred and three patients with no active manifestation of herpetic eye disease within the previous month but with a history of an episode within the previous year were randomised to receive aciclovir 400 mg twice a day or placebo for a period of one year. Patients were reviewed five times during the first month and three times in the six months following cessation of treatment. Primary outcome was time to HSV recurrence in either eye. RFS – Recurrence Factor Study Patients were recruited with a history of at least one episode of herpetic eye disease were asked to fill out a questionnaire every week for a year to monitor acute and chronic stressors. These included general stress level, seven specific stressors (e.g., financial, emotional, etc.), self-reported infections, systemic illness, sunlight exposure, contact lens use and menstruation. Patients were examined five times within the first 12 months and twice during the following six months and whenever they reported new eye symptoms. Primary outcome was time until first recurrence of herpetic eye disease.

HEDS-2 Results EKT – Epithelial Keratitis Trial There was no evidence for any benefit from the addition of oral aciclovir in preventing future episodes of stromal keratitis or iridocyclitis. APT – Aciclovir Prevention Trial Four percent of patients on aciclovir and 5% of patients on placebo discontinued treatment due to side effects. Patients on aciclovir had a 41% reduction in any herpetic episode and a 50% reduction in stromal keratitis. There was no rebound in the rate of herpetic disease after the cessation of aciclovir, neither was the benefit of aciclovir maintained after treatment ended.

RFS – Recurrence Factor Study Twenty-two percent of patients experienced an episode of herpetic eye disease within one year. No associations were made between stressors and recurrences of herpetic eye disease.

Weaknesses Many patients failed to attend the full schedule of follow-up appointments. In the Recurrence Factor Study, half the patients who had a recurrence did not have a valid questionnaire.

Key messages

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1. Short-term oral aciclovir during an acute episode of herpetic epithelial disease does not reduce the risk of further episodes. 2. However, long-term aciclovir is well-tolerated and offers a significant reduction in the number of episodes of recurrence. 3. Environmental stressors, sunlight, and contact lens use have not been shown to be associated with recurrences of herpetic eye disease.

5

Endophthalmitis Vitrectomy Study (EVS) Study design: RCT

Evidence level: 1b

Arch Ophthalmol 1995;113:1479 | Curr Opin Ophthalmol 1996;7:84 | Arch Ophthalmol 2001;119:650.

Key questions 1. What is the role of immediate pars plana vitrectomy in the management of post-operative endophthalmitis? 2. What is the role of intravenous antibiotics in the management of post-operative endophthalmitis?

Aims Although intravitreal injection of broad spectrum antibiotics was already known to be effective in the management of post-operative endophthalmitis, it was uncertain whether pars plana vitrectomy provided an additional benefit. Theoretical advantages included removal/dilution of the infecting organism and toxins, removal of an opaque vitreous and membranes potentially inducing retinal detachment. Furthermore, intravenous antibiotics have been routinely given for endophthalmitis without an evidence base, and this study assessed whether they were necessary.

Methods

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Participants: Four hundred and twenty patients at 24 centres in US over a four-year period. Inclusion criteria: • Clinical symptoms and signs of bacterial endophthalmitis within six weeks of cataract surgery or secondary intraocular lens insertion; • Visual acuity (VA) between 20/50 and perception of light; • Anterior segment view clear enough to permit pars plana vitrectomy, but enough media opacity to prevent visualisation of second order retinal arterioles. Exclusion criteria: • Age < 18 years; 6

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• • • •

Pre-operative ocular comorbidity limiting best corrected visual acuity to 20/100 or worse before the onset of cataract; Previous ocular surgery or penetrating trauma including intravitreal injections; Moderate to severe retinal or choroidal detachment at the time of presentation; Intolerance to the study antibiotics (with the exception of β-lactams); A strong suspicion of fungal endophthalmitis.

Groups: Participants were randomised to a 2x2 treatment matrix based on vitrectomy vs. vitreous tap, and intravenous antibiotics (ceftazidime and amikacin) vs. no intravenous antibiotics. All patients received: • Intravitreal vancomycin and amikacin; • Subconjunctival vancomycin, ceftazidime and dexamethasone; • Topical amikacin, vancomycin, cycloplegic agent and prednisolone acetate. Patients were permitted reinjection of intravitreal antibiotics at 36-60 hours based on specified criteria. Primary endpoint: VA. Secondary endpoint: Clarity of ocular media.

EVS Follow-up: At three and nine months.

Results VA: Eighty-six percent of patients presented with a VA worse than 5/200. Twenty-six percent of patients had perception of light (PL) only at presentation. There was no difference in VA outcome between vitrectomy vs. vitreous tap in those with visual acuity better than PL at presentation. In those presenting with PL vision, the vitrectomy group had a statistically significant difference in VA at nine months: • 33% vs. 11% achieved VA of 20/40 or better; • 56% vs. 30% achieved VA of 20/100 or better; • 20% vs. 47% had severe visual loss. There was also a significantly higher rate of phthisis and enucleation in the vitreous tap group (23% vs. 7%) in those presenting with PL vision. Media clarity: The vitrectomy group had a significantly clearer media at three months. There was no significant difference at nine months.

Subgroups: Diabetic patients within the study (n = 58) had worse vision at presentation, but did better with vitrectomy, regardless of VA (57% achieved 20/40 compared with 40% in the vitreous tap group. This was not statistically significant. Intravenous antibiotics: There was no significant difference in VA or media clarity between the groups which did/did not receive intravenous antibiotics.

Weaknesses Cataract surgery was routinely performed by extracapsular cataract extraction; relevance to modern-day phacoemulsification surgery is uncertain. Additionally it has become common practice to inject intra-cameral cefuroxime at the end of cataract surgery, which was not previously available. The use of steroids is controversial, though most studies commenting on this refer to intravitreal steroids, whereas this study involved subconjunctival injection. The outcomes of this study may not be applicable to endophthalmitis from other forms of ocular surgery as only lens-related operations were included by the EVS.

Key messages

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1. Intravenous antibiotics do not affect the outcome of post-operative endophthalmitis. 2. Pars plana vitrectomy should be considered in those patients presenting with post-operative endophthalmitis and PL VA or in diabetics with any VA.

7

European Society for Cataract and Refractive Surgeons (ESCRS Study) Study design: RCT

Evidence level: 1b

J Cataract Refract Surg 2006;32:407 | J Cataract Refract Surg 2007;33:978 | J Cataract Refract Surg 2008;34:1439 | J Cataract Refract Surg 2009;35:1523.

Key questions 1. What is the role of intra-cameral cefuroxime in preventing infectious endophthalmitis postcataract surgery? 2. What is the role of peri-operative topical levofloxacin in preventing infectious endophthalmitis post-cataract surgery?

Aims To establish, by means of a large and well-designed trial, evidence for the role of topical or inter-cameral antibiotics as prophylaxis for post-operative infectious endophthalmitis after phacoemulsification surgery. Prior to this study, the only proven method to reduce post-operative endophthalmitis was pre-operative povidone-iodine and antibiotic prophylaxis was likely to be non-standardised and not evidence-based with a true rate of endophthalmitis of approximately 0.15%.

Methods Participants: This prospective partially masked randomised trial took place at 24 European centres.

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Inclusion criteria (unless stated otherwise): • Age > 18 years undergoing one-stage phacoemulsification surgery. Exclusion criteria: • Allergy to penicillins, cephalosporins or iodine; • Long-term nursing home patients; • Patients with only one eye; • Pregnancy; • Combined surgery or complicated cataracts; • Significant ocular surface disease (severe blepharitis/atopic keratoconjuncitivitis, ocular cicatricial pemphigoid, severe thyroid disease); 8

•

Patients with open infection anywhere.

Groups: Sixteen thousand six hundred and three participants were randomised to a 2x2 treatment matrix based on intra-cameral cefuroxime (1 mg/0.1 ml) at the end of surgery vs. none, and peri-operative levofloxacin drops (0.5%) vs. none. In addition, all patients received: • Povidone-Iodine 5% drops at a minimum of three minutes before surgery; • Levofloxacin 0.5% drops four times a day for six days post-operatively. Primary endpoint: Total rates of endophthalmitis in each of the four treatment groups, and rates of culture/polymerase chain reaction (PCR)-positive endophthalmitis. Effect of risk factors on endophthalmitis was also investigated as a secondary endpoint.

ESCRS Study Results

Weaknesses

Rates of endophthalmitis: In total there were 29 cases of endophthalmitis, with 20 proven by microbiological results. Total rates of endophthalmitis were 0.345% (no antibiotics), 0.247% (levofloxacin drops), 0.074% (intra-cameral cefuroxime) and 0.049% (levofloxacin + cefuroxime). Odds ratio (OR) for endophthalmitis in the groups not receiving intra-cameral cefuroxime = 4.92.

Levofloxacin drops were chosen as the topical antibiotic during the post-operative period for all patients. This choice may have confounded the effect of the peri-­ operative levofloxacin. Results may be difficult to apply for surgeons who do not use levofloxacin as their post-operative antibiotic. Important risk factors for endophthalmitis were excluded in the criteria of selection, e.g., ocular surface disease and combined surgery. At the time that the study was conducted, cefuroxime was not available as a sterile preparation licensed for intra-cameral use and each centre had to prepare the drug locally.

Other risk factors for endophthalmitis: Logistic regression analysis identified the following as potential risk factors for endophthalmitis at p < 0.05: Site of incision (clear corneal incisions OR = 5.88), any surgical complications (OR = 4.95), intraocular lens (IOL) optic material (silicone IOL, OR = 3.13). When only microbiology positive endophthalmitis was considered, men were significantly more likely to develop endophthal­ mitis (OR = 2.70).

Key messages

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1. Intra-cameral cefuroxime significantly reduces the rates of post-operative endophthalmitis after phacoemulsification cataract surgery. 2. Rates of endophthalmitis were significantly lower with scleral tunnels, although only 2/24 centres in the study routinely performed these sections, introducing bias. 3. The incidence of surgical complications or using an IOL with silicone optic were also found to increase rates of endophthalmitis. Men were more likely to have a culture/PCR-proven endophthalmitis than women.

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Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study design: Longitudinal, descriptive Evidence level: 3 Cornea 2000;501-507 | Cornea 2006;16-25 | Cornea 2006;794-800 | Invest Ophthalmol Vis Sci ­2006;489-­500 | Cont Lens Anterior Eye 2007;223-232.

Key questions 1. What is the natural history of keratoconus? 2. What are the risk factors for progressive disease and scarring?

Aims This study aimed to follow a large number of patients with keratoconus, to characterise changes in vision, corneal curvature and opacity, and quality of life over time. The study also sought to determine risk factors associated with these changes.

Methods Participants: One thousand two hundred and nine patients were included from 16 centres in the USA.

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Inclusion criteria: • Age > 12 years; • Irregular corneal astigmatism by keratometric mires or retinoscopy; • At least one biomicroscopic sign of keratoconus (Vogt’s striae, Fleischer’s ring > two mm, apical corneal scarring); • Absence of other ocular disease. Exclusion criteria: • Ocular comorbidities

10

Study measures: Patients were examined annually to assess: • Visual acuity (VA); • Patient-reported quality of life (National Eye Institute Visual Function Questionnaire) (NEI-VFQ); • Manifest refraction; • Keratometry; • Photodocumentation of the cornea to identify central corneal scarring; • Photodocumentation of the flattest contact lens that just clears the cornea; • Slit-lamp biomicroscopy; • Corneal topography; • In rigid contact lens wearers, the fluorescein pattern of the patient’s habitual contact lenses was photodocumented. Follow-up: Eight years.

CLEK Results Baseline findings: The CLEK Study patients had a mean age of 39.3 ± 10.9 years. Fifty-seven percent of subjects were male, 14% reported positive family history in first- or second-degree relatives. Fifty-three percent had a history of atopy and 50% reported frequent eye rubbing. Longitudinal follow-up: Over seven years, the mean reduction in best corrected letters read was 2.03 high contrast letters and 4.06 low contrast letters. High- and low-contrast Best corrected (with contact lens) VA drop of two lines or more in at least one eye occurred in 19% and 31% of subjects respectively. Average increase in the flat keratometric reading was 1.60 D over eight years or 0.20 D ± 0.80 D per year. Twenty-four percent of patients had a > 3 D increase in their flat keratometric reading. Risk factors for decline in VA were identified as age 1 D; ᵒᵒ Increase in astigmatism by subjective refraction > 1 D; ᵒᵒ Decrease in back optic zone radius of prescribed contact lens > 0.1 mm. 12

Exclusion criteria: • Corneal thickness < 400 µm; • Axial corneal scarring; • Previous refractive or other corneal surgery; • History of other corneal or ocular surface disorders; • Pregnancy or breast feeding. Groups: The treatment arm received cross-linking with a modification of the Dresden protocol (3 mW/cm2 for 30 minutes). The control group did not receive a sham treatment. From six months onwards, those in the control group were offered corneal cross-linking if their keratoconus was found to be progressing or corneal transplantation if required. If either were performed data collection was discontinued. Primary endpoint: Kmax values at three, six, 12, 24 and 36 months measured by video-keratography (Orbscan II, Bausch & Lomb).

Results

Weaknesses

Kmax: The treatment group had regression of their Kmax by -0.72 ± 0.15 D at 12 months and -1.03 ± 0.19 D at 36 months compared to progression in the control eye group by 1.75 ± 0.38 D (p < 0.001). Those in the control group who reached the follow-up assessment at 36 months had a mean change from baseline of 0.78 ± 0.29 D (p = 0.01). The authors observed that those with a greater Kmax initially (> 54.0 D) had a greater improvement in their Kmax after treatment.

Out of 48 initial eyes in the control group, data collection was discontinued in 21, with 12 having cross-linking and five having corneal transplantation. This reduced the ability to detect differences between the two groups. Even those who remained in the control group as ‘non-progressors’ may have been progressing slowly. Many statistical tests were conducted without performing any compensation for the increase in Type-I errors. Corneal thickness at the thinnest point or apex was not one of the criteria for progression. Three criteria were selected as indicators of progression but only one (Kmax) was taken as the primary end point to evaluate that progression had been arrested (or reversed).

Secondary outcomes: There were no statistically significant changes in best spectacle corrected VA, subjective refraction, central corneal thickness or endothelial cell density between the groups at any time point (the treated eyes were thinner at 12 months). However, the treatment group had a statistically significant improvement in unaided VA compared to the control group. There were two complications in the treatment group, one patient in the treatment group had diffuse corneal oedema at one week and another patient had suspected microbial keratitis at day 2.

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Key messages 1. Cross-linking improved the Kmax and uncorrected visual acuity compared to controls. 2. Some eyes in the treatment group showed continuing improvement up to 36 months. 3. Those who remained in the control group until 36 months with ‘nonprogressive’ keratoconus had a statistically significant increase in Kmax compared to their baseline. 4. Those with a greater Kmax may have more to gain from treatment, although these eyes may also have thinner corneas precluding cross-linking.

13

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14

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Glaucoma

Section editor: Prof. Keith Martin

Ocular Hypertension Treatment Study (OHTS) Study design: RCT

Evidence level: 1b

Design/baseline ‒ Arch Ophthalmol 1999;117:573 | Results ‒ Arch Ophthalmol 2002;120:701 | Risk factors ‒ Arch Ophthalmol 2002;120:714.

Key questions 1. 2.

Does treatment of OHT reduce the likelihood of developing glaucomatous optic nerve damage? Which people with OHT are most likely to develop glaucoma?

Aims Glaucoma is a leading cause of blindness, and ocular hypertension (OHT) is the major modifiable risk factor. The OHTS aimed to evaluate the safety and efficacy of topical ocular hypotensive medication in preventing or delaying glaucoma in people with OHT. The secondary aim was to identify risk factors predicting which people with OHT will develop glaucoma.

Methods

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Participants: One thousand six hundred and seven subjects were recruited from 22 clinical centres across the USA. Overall, the mean age was 55.4 years, 57% were women, 69.5% were white and 25.0% were African-American. Inclusion criteria: • At least one eye intraocular pressure (IOP) 24-32 mmHg; • Fellow eye IOP 21-32 mmHg; • Age 40-80 years; • Normal reliable Humphrey 30-2 visual field (VF); • Normal optic discs. Exclusion criteria: • Acuity < 6/12 (20/40); • Previous intraocular surgery (except uncomplicated extracapsular cataract surgery, strabismus surgery, cosmetic eyelid surgery or radial keratotomy); • Secondary causes of elevated IOP including steroids, angle closure; 16

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• • •

Other causes of visual field or optic disc abnormality, or cup-to-disc ratio (CDR) asymmetry > 0.2, or inability to visualize/photograph optic discs; Diabetic retinopathy; Pregnancy or breast feeding; Severe illness.

Groups: Participants were randomly assigned (stratified by centre and race) to treatment or observation. Treatment was using any commercially available drops to achieve an IOP < 24 mmHg and a 20% reduction from baseline in the eye with highest IOP. Primary endpoint: Confirmed abnormality of VF or optic disc (glaucoma). Secondary endpoints: Visual acuity (VA), cataract, quality of life. Ancillary studies included confocal scanning laser ophthalmoscopy (CSLO), and corneal imaging. Follow-up: > 13 years reported.

OHTS Results Treatment received: Half of the treated patients achieved target IOP on one medication. Initially, 90% received a β-blocker drop, but over time this fell to 65% at six years with 45% taking prostaglandin analogue and 20% taking topical carbonic anhydrase inhibitors. Development of glaucoma: After an average six years, glaucoma developed in 4.4% of treated and 10.9% of observed participants (hazard ratio 0.40, 95% CI 0.27-0.59, p < 0.0001). Around 55% of eyes judged to have progressed had disc changes, 36% had field defects, and 9% had both concurrently. With 13 years follow-up (both groups treated after six years), 16% of the treated and 22% of the observed group developed glaucoma (difference remained 6%). Trend-based analyses showed the rate of field deterioration was slow overall, with six months, 17% had changes in iris colour, lashes or darker lids (c.f. 7.6% observed). Acuity did not differ, but 6.4% treated and 4.3% observed had cataract surgery. No serious or systemic symptoms differed between groups.

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Calculating risk of glaucoma: An important outcome of OHTS was the finding that reduced central corneal thickness (CCT) was a powerful risk factor for developing glaucoma. While CCT affects tonometry, it has been suggested that CCT may also be

an independent risk factor for glaucoma, and adjusting the IOP for CCT did not improve accuracy of risk models in OHTS. The other risk factors for glaucoma in multivariate models were age, IOP, pattern standard deviation on VF, vertical CDR, and there was an unexpected protective effect of diabetes mellitus. Male gender, African or Hispanic race, and heart disease were only risks in the univariate model, and important negative findings were that family history, blood pressure and myopia did not predict glaucoma in OHT. A risk calculator was derived from these data, and has been validated and extended with data from EGPS. Ancillary studies: The CSLO study found baseline abnormalities of CSLO predict the development of glaucoma, but at least 75% of those with abnormal CSLO never develop glaucoma. Specular and confocal microscopy indicated reduced sub-basal nerves but no changes in the keratocytes or corneal endothelium in the treated group. Age-related corneal thinning of 0.6 μm/year was observed, and was accelerated by prostaglandin therapy, but this was deemed unlikely to affect tonometry or clinical decisions over time. A later analysis of IOP in relation to the timing of cataract surgery provided important evidence that routine cataract surgery lowers IOP in OHT.

Weaknesses A 20% reduction was small but achievable; perhaps larger changes in IOP would have a greater effect on risk. The threshold for confirmed glaucoma was set high.

Key messages 1. The risk of glaucoma in OHT is low (~10% in five years), but can be reduced safely with drops to ~5%. 2. CCT is a major independent risk factor for glaucoma. 3. Risk calculators can help estimate who will benefit from treatment. 4. Cataract surgery reduces IOP in OHT.

17

European Glaucoma Prevention Study (EGPS) Study design: RCT

Evidence level: 1b

Design ‒ Ophthalmology 2002;109:1612 | Results ‒ Ophthalmology 2005;112:366 | Risk factors ‒ Ophthalmology 2007;114:3.

Key questions 1. Does treatment of ocular hypertension (OHT) with topical dorzolamide reduce the likelihood of developing glaucoma? 2. What risk factors predict the development of glaucoma in OHT?

Aims The EGPS aimed to assess the safety and efficacy of topical dorzolamide against placebo for preventing or delaying open-angle glaucoma (OAG) in patients with OHT. The placebo control was an important improvement on the OHTS but this limited the masked treatment to one drug only.

Methods

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Participants: One thousand seventy-seven participants were enrolled from 18 European centres. Forty-five percent were male, mean age was 58 years and mean baseline intraocular pressure (IOP) was 24 mmHg. Inclusion criteria: • Age ≥ 30 years; • IOP 22-29 mmHg in at least one eye (mean of two measures). When both eyes were eligible, the mean IOP was recorded for that participant; • Two normal and reliable visual field (VF) tests; • Normal optic discs; • Open angles (normal or pigment dispersion or pseudoexfoliation syndromes); • Clear media, refraction less than -6 D myopia. Exclusion criteria: • Any glaucomatous optic neuropathy; • Visual acuity (VA) < 6/12 (20/40) in eligible eyes; • Eye factors: Congenital abnormalities or acquired ocular conditions, abnormal optic disc, previous intraocular surgery, argon laser trabeculoplasty 18

• •

•

within three months, secondary causes of elevated IOP, diabetic retinopathy; Any condition affecting visual field; Systemic factors: Conditions associated with glaucoma (migraine, hypotension, Raynaud, transient ischaemic attack), pregnant or nursing women, severe illness affecting participation, contraindication to dorzolamide; Single-eyed patients.

Groups: Patients were randomised to the treatment with dorzolamide or a placebo in either one or both eyes as necessary. Endpoints: Development of primary OAG (POAG) confirmed visual field and/or agreed optic disc changes. A safety endpoint meant that participants with IOP ≥ 35 mmHg twice exited the trial. Follow-up: Five years.

EGPS Results IOP results: Baseline mean IOP was 23.6 mmHg in both groups, with a highly skewed distribution so that most participants had an IOP < 25 mmHg. Both groups had a decrease in IOP immediately after enrolment and decreasing IOP over follow-up, with a greater reduction in the dorzolamide group (mean IOP during treatment 19.3 mmHg, 14.5% decrease at six months, 22.1% at five years) compared to the placebo group (mean 20.4 mmHg, 9.3% decrease at six months, 18.7% at five years, p < 0.0001). Development of glaucoma: After five years, the cumulative probability of developing glaucoma was 13.4% in the dorzolamide group and 14.1% in the placebo group (p = 0.45). Approximately half of the cases of glaucoma were detected by optic disc photography without field loss.

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Safety and VA: The percentage exiting the trial due to the safety endpoint (IOP > 35 mmHg) was 0.2% in the dorzolamide group and 2.2% in the placebo group. Including these safety endpoints as POAG did not affect the results (p = 0.1). Serious adverse events were no different between groups, but ocular adverse events, especially stinging, and taste disorder were more common in the dorzolamide group (22.8% ocular 2.8% taste) than the placebo group (6.5% ocular, 0.1% taste).

Risk factors for glaucoma: In multivariate models age, vertical cup-to-disk ratio (CDR), CDR asymmetry, higher pattern standard deviation (PSD), lesser central corneal thickness (CCT) were predictive of glaucoma. IOP, exfoliation and cardiovascular disease were risk factors in univariate models, but not on multivariate analysis. The contribution of individual risk factors to overall risk was similar to the OHTS. Diabetes was not associated with the development of glaucoma.

Weaknesses There was much analysis of why the EGPS design did not show treatment benefit. The study design involved dorzolamide vs. placebo treatment alone; a target IOP had not been set and those achieving IOP control were not compared to uncontrolled. Baseline IOP was recorded at recruitment by an unmasked physician twice on the same day, resulting in the probable inclusion of near-normal participants and contributing to regression to the mean (both groups IOPs decreased to normal with time). Around 40% of participants did not reach the end of the study. There also was selective drop-out of participants with uncontrolled IOP, much more common in the placebo group, but inclusion of these participants as glaucoma endpoints did not bring results to statistical significance. Together, these factors resulted in a small IOP lowering effect in the treatment arm, small groups at the end of the study, and an undetectable effect from treatment in terms of preventing progression to glaucoma. This design was used to reduce bias toward a treatment benefit, but also limited the usefulness of the study.

Key messages 1. Treatment with dorzolamide alone did not reduce the likelihood of developing glaucoma in patients with OHT. This lack of effect could have been due to factors in the study design, particularly selection bias, regression to the mean and a relatively weak IOP lowering effect of dorzolamide alone. 2. Risk factors for glaucoma were similar to the OHTS, including a thin cornea.

19

Early Manifest Glaucoma Trial (EMGT) Study design: RCT

Evidence level: 1b

Design/baseline ‒ Ophthalmology 1999;106:2144 | Initial results ‒ Arch Ophthalmol. 2002;120:1268 | Long-term risks ‒ Ophthalmology 2007;114:1965.

Key questions 1. Does intraocular pressure (IOP) lowering affect the outcome in open-angle glaucoma (OAG)? 2. What ocular and systemic factors, at baseline and during follow-up, affect the rate of visual loss in glaucoma?

Aims The EMGT aimed to evaluate the effectiveness of reducing IOP in early, previously untreated OAG. Secondary aims were to explore factors related to glaucoma progression and to study the natural history of the disease.

Methods

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Participants: When the study was planned, it was thought to be unethical to randomise known glaucoma patients to no treatment. Therefore, a population screening exercise was undertaken in Malmö, Sweden, where 44,243 residents aged 57-76 years were screened, plus a low number of referrals from ophthalmologists, resulting in 255 eligible confirmed new cases of OAG. The mean age was 68 years, 66% were women, almost all were white, and mean baseline IOP was 20.7 mmHg (52% had baseline IOP ≤ 21 mmHg). Inclusion criteria: • New diagnosis of early manifest OAG (primary, ­normal-tension or exfoliative); • Reproducible visual field defect in at least one eye; • Age 50-80 years. Exclusion criteria: • Advanced field loss (MD worse than -16 dB) or threat to fixation; • Visual acuity (VA) < 6/12 (20/40); • Mean IOP > 30 mmHg or any IOP > 35 mmHg in either eye; 20

• •

Cataract; Any condition affecting reliable field results or ability to participate.

Groups: Participants were randomly allocated to treatment or non-treatment groups, and one or both eyes were treated in the same manner. All eyes randomised to treatment received 360 degree argon laser trabeculoplasty and topical betaxolol 0.5% twice daily. If IOP rose over 25 mmHg twice or over 35 mmHg once, latanoprost 0.005% was added. Primary endpoint: Progression of visual field defect or of optic disc cupping. Follow-up: Median eight years (range 0-11 years).

EMGT Results IOP reduction: The mean IOP in treatment group fell from 20.6 to 15.5 mmHg, a reduction of 25% that was maintained throughout the follow-up. The mean IOP in the control group hardly changed from 20.9 to 20.8 mmHg. Those with a higher baseline IOP had a greater lowering of IOP from treatment. Untreated IOP was very stable, with only the exfoliation subgroup showing a tendency to increasing IOP over an average six years. Visual field (VF) outcomes: After eight years of follow-up, 45% of the treated group had progressive VF loss and 62% of the untreated group had progression (p = 0.007). Progression occurred earlier in the control group (48 months, versus 66 months in treated group), with mean MD loss of 2.24 dB in the treated group and 3.90 dB in the controls. The overall adjusted hazard ratio for the treated group was 0.50 compared to controls. Only one of 136 patients that progressed showed disc change without VF deterioration. Risk factors for VF deterioration: The risk of progression increased with exfoliation, bilateral glaucoma, higher IOP, worse baseline MD, older age and low ocular perfusion pressure (in decreasing order of risk). Thin central corneas and cardiovascular

disease were risk factors in those with higher IOP, and in those with lower IOP having low blood pressure was a risk factor for progression. During follow-up, there was a consistent risk reduction from IOP lowering by around 10-13% for every one mmHg of IOP lowering. Disc haemorrhages were associated with higher risk of progression, but were not associated with IOP or treatment. Amongst controls, those with exfoliation progressed most and fastest, while normal-tension patients progressed least and slowest. IOP fluctuation was not associated with risk of progression. Side effects: Few systemic or ocular side effects were identified but all were more common in the treated group. Nuclear cataract developed faster in the treated group and six had surgery (compared to two controls, overall rate only 3%). Side effects were rarer and milder than those described in studies with glaucoma surgery.

Weaknesses The EMGT criteria for field progression were more sensitive and less specific than the CIGTS or AGIS criteria. The observation group was not placebo-controlled and investigators were not masked. The treatment regime was perhaps unusual, but effective.

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Key messages 1. IOP at baseline and during follow-up were key risk factors for progression of early glaucoma, with approximately 10% risk reduction for every one mmHg reduction in mean IOP across the treated population. Lower IOP resulted in slower and less progression in early OAG. 2. Exfoliation syndrome, bilateral and more advanced disease, older age, low ocular perfusion pressure, thin central corneas and cardiovascular disease were all risk factors for progression. 3. Treatment for glaucoma with ALT, betaxolol and latanoprost was associated with an increased rate of cataract, but less so than surgery.

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United Kingdom Glaucoma Treatment Study (UKGTS) Study design: RCT

Evidence level: 1b

Design: Ophthalmology 2013;120:68. Baseline: Ophthalmology 2013;120:2540. Results: Lancet. 2014;385:1295

Key questions 1. Does treatment with a prostaglandin analog (latanoprost) reduce visual field deterioration in open angle glaucoma (OAG) within two years? 2. Can the rate of field loss, and optic disc imaging be used as trial outcomes to help shorten trials? 3. What risk factors predict field deterioration? 4. How are field loss and quality of life associated in open angle glaucoma?

Aims The UKGTS was the first randomized, double masked, placebo-controlled trial for medical treatment of OAG. The major objectives of this study were assessing the impact of prostaglandin analogue treatment ( latanoprost 0.005%) on visual field (VF) preservation, and testing new methods to shorten the duration of glaucoma trials, specifically using the rate of visual field deterioration and optic nerve head (ONH) imaging as trial outcomes. Secondary objectives also included identification of risk factors for VF deterioration and evaluation of the association between VF loss and measures of quality of life (QoL).

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Methods Participants: 516 patients were recruited from 10 UK hospitals. Inclusion • Newly detected, previously untreated OAG (including pseudoexfoliation) in either eye with two reliable and consistent VF tests. • Age older than 18 years • Acuity ≥ 6/12 (20/40) Exclusion • Moderately advanced VF loss or a threat to fixation in either eye; 22

• • •

Untreated IOP ≥ 30 dB or IOP of > 35 mmHg on 2 occasions in either eye Inability to obtain ONH imaging, cataract, or diabetic retinopathy Previous surgery (except uncomplicated cataract surgery >1 year before)

Groups: Participants were randomly allocated (1:1) to latanoprost 0.005% or placebo eye drops, once a day in both eyes. Both drops had benzalkonium preservative 0.2 mg/mL. Primary endpoint: Time to confirmed VF deterioration (similar to EMGT). Secondary endpoints: Velocity of VF loss in one eye or both, rate of nerve fibre loss (GDx scanning laser polarimetry and OCT) or disc rim loss (HRT scanning laser ophthalmoscopy), IOP change. Follow up: 24 month

UKGTS Results The data safety monitoring committee requested an interim analysis which led to early conclusion of the trial. 461 patients were analysed for primary outcome. Effect of latanoprost on IOP The initial change in IOP in the placebo group was -1.4 mmHg from a baseline of 20.5 mmHg and in the latanoprost group was 5.0 mmHg from a baseline IOP of 19.6 mmHg (26% drop). This effect was maintained. Adverse events were mild and very similar between groups, patients lost to follow up and withdrawing due to medication intolerance showed no difference between groups. Effect of latanoprost on glaucoma progression Within 24 months, 59 of 230 patients in the placebo group (26%) and 35 of 231 in the latanoprost group (15%) showed glaucomatous field progression (p = 0.006). Time to deterioration was also longer in the latanoprost group (HR 0.44, p = 0.0003).

Risk factors for progression Age ≥ 65y, an initial field MD ≤ -4.5 dB, and baseline IOP ≤ 21 mmHg were risk factors for progression, and each of these was associated with a stronger benefit from latanoprost treatment compared with placebo. Results relating to IOP measurement devices, optic disc imaging and quality of life assessments had not been published by April 2017.

Weaknesses The study design was strong as it replicated usual clinical practice with broad inclusion criteria. There was moderate loss of patients to follow up, but this was considered and did not appear to introduce systematic bias.

Key messages

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1. Latanoprost reduces IOP more than placebo and reduces the rate of visual field loss by over 50% within two years. 2. Clustering of visual field tests and time-to-event analysis may allow shorter glaucoma trials.

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Advanced Glaucoma Intervention Study (AGIS) Study design: RCT

Evidence level: 1b

Ophthalmology 1998;105:1146 | Risk factors ‒ Am J Ophthalmol 2000;130:429 | Long term results ‒ ­Ophthalmology 2004;111:651

Key questions 1. What is the clinical course of medically uncontrolled glaucoma and how does this relate to risk factors including intraocular pressure (IOP)? 2. What is the best initial surgical strategy to lower IOP in medically uncontrolled glaucoma? 3. Do pre-operative factors affect the success of IOP lowering therapies?

Aims In the 1980s, argon laser trabeculoplasty (ALT) and trabeculectomy were both used as treatments for medically uncontrolled glaucoma. The AGIS study was designed to answer several questions about medically uncontrolled glaucoma: the course and prognostic factors, whether initial therapy with ALT or trabeculectomy were more effective in preserving vision, and complication rates of surgery.

Methods

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Participants: Seven hundred eighty-nine eyes of 591 patients (451 eyes of 332 black patients and 325 eyes of 249 white patients and 13 eyes of ten patients of other race) were randomised across 11 centres in the USA. Inclusion criteria: • Age 35-80 years; • Primary open-angle glaucoma (POAG) (or angle open after laser iridotomy); • IOP not controlled on maximal tolerable medical therapy; • Phakic with acuity at least 6/24 equivalent; • A table of specific combinations of elevated IOP and visual field (VF) defect was used to define ‘uncontrolled’ glaucoma. The participants had a range of field defects from very mild to severe. The same table was used to determine if a second or third operation was required. 24

Exclusion criteria: • Secondary glaucoma or congenital angle anomalies; • Other active eye diseases, particularly those that cause field loss, or previous surgery (except laser iridotomy or localized retinopexy). Groups: All patients were randomised to a sequence of surgical interventions: either (1) ALT followed if necessary by trabeculectomy, followed if necessary by repeat trabeculectomy (the ATT group); or (2) trabeculectomy followed if necessary by ALT, followed if necessary by repeat trabeculectomy (the TAT group). Primary endpoint: Visual acuity (VA) or VF (field scored 0 normal to -20 blind). Follow-up: Seven years initially, more than ten years reported.

AGIS Results Effect of IOP on glaucoma progression: This study showed a strong association between IOP exposure and VF loss in glaucoma and was instrumental in persuading many clinicians to aim for a lower target IOP in advanced glaucoma than they had previously considered necessary. Later analysis suggested IOP fluctuation as an independent risk for VF progression by point-wise linear regression, although the interpretation of these results has been controversial. Predictive analysis showed that those with an initial mean IOP < 14 mmHg over the first 18 months after surgery had mean VF score deterioration of one point and those with an initial average IOP ≥ 18 mmHg had a mean score deterioration of three points over seven years. Likewise, the associative analysis showed that having an IOP < 18 mmHg on 100% of follow-up visits resulted in a mean score deterioration of zero, but those achieving 18 mmHg on < 100% of visits had a mean deterioration of two to three points. Overall risk of legal blindness was moderately high: in black patients ATT 11.9% and TAT 18.5% and in white patients ATT 9.9% and TAT 7.3%. Most effective initial surgical intervention: Throughout the seven-year follow-up, those eyes initially treated with trabeculectomy had greater mean IOP reductions, and those eyes initially treated with ALT were more likely to have a second operation. In white patients visual field was better preserved by

TAT only after the first year of follow-up, and acuity was better preserved by ATT throughout follow-up. This VF advantage of initial trabeculectomy was most significant in the ten-year follow-up report. However, in black patients, ALT had a greater chance of success and trabeculectomy had a greater chance of failure. Black patients had higher IOP, more VF loss and more medications with fewer drop intolerances. For black patients, the risk of VF or VA loss was less for the ATT sequence throughout the seven years, and out to ten years. Complications of trabeculectomy: The relative risk of cataract in the five years after trabeculectomy was 1.78 compared to those participants who avoided trabeculectomy. Complications further increased the risk of cataract. Youth and high IOP were key risk factors for failure of either ALT or trabeculectomy. Diabetes mellitus and post-operative complications such as IOP spikes or persistent inflammation were also significant risk factors for trabeculectomy failure.

Weaknesses The study was designed to evaluate ALT and trabeculectomy, yet many of the most cited conclusions from the AGIS study are based on meta-analysis rather than on the original clinical question around which the trial was designed.

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Key messages 1. IOP is strongly correlated with risk of visual loss in medically uncontrolled glaucoma. 2. Achieving an IOP < 14 mmHg greatly reduces the risk of progression in medically uncontrolled glaucoma. 3. Trabeculectomy achieved a larger, more sustained drop in IOP than ALT, but the benefit of low IOP in preserving VF was only apparent in longer-term follow-up of white patients. 4. Black patients with glaucoma have greater success with ALT and lower success with trabeculectomy, compared to white patients. For black patients the risk of visual loss is lower with ALT as the initial treatment.

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Collaborative Initial Glaucoma Treatment Study (CIGTS) Study design: RCT

Evidence level: 1b

Initial results ‒ Ophthalmology 2001;108:1943 | Ophthalmology 2011;118:1766.

Key questions 1. Is initial surgical treatment or medical treatment better for preserving vision and quality of life in patients with newly diagnosed glaucoma? 2. What factors predict deterioration of vision or quality of life in glaucoma?

Aims CIGTS was a randomised, controlled clinical trial designed to determine whether patients with newly diagnosed open-angle glaucoma (OAG) are better treated by initial treatment with medications or by immediate trabeculectomy.

Methods

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Participants: Six hundred and seven patients were enrolled from 14 participating centres in the USA. Overall, 45% were women and 56% were white, with average age 57.5 years and baseline IOP of 27.5 mmHg. Inclusion criteria: • Newly diagnosed OAG (primary, pseudoexfoliative, or pigmentary); • Age 25-75 years; • Visual acuity (VA) ≥ 6/12 (20/40); • Intraocular pressure (IOP) ≥ 20 mmHg with visual field (VF) defect and/or glaucomatous optic disc, according to criteria to diagnose very-likely glaucoma. Exclusion criteria: • Use of glaucoma medication > 14 days; • Severe VF defect; • Ocular disease that might affect measurement of IOP, acuity, or VF, particularly diabetic retinopathy, cataract or previous ocular surgery. 26

Groups: Participants were randomised to receive medication or trabeculectomy initially. The same protocol was used, as needed, on both eyes. A target IOP was generated for each eye as a function of baseline IOP and field loss, and treatment was increased according to a flowsheet if that target IOP was not met. The medical group received escalating medication, followed as needed by argon laser trabeculectomy (ALT), trabeculectomy with optional 5-fluorouracil (5-FU), further medication, repeat trabeculectomy with antimetabolite, medication, then treatment at the doctor’s discretion. The trabeculectomy group received a trabeculectomy within two weeks of enrolment (5-FU optional), followed by ALT, medication, repeat trabeculectomy with antimetabolite, medication, then treatment at the doctor’s discretion. Primary endpoint: VF score (0 normal – 20 blind) or mean deviation (MD). Secondary endpoints: Quality of life and visual function, VA, IOP, cataract. Follow-up: Nine to ten years reported.

CIGTS Results Both groups had a substantial lowering of IOP, but trabeculectomy was lower: The trabeculectomy group mean IOP fell 48% from 27 mmHg to 14-15 mmHg over nine years. The medication group mean IOP fell 40% from 28 mmHg to 17-18 mmHg over nine years. Higher IOP at baseline was associated with younger age, males, and secondary glaucoma. During the stable period of follow-up, higher IOP was associated with treatment group, and weakly with baseline IOP, field defect, lower education level, and hypertension. Smoking increased IOP amongst the surgical group.

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There was minimal progression of VF loss in either group: The trabeculectomy group baseline MD of -5.7 dB was essentially unchanged at five years (-5.3 dB) or eight years (-6.3 dB). The medical group baseline MD of -5.2 dB improved to -4.8 dB at year one to two, but then worsened to the same level as the surgical group at five years (-5.5 dB) and eight years (-6.1 dB). Regression analyses, including the effect of cataract and the baseline field difference, indicated no effect of treatment group on VF. There was a subtle interaction effect that indicated those with poor baseline had an advantage from surgery (e.g., baseline -10 dB had difference 1.03 dB at seven years, p = 0.01). Overall the risk of -3 dB worsening of MD was 13.0% at five years and 21.3 % at eight years in the trabeculectomy group, and 15.9% at five years and 25.5% at eight years in the medical group. A variable 12-17% showed substantial improvement in either group (MD +3 dB) and the

consistency and association with IOP suggested the improvement was real. Older age, non-white race, diabetes mellitus, and development of cataract were identified as risk factors for field deterioration, as well as maximal IOP and IOP fluctuation between visits. Cataract was more common after trabeculectomy: The relative risk of cataract surgery within five years of randomization was 3.76 for the trabeculectomy group, but after five years the risk of cataract surgery was higher in the medical group, so the final risk of cataract surgery at ten years was around 22% in the surgical group and 14% in the medical group. Cataract surgery increased the acuity, VF score and mean deviation, and quality of life measurements. Older age, diabetes, myopia, and exfoliation were risk factors for cataract surgery. Quality of life: Quality of life and visual function questionnaires correlated only weakly (r = 0.15-0.20) with monocular or binocular VF variables. There were no substantial differences between treatment groups, even after accounting for cataract.

Weaknesses The lack of effect of IOP on vision, and lack of effect of treatment choice on quality of life surprised many. It was thought that longer follow-up would reveal differences, but this has not yet been demonstrated. Inclusion criteria may have allowed some with OHT and a low risk of glaucomatous visual loss.

Key messages 1. Both medication and trabeculectomy can be effective in lowering IOP by ≥ 40%, which prevents loss of VF. 2. Initial trabeculectomy results in a lower IOP in the longer term, but is associated with a greater risk of cataract in the first five years. 3. VF progression is more common in those with variable IOP.

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Collaborative Normal-Tension Glaucoma Study (CNTGS) Study design: RCT

Evidence level: 1b

Am J Ophthalmol 1998;126:487 | Am J Ophthalmol 1998;126:498 | Ophthalmology 2001;108:247 | Am J Ophthalmol 2001;131:699 | Am J Ophthalmol 2003;136:820.

Key questions 1. Is intraocular pressure (IOP) part of the disease process in normal-tension glaucoma (NTG)? 2. Should doctors recommend lowering the IOP in NTG? 3. Is it practical to lower the pressure in NTG?

Aims The main focus of the study was to understand the disease of NTG, that is, to determine whether IOP was involved in the pathogenic process. In that sense it was not a clinical trial, but had clear implications for management of patients. It was also the aim to learn more about the untreated natural history of the disease.

Methods

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Participants: One hundred forty-five eyes of 145 patients were randomised. There were 24 participating centres in the USA, Canada, The Netherlands and Finland. Inclusion criteria: • NTG with both disc and field changes, that also had either (a) fixation threatened; or (b) observed progression on discs or fields; or(c) development of a new optic disc haemorrhage; • Untreated IOP median ≤ 20 mmHg and never > 24 mmHg; • Reliable automated field tests and pupil of ≥ 2.5 mm diameter. Exclusion criteria: • Systemic beta-blockers or clonidine; • Non-glaucomatous conditions, narrow angles, or advanced field loss; • Previous ophthalmic laser, cycloablation or intraocular surgery; 28

•

Reduced visual acuity (VA) worse than 6/9 (20/30).

Groups: The least-affected eye that qualified for the study was randomised to untreated control arm or a 30% reduction in IOP. Methods used to reduce pressure were pilocarpine, argon laser trabeculoplasty, and trabeculectomy surgery at the clinician’s discretion: beta blockers and adrenergic agonists were forbidden. Primary endpoint: Sensitive criteria for subtle visual field progression. Follow-up: Five to eight years.

CNTGS Results Natural history of NTG is variable: Half of untreated patients showed no progression at five years, but a smaller number progressed rapidly in the first few months. Much of the progression was deepening and localised expansion of existing defects, not new defects. Females, especially those with a history of migraine and participants with disc haemorrhages were all more likely to progress. Risk factors for the prevalence of NTG such as age and baseline IOP were not risk factors for progression. Pressure lowering in NTG is possible: In the early 1990s it was an important finding that half of patients with NTG could achieve a 30% pressure lowering without trabeculectomy surgery (or beta blockers or adrenergic agonists). With modern glaucoma drops including prostaglandin analogues, this proportion is likely to be higher now.

IOP is important in NTG: Those whose pressure was lowered by 30% had a slower rate of progression than untreated controls. Overall, 35% controls progressed at five years, and 12% of the treated group. In the intention-to-treat analysis, the difference was only evident when the effect of cataract was removed. That is, lowering the pressure with tra­ beculectomy caused cataracts, masking the benefit of a low IOP. Females had a greater benefit from treatment, as did those with family history of glaucoma. Those with disc haemorrhage had no benefit from IOP lowering, and neither did those with more advanced glaucoma, migraine, cardiovascular disease, family history of stroke.

Weaknesses NTG is a heterogeneous condition and it remains difficult to predict whether individual patients will benefit from treatment. Many patients encountered in practice fall outside of the study criteria.

Key messages

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1. NTG is a heterogeneous and multifactorial condition with variable rates of progression. IOP is a risk factor for development of NTG, and IOP lowering reduces the rate of progression. 2. There are separate factors that contribute to the incidence of NTG, to the risk of progression and to the likelihood of benefit from therapy. These factors differ, indicating subtleties about the process of NTG. 3. Patients with NTG can be observed as half will not progress untreated, but if progression is occurring, a 30% reduction in IOP is a practical and beneficial treatment.

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Low-Tension Glaucoma Treatment Study (LoGTS) Study design: RCT

Evidence level: 1b

Design/baseline ‒ Ophthalmology 2005;112:376 | Results ‒ Am J Ophthalmol 2011;151:671 | Risk factors ‒ Am J Ophthalmol 2012;154:702.

Key question 1. Does topical brimonidine have a neuroprotective effect in addition to the intraocular pressure (IOP)-lowering effect, in the context of normal-tension glaucoma (NTG)?

Aims Although lowering of IOP is known to be helpful in NTG, some treated patients with low IOP continue to worsen, so additional neuroprotective therapies are sought. Topical administration of brimonidine reaches the optic nerve head, and had shown promise as a neuroprotective agent in animal models, but brimonidine also lowers the IOP, which is itself neuroprotective. This study aimed to test whether there was an neuroprotective benefit of topical brimonidine in NTG, using a comparison to timolol which has similar IOP-lowering effect (but no other hypothesized neuroprotective effect).

Methods

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Participants: One hundred seventy-eight participants with NTG at 13 centres in USA. Inclusion criteria: • All IOP measures ≤ 21 mmHg; • Open iridocorneal angles on gonioscopy; • Reproducible glaucomatous visual field (VF) defect; • Consistent glaucomatous optic disc appearance. Exclusion criteria: • Age < 30 years; • Visual acuity (VA) < 6/12 in either eye; • Severe glaucoma with field mean deviation (MD) 14 days in last six months, > one medication at any point, prior evaluation of drug efficacy; • Severe field defect; • Contra-indication for use of study medications, or the systemic use of steroid, adrenaline or clonidine;

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Ocular conditions: previous ocular surgery, any barrier to 310 degrees of trabecular meshwork (TM) for ALT treatment, diabetic retinopathy, rubeosis; Unreliable or unobtainable fields, disc photographs, or two years follow-up.

Groups: One eye of each participant was randomly assigned to ALT followed by medical treatment if needed (laser first, LF). Treatment was delivered in two sessions of 180 degrees (45-50 burns, 600-1200 mW to blanch or barely form a bubble) separated by four weeks. The other eye was assigned to timolol 0.5% drops twice daily (medication first, MF). Medical treatment for either eye was increased if IOP was ≥ 22 mmHg or a reduction of 20% was not achieved, according to a sequence: timolol, dipivefrin, low then high dose pilocarpine, then combinations of drops. Primary endpoint: IOP. Secondary endpoints: Field and disc changes, VA. Follow-up: Two years minimum, over nine years reported.

GLT Results IOP: The LF eyes had very slightly lower IOP through follow-up, falling from 27 to 18 mmHg (mean reduction -9.1 mmHg). The MF eyes fell from 27 to 19 mmHg (mean reduction -8.7 mmHg at 3.5 years of follow-up, overall IOP Δ 1.3 mmHg, p < 0.001). Medications and surgery: At median follow-up of three years, 20% of LF eyes were on no medication, and another 20% were on timolol alone. In the MF eyes only 15% were on timolol alone (p < 0.001). Overall 17% of the LF eyes required further ALT, systemic medication or surgery, compared to 31% of the MF eyes. Safety and VA: Some side effects were noted, but overall laser and medication were both found to be safe in this group. Unlike previous reports, there appeared to be only a small -0.5 mmHg effect of monocular timolol on the contralateral eye. VA deteriorated slightly in LF- and MF-treated eyes during the study, but was not significantly different between treatment groups.

VFs and optic discs: Visual field tests varied and improved slightly over follow-up on average. There was a trend towards increased likelihood of confirmed worsened field tests in the MF eyes (39%) compared to the LF group (29% at 3.5 years, p = 0.09). Some other measures of visual field deterioration also favoured the LF eyes. Very small changes in CDR and optic disc appearance were found to be statistically significant, but were unlikely to have been clinically significant.

Weaknesses The specific enrolment criteria, including the restriction to previously untreated phakic patients, make generalising the findings of this study to other patient groups difficult. The medications available to the study in the late 1980s were poorer than those available 30 years later. Effective ALT treatment requires considerable skill and therefore results might be different outside the context of a clinical trial where ALT was performed mainly by glaucoma experts. The results of current clinical trials directly comparing selective laser trabeculoplasty to prostaglandin analogue treatment are awaited with interest.

Key messages

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1. Initial treatment with ALT resulted in fewer medications and slightly lower IOP at three years compared to initial treatment with timolol 0.5%. 2. No significant differences in visual function were observed between groups during the course of the trial.

33

5-Fluorouracil Filtering Surgery Study (FFSS) Study design: RCT

Evidence level: 1b

Am J Ophthalmol 1989;108:625 | Am J Ophthalmol 1996;121:349.

Key question 1. Does post-operative 5-fluorouracil (5-FU) treatment improve the success rate or safety of trabeculectomy surgery in eyes with uncontrolled glaucoma and poor prognoses?

Aims The FFSS aimed to determine the long-term safety and efficacy of post-operative 5-FU treatment after tra­ beculectomy in eyes with uncontrolled glaucoma and poor prognoses.

Methods Participants: Two hundred and thirteen participants (one eye per participant) were recruited from seven clinical centres in the USA. The mean age was 61 years, 52% were male, 19% were black, 18% had ocular inflammation, there was an average of 2.2 previous eye operations, and mean preoperative intraocular pressure (IOP) was 34 mmHg.

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Inclusion criteria: • Patients with uncontrolled glaucoma on maximal tolerated medical therapy, IOP > 21 mmHg, and previous cataract extraction or failed filtering surgery were invited to participate. Exclusion criteria: • Age < 18 years; • Pregnant women; • Unable or unwilling to consent or follow-up as required; • Previous 5-FU systemically or in the study eye; • Eye factors: No perception of light, rubeosis, dislocated lenses, or open angles that had not been treated with argon laser trabeculoplasty initially.

34

Groups: Randomisation occurred on the first post-operative day after trabeculectomy, when the wound was shown to be watertight. Participants were randomised 1:1 to receive post-operative subconjunctival injections of 5.0 mg 5-FU in 0.5 mL twice daily on days 1-7 and once daily on days 8-14. Primary endpoint: Failure defined as IOP > 21 mmHg at one year or re-operation. Secondary endpoints: IOP, complications, medications, risk factors. Follow-up: Over five years reported.

FFSS Results Success and failure: Recruitment was concluded before the target sample size at the recommendation of the Data Safety and Monitoring Committee because there was a significant difference in outcomes. At one year, 27% of the 5-FU group and 50% of the control group had failed. Using survival analysis, the proportion surviving in the 5-FU group were 80% at one year, 56% at three years, and 48% at five years, compared to the control group 60% at one year, 28% at three years and 21% at five years. These values were not greatly different between those who had previous cataract surgery or previous filtering surgery. Many risk factors for failure were analysed by various methods at different time points with variable results. At five years, the risk of failure was reduced by 5-FU treatment, increased time since previous eye surgery, fewer previous operations, lower pre-operative IOP, and non-Hispanic ethnicity. Secondary angle closure, inferior trabeculectomy and reduced pre-operative acuity were risk factors that were only significant in univariate models because of their association with the severity of preoperative IOP and the likelihood of recent surgery.

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Short term IOP differences: The mean IOP was between six to eight mmHg in both groups for the first six days after trabeculectomy, and then the two groups diverged, with the standard group increasing to a mean IOP of 18 mmHg at 14 days while the 5-FU group mean IOP remained in the range of six to nine mmHg. At one month mean IOP was 12 mmHg

in the 5-FU group and 23 mmHg in the control group. In the 5-FU group 33% had an IOP > 21 mmHg within the first year, compared to 77% in the control group. Medications: Of those who returned at one year and had not undergone reoperation, 66% of the 5-FU group and 36% of the control group were not on any glaucoma medications. At five years, 41% of 5-FU group and 21% of the control group were on no medications. Safety and complications: The mean acuity was worse in the 5-FU group for the first month only, and both groups had gradually decreasing acuity over five years. There were significantly more complications in the 5-FU group, notably wound leak, punctate epitheliopathy, epithelial defect, and bleb rupture (delayed leak from new site). Corneal endothelial cell counts were similar in both groups. In the 5-FU group, 21% had a persistent epithelial defects beyond 14 days (c.f. 6% controls) and one 5-FU patient developed a bacterial corneal ulcer with perforation. Two in the 5-FU group and one in the control group had late endophthalmitis associated with bleb leaks.

Weaknesses This intensive post-operative regimen is no longer common practice, indicating that many specialists felt the complications were increased by an excessive number of 5-FU injections.

Key message 1. In these high-risk eyes with uncontrolled glaucoma, poor prognosis and previous surgery, using intensive post-operative 5-FU treatment does improve the likelihood of a low IOP and results in less reoperations, but at the expense of increased complications.

35

Tube Versus Trabeculectomy (TVT) study Study design: RCT

Evidence level: 1b

Design/baseline ‒ Am J Ophthalmol 2005;140:275 | Five-year Results ‒ Am J Ophthalmol 2012;153:789 | Five-year Complications ‒ Am J Ophthalmol 2012;153:804.

Key question 1. In patients with previous intraocular surgery who are at moderate risk of trabeculectomy failure, is trabeculectomy or Baerveldt tube implant the safer and/or more effective option?

Aims Trabeculectomy has been the most common operation for glaucoma, with tube shunts often reserved for cases viewed to be at higher risk of trabeculectomy failure in many centres. However growing experience with tube implants has prompted their use in lower risk cases. The TVT study aimed to compare the safety and efficacy of non-valved tube implantation to trabeculectomy with mitomycin C in patients with previous intraocular surgery.

Methods

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Participants: Two hundred and twelve participants (one eye per participant) from 17 centres in USA and UK. The mean age was 71 years, 53% were women, baseline mean intraocular pressure (IOP) was 25.3 mmHg on 3.1 medications, and 81% had primary open-angle glaucoma (POAG). Previous surgery was 44% cataract, 35% trabeculectomy, and 20% combined/both. Inclusion criteria: • Inadequately controlled glaucoma with 18 ≤ IOP ≤ 40 mmHg on maximal tolerated medical therapy; • Either cataract surgery with intraocular lens implant or previous trabeculectomy; • Age 18-85 years. Exclusion criteria: • No light perception; • Pregnant or nursing women;

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•

•

High risk: Neovascular glaucoma or proliferative retinopathy, iridocorneal endothelial syndrome, epithelial/fibrous down growth, aphakia, vitreous in the anterior chamber requiring vitrectomy, chronic or recurrent uveitis, severe posterior blepharitis, or those unwilling to cease contact lens use; Surgical factors: Previous cyclodestruction, scleral buckle silicone oil, conjunctival scarring preventing superior trabeculectomy, anticipation of additional ocular surgery or need for other concurrent surgery.

Groups: Participants were randomised to placement of a 350-mm2 Baerveldt glaucoma implant or a trabeculectomy with MMC (0.4 mg/ml for four minutes). Primary endpoint: Failure was IOP ≥ 21 mmHg or < 20% reduction from baseline on two visits after three months, IOP ≤ 5 mmHg on two visits after three months, loss of light perception or reoperation for glaucoma (including diode laser cycloablation). Secondary endpoints: IOP, visual acuity (VA), use of glaucoma medication, complications, visual fields (VF), quality of life. Follow-up: Over five years reported.

TVT Results IOP results: After the first three months (where tube group had higher IOP) there were no significant differences in mean IOP between treatment groups, and throughout follow-up both groups had mean IOP between 12 and 14 mmHg. In both groups 64% had an IOP of 14 mmHg or less at five years. The mean IOP at five years in the tube group was 14.4 mmHg and in the trabeculectomy group was 12.6 mmHg (p = 0.12). In the first two years there was a greater use of glaucoma medications in the tube group, but by five years the mean number of glaucoma medications was very similar (tube 1.4, trabeculectomy 1.2, p = 0.25) Failure and survival: A significantly higher failure rate was seen in the trabeculectomy group (50%) compared to the tube group (33%) (p = 0.034, adjusted χ2 test; hazard ratio 2.15, p = 0.02). In the trabeculectomy group, more of the successes were complete success (29%, with 21% qualified success) compared to the tube group (25%, with 42% qualified success). The main difference in type of failures was that trabeculectomy group had 13 failures for hypotony, compared to three in the tube group, but there were also more high IOP failures in the trabeculectomy group. Pre-operative or demographic factors did not predict failure.

Re-operation: There were 18 re-operations for glaucoma in the tra­ beculectomy group, compared to eight in the tube group (5y cumulative rate 29% trabeculectomy, 9% tube, P = 0.025). This re-operation was placement of a tube in 15 of the trabeculectomy group and four of the tube group, and diode laser cyclo-ablation occurred in four of the tube group and one of the trabeculectomy group. Complications: More patients experienced early complications in the first month after trabeculectomy (37%) than the tube group (21%, p = 0.012, χ2 test). Wound leak, dysaesthesia and bleb leaks were more common in the tra­ beculectomies, with a trend toward more hyphaema. Late complications, and serious complications resulting in reoperation or two-line reduced acuity were not different between groups (of patients 22% tube, 20% trabeculectomy, p = 0.79, χ2 test).

Weaknesses Many patients do not meet the enrolment criteria of the TVT study, and so the results may be less applicable to dissimilar groups.

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Key messages 1. The Baerveldt 350-mm2 glaucoma drainage device was at least as safe and effective as trabeculectomy in this setting of medium-risk uncontrolled glaucoma with previous surgery. The failure rate for trabeculectomy averaged around 10% per year, consistent with previous surgical trials (e.g., FFSS), but the failure rate for tube implants was closer to 5% per year (better than previous cohorts). 2. The average IOP from trabeculectomy and tube are similar (12-14 mmHg), but trabeculectomy resulted in more hypotony as well as high IOP failures, as well as more complications and reoperation.

37

Ahmed Baerveldt Comparison (ABC) and Ahmed Versus Baerveldt (AVB) Studies Study design: RCT

Evidence level: 1b

ABC Design and baseline ‒ Ophthalmology 2011;118:435 | ABC 5y results ‒ Ophthalmology 2015;122:308 | AVB Design and baseline ‒ Ophthalmology 2011;118:2172 | AVB 3y results ‒ Ophthalmology 2013;120:2232.

Key question 1. How do the safety and efficacy characteristics of Ahmed and Baerveldt drainage devices compare in uncontrolled advanced glaucoma?

Aims These two parallel studies were conducted to compare safety and efficacy of the two most widely-used glaucoma drainage devices. There are potential safety advantages with the Ahmed device (flow restrictor, immediate drainage, small plate of 184 mm2), but it also has a more bulky profile and a tendency to encapsulation. The Baerveldt device has potential efficacy advantages (no restrictor, large plate of 350 mm2), but also requires delayed drainage, and is implanted under the rectus muscles which may cause diplopia.

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Methods Participants: Consecutive patients were recruited from international eye clinics (ABC n = 276, AVB n = 238), and only one eligible eye was enrolled. In ABC the mean age was 64 years (66y AVB), 52% were male (45% AVB), 49% were white (71% AVB). Baseline intraocular pressure (IOP) was 31.8 mmHg (31.4 AVB) on 3.4 medications (3.1 AVB) medications. 40% had primary open angle glaucoma (POAG)(50% AVB) and 29% had neovascular glaucoma (21% AVB). Thus, the two studies had very similar participants. Inclusion criteria: • Age ≥ 18 years (and ≤ 85 years in ABC); • Inadequately controlled glaucoma on maximal tolerated medical therapy;

38

•

Primary glaucoma with previous intraocular surgery (in AVB a failed trabeculectomy only) or secondary glaucoma at risk of trabeculectomy failure.

Exclusion criteria: • No light perception; • Unwilling or unable to attend for required follow-up; • Previous cycloablation, aqueous shunt surgery, or scleral explant (in ABC); • Silicone oil, vitreous in anterior chamber, systemic uveitis syndromes, nanophthalmos, Sturge Weber syndrome (all exclusions in ABC only), or requirement for other concurrent eye surgery (both studies). Groups: Participants were randomised into Ahmed FP-7 or Baerveldt 350 groups. The randomization was stratified for ocular risk factors. Endpoints: Failure was defined as IOP > 21 mmHg or less than 20% reduction twice after three months, IOP ≤ 5 mmHg twice after three months, more glaucoma surgery, removal of implant or loss of light perception (vision threatening complications were criteria for failure in AVB). Re-operation for exposed, blocked or retracted tubes was a safety outcome but not failure. Follow-up: Five years (3y AVB).

ABC & AVB Results IOP results: In both studies, the Ahmed group had a lower mean IOP at day one and week one, but after that the Baerveldt group had one to two mmHg lower mean IOP, reaching statistical significance at some time points. In the ABC at five years the Ahmed group mean IOP was 14.7 mmHg compared to Baerveldt 12.7 mmHg (p = 0.015). In the AVB at three years the Ahmed group mean IOP was 15.7 mmHg compared to Baerveldt 14.4 mmHg (p = 0.09). Medications: In both studies, there was a tendency to more medications in the Ahmed group (ABC at five years: Ahmed 2.2, Baerveldt 1.8, p = 0.28, but statistically significant at most earlier time points; AVB at three years: Ahmed 1.8, Baerveldt 1.1, p = 0.002). In the AVB, 25% of Ahmed group had no medications at three years compared to 50% of the Baerveldt group. Safety and failures: In the ABC, the overall risk of failure was similar between groups, but the reasons were different. At five years, 40% had failed in the Ahmed group, of which 80% were due to inadequate IOP control. In the Baerveldt group 35% had failed, of which 53% were due to inadequate IOP control and 47% were due to hypotony, loss of light perception or other complications. There were statistically significantly more failures in the Ahmed group when failure was defined by more stringent IOP cut-offs

of 17 or 14 mmHg. Re-operation rate was significantly higher in the Ahmed group (21% vs. 9%, p = 0.010). Visual acuity (VA) fell by two lines in 43% of participants in both groups of the ABC study. AVB results were very comparable; the risk of failure was similar in the two groups at the 21 mmHg cut-off, but at the pre-determined cut-off of 18 mmHg the risk of failure was greater in the Ahmed group. At three years, 51% in the Ahmed group and 34% in the Baerveldt group had failed at this cut-off of 18 mmHg (p = 0.013). Most of the failures were due to uncontrolled IOP, but there were more in the Baerveldt group who failed due to loss of light perception or devastating complications (26% of failures compared to 6% of the Ahmed group failures). Of the complications, only encapsulated bleb differed between groups: Ahmed 11%, Baerveldt 3% (P = 0.01).

Weaknesses It is important to recognize that these trials involved medically uncontrolled glaucoma patients with either previous intraocular surgery or secondary glaucoma at high risk of trabeculectomy failure., The limitations of generalising the results to other groups should be carefully considered. Measures of optic nerve structure or function were not included. Neither surgeon nor patient were masked to the implant type. Only these two specific models were compared, limiting the scope of the study.

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Key message 1. The two studies had very similar results and validate each other. The Ahmed valve had one to two mmHg higher IOP in the long term, more failures and more reoperation for IOP control, but the Baerveldt group had higher IOP in the immediate post-operative period and had more failures due to hypotony, complications and visual loss.

39

Effectiveness in Angle-closure Glaucoma of Lens Extraction (EAGLE) Study Study design: RCT

Evidence level: 1c

Trials 2011;12:133 Lancet 2016;388:1389 BMJ Open 2017;7:e013254

Key questions 1. For people with primary angle closure (PAC) and high intraocular pressure (IOP) or glaucoma (PACG) and no cataract, is early lens extraction (LE) or standard care with laser iridotomy and medical care more effective to maintain quality of life and lower IOP? 2. Is LE or standard care more cost-effective in the medium term?

Aims Although LE is thought to be a definitive cure for angle closure and can correct refractive error, surgery has risks that must be considered, particularly in patients with good vision and no cataract. Standard care (SC) with laser iridotomy and medication followed by iridoplasty and glaucoma surgery (when necessary) tends to result in more follow up visits, more medication and potentially more complicated surgery later. The EAGLE study hypothesized that those randomized to early LE will have a higher quality of life, lower IOP and a lower glaucoma surgery rate than those randomized to SC at three years.

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Methods Participants: Four hundred and nineteen patients were randomized from 22 centres in the United Kingdom, 7 in East Asia and one in Australia. The mean age was 67 years, overall 37% had PAC and 63% had PACG, 31% were of Chinese ethnicity and 58% were women. Inclusion • PACG with IOP > 21 mmHg or PAC with IOP ≥ 30 mmHg • Newly diagnosed with no treatment • ≥ 1800 appositional or synechial iridotrabecular contact • Phakic • Age ≥ 50 years 40

Exclusion • Advanced glaucoma (MD ≤ -15 dB or cup-to-disc ratio ≥ 0.9) • Previous acute angle closure (AAC) • Symptomatic cataract • Previous ocular surgery including any laser procedure Groups: Participants were randomized 1:1 between LE or SC. The LE group had phacoemulsification and intraocular lens implant, followed by escalation of medical treatment and then trabeculectomy as required. The SC group had laser iridotomy, laser trabeculoplasty if angle closure persisted, escalation of medical treatment then trabeculectomy as required. Primary endpoints: European Quality of Life - 5-dimension (EQ5D) questionnaire, IOP, and incremental cost-effectiveness ratio (ICER = ∆cost/∆quality-adjusted life year, QALY). Secondary endpoints: Trabeculectomy rate, field loss. Follow up: 3 years

EAGLE Results Quality of life and vision In the LE group the EQ-5D questionnaire score was 0.87 at baseline and rose to 0.90 at 12 months then declined back to 0.87 at 3 years, while in the SC group the baseline was 0.88, falling to 0.86 at 12 months and further declining to 0.84 at 3 years. The difference at 3 years of 0.052 was statistically significant (P = 0.005). Two other patient reported measures of health-related quality of life and visual function both showed a small increase in function for the LE group and a small decrease in function for the SC group, each statistically significant. Acuity was better in the LE group and fields did not differ between groups. IOP, medications, and trabeculectomy surgery In the LE group, the mean baseline IOP of 29.5 mmHg fell to 15.7 mmHg at 6 months and then remained stable at 16.6 mmHg at 3 years. The SC group baseline IOP of 30.3 mmHg fell to 19.2 mmHg at 6 months then fell slightly further to 17.9 mmHg at 3 years. This difference of 1.2 mmHg at 3 years was statistically significant (P = 0.004). At 3 years, 61% of the LE group and 21% of the SC group were on no glaucoma medications, and the mean number of drops was 0.4 in the LE group and 1.3 in the SC group (P < 0.0001). There were 6 trabeculectomies in the SC group but only 1 in the LE group.

Safety, complications 25 of the LE group and 50 of the SC group had complications. In the LE group there were six complications from initial surgery (3%) including one with irreversible loss of 2 lines, while 16 (8%) of the SC group had minor bleeding with the laser iridotomy. Three in the LE group and one in the SC group returned to theatre. Malignant glaucoma occurred in one of LE group and two of SC group. Cost effectiveness Economic analysis was based on the 285 participants from UK in the context of National Health System (NHS) care. Within the 3 years of the study the LE group cost £2467 per case compared to the SC group £1486 per case, with an incremental cost effectiveness ratio (ICER, ∆cost/∆QALY) between £8,400 and £14,284. These give a high likelihood of cost effectiveness if each QALY is valued over £20,000. Models to extrapolate further into the future indicated a declining ICER of £7,090 at 5 years and cost saving from LE at 10 years.

Weaknesses It was not possible to mask interventions from participants or clinicians. The gonioscopy reporting was largely incomplete. The economic analysis was generalizable only in a UK context. It may be that these findings are not generalizable to an entirely Asian population.

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Key messages 1. In the context of PAC with IOP > 30 mmHg or PACG with IOP > 21 mmHg and no visually significant cataract, early LE results in greater overall quality of life, lower IOP, and fewer medications or ongoing glaucoma interventions when compared to laser iridotomy, iridoplasty, and medical treatment. 2. Immediate LE would seem likely to be cost effective, particularly in the longer term.

41

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42

Retina

Copyright © 2017. Kugler Publications. All rights reserved.

Co-author: Dr. Neil Avery Section editor: Prof. Paul Mitchell with contribution by Dr. Neil Sharma

Diabetic Control and Complication Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) trial Study design: RCT

Evidence level: 1b

Initial DCCT results ‒ New Engl J Med 1993;329:977 | EDIC retinopathy data ‒ Arch Ophthalmol 2008;126:1707.

Key questions 1. 2.

Does intensive blood sugar control with insulin reduce the incidence, progression or severity of diabetic retinopathy or other complications in patients with Type 1 diabetes mellitus? How does glucose control affect these risks in the longer term?

Aims The DCCT was designed to compare conventional and intensive insulin therapy for Type 1 diabetes mellitus (T1DM) with regard to the effect on development or progression of microvascular, macrovascular and neurological complications. Diabetic retinopathy (DR) was the primary outcome.

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Methods

Groups: Conventional therapy consisted of one or two insulin injections per day with daily glucose monitoring and education about diet and exercise. Intensive therapy was designed to achieve normal blood glucose levels with three or more injections or use of an insulin pump, based on glucose monitoring at least 4x/day and anticipated diet and exercise, with monthly visits and regular telephone advice.

Participants: One thousand four hundred forty-one participants Primary endpoint: were recruited from 29 centres across the USA. Mean DR-grading based on the 25-step grading of the age was 27 years, 53% were male, and 97% were white. Early Treatment Diabetic Retinopathy Study, with a three-step sustained worsening of DR grade being the Inclusion criteria: primary outcome in both the primary and secondary • Insulin-dependent diabetes mellitus, proven with subgroup. deficient C-peptide secretion; • Age 13-39 years; Secondary endpoints: • No hypertension, hypercholesterolemia, severe Proliferative or severe non-proliferative DR requiring diabetic complications or medical conditions. treatment, nephropathy, neuropathy, neuropsychological outcomes, macrovascular complications, and Subgroups: quality of life. • Primary prevention: T1DM 1-5 y, no DR, albuminuria < 40 mg/day; Follow-up: • Secondary prevention: T1DM 1-15 years, DR very Mean 6.5 years of DCCT, plus ten years of continued mild to moderate grade, albuminuria < 200 mg/day. follow-up in EDIC.

44

DCCT-EDIC Results Glycaemic control: Adherence to assigned treatment was very high, resulting in large significant differences in glycated haemoglobin (HbA1c) between groups throughout the DCCT study (conventional group HbA1c around 9%, intensive group HbA1c around 7% throughout DCCT, P < 0.001). Around 44% of the intensive group achieved the target HbA1c ≤ 6.05%, but only 5% maintained an average HbA1c at this level. After the DCCT close-out, patients were observed in the EDIC study with treatment at their doctor’s discretion, and the two groups had very similar HbA1c around 8% (from four years after DCCT close-out there were no differences between group HbA1c).

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DR in DCCT: In the primary prevention group, the incidence of sustained DR diverged after 36 months (after nine years, 23 patients in the intensive group and 91 in the conventional group had retinopathy) and the odds reduction was 76%. In the secondary prevention group the intensive group had a higher risk of progression in the first three years, but then a reduced risk after that (after nine years, 77 in the intensive group and 143 in the conventional group had progression; odds reduction 54%). There was a similar reduction in the risk of proliferative DR or laser treatment. The risk reduction in both groups increased with time.

Nephropathy, neuropathy and macrovascular outcomes: Rates of microalbuminuria, albuminuria and clinical neuropathy were reduced by intensive therapy in both the primary and secondary prevention groups. In this young patient group, macrovascular events were rare and not statistically different. Hypercholesterolaemia was reduced by intensive insulin therapy. Safety: Mortality did not differ between groups (seven in intensive, four in conventional groups). The risk of hypoglycaemia was three times higher in the intensive group (coma or seizure 16 per 100 patient years in intensive, five per 100 patient years in conventional). Hypoglycaemia did not contribute to deaths, vascular events, or accidents requiring hospitalizations. One fatal car accident in each group was attributed to hypoglycaemia and one bystander was killed by a hypoglycaemic driver. Neuropsychological and quality of life outcomes had no measurable differences between groups. EDIC retinopathy outcomes: Four years after finishing of DCCT, the treatment and HbA1c were no different between groups, but after adjusting for differences in DR, the risk of progressive or severe DR in the intensive group continued to be reduced for at least six more years. This powerful evidence of a persisting benefit following intensive therapy has been termed metabolic memory: this may relate to advanced glycation end products, oxidative damage, epigenetic modifications, insulin receptor effects, or a combination of factors.

Key messages 1. Glycemic control is the most powerful factor in reducing the risk of diabetic complications, including DR. 2. Intensive diabetic control is associated with more hypoglycemia. 3. Metabolic memory refers to a long-term benefit of glycemic control.

45

United Kingdom Prospective Diabetes Study (UKPDS) Study design: RCT

Evidence level: 1b

Lancet 1998;352:837-853 | BMJ 1998;317:703-713 | BMJ 2000;321:405-412 | Arch Ophthalmol 2004;122:16311640.

Key questions 1. Does intensive blood sugar control reduce the incidence, progression or severity of diabetic retinopathy or other microvascular complications in patients with Type 2 diabetes mellitus (T2DM)? 2. How does blood pressure (BP) control in hypertensive diabetic patients affect these risks of microvascular complications?

Aims The UKPDS was a multi-centred RCT designed to compare conventional vs. intensive blood glucose therapy and tight vs. ‘less tight’ hypertension control for T2DM with regard to the effect on development or progression of microvascular and macrovascular outcomes.

Methods

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Participants: Three thousand eight hundred sixty-seven participants were recruited from 23 centres across the UK. Median age was 54 years, 58% were male, and 81% were white. Inclusion criteria: • Newly-diagnosed Type 2 diabetes; • Age 25-65 years; • Two fasting blood glucoses (FBG) > six mmol/L on two occasions one to three weeks apart. Exclusion criteria: • Ketonuria > three mmol, serum creatinine > 175 µmol/L; • Diabetic retinopathy requiring treatment; • Severe concurrent illnesses, malignant hypertension, angina or heart failure, uncorrected endocrine disorder, > one previous vascular event, MI within one year. 46

Groups: • Blood glucose: patients were randomised to oral diabetes medications/insulin with target FBG < six mmol/L or best achievable FBG with diabetic diet alone; • Hypertension: 1148 hypertensive patients within the study were randomised to target BP of < 150/85 or < 180/105. Primary endpoint: Deaths related to diabetes or all-cause mortality. Secondary endpoints: Macrovascular and microvascular complications of DM; diabetic retinopathy (DR) endpoints included vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in an eye (< 6/60), or cataract extraction. Follow-up: Median follow-up was ten years.

UKPDS Results Effects of initial retinopathy: DR was present at baseline in 39% of men and 35% of women, with 97% of these patients having minimal retinopathy (< four micro-aneurysms). Significant retinopathy (CWS or IRMA) was found in 8% of men and 4% of women at presentation. Of the patients with ≥ five micro-aneurysms in one eye at the beginning of the study, > 40% required photocoagulation or had vitreous haemorrhage by 12 years. Effect of BP control: Mean BPs in the tight and ‘less-tight’ groups were 144/82 and 154/87 mmHg respectively. Tight control of BP resulted in a significant decrease in the number of micro-aneurysms, cotton wool spots and hard exudates at 7.5 years. Patients in the tight control of BP group

received less retinal laser, with the main difference being the rates of laser for maculopathy (RR = 0.58). There was significantly less progression in the grading of diabetic retinopathy at 4.5 years (RR = 0.75) Significantly less eyes developed blindness in the tight control group (RR = 0.76). Effect of glycaemic control: Over ten years, the HbA1c was 7.0% in the intensive group compared with 7.9% in the conventional group, with a 25% risk reduction for the microvascular endpoints in the intensive group. Overall, each 1% decrease in HbA1c was associated with a 37% decrease in risk for the microvascular endpoints. There was a 29% reduction in the need for laser photocoagulation in the intensive group over 12 years.

Key messages

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1. Tight glycemic and BP control are important factors in reducing the progression of DR. 2. Reducing HbA1c is strongly associated with a reduction in the risk of retinopathy. 3. Change in the course of retinopathy was not evident before three years of tighter control. 4. Initial number of micro-aneurysms at presentation is associated with long-term risk of DR complications.

47

Diabetic Retinopathy Study (DRS) Study design: RCT

Evidence level: 1b

Arch Ophthalmol 1979;97:654-655 | IOVS 198;21:1-226 | IOVS 1985;26:983-991 | Int Ophthalmol Clin 1987;27:239-253 | IOVS 1989;30:23-28.

Key questions 1. 2. 3.

What is the effect of pan-retinal photocoagulation (PRP) on proliferative diabetic retinopathy (PDR)? Can PRP reduce severe vision loss in diabetic retinopathy (DR)? What is the natural course of PDR?

Aims Laser photocoagulation had become commonly used in the management of DR by the 1970s. The DRS was a multi-centred RCT designed to evaluate the efficacy and safety of PRP in patients with treatment naïve proliferative DR.

Methods Participants: One thousand seven hundred fifty-eight participants were recruited from 15 centres over a three-year period. Mean age was 43 years, 45% were Type 1 diabetics.

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Inclusion criteria: • Proliferative DR in at least one eye or severe non-proliferative DR in both eyes; • Visual acuity (VA) of 20/100 or better in each eye; • Both eyes suitable for laser. Exclusion criteria: • Prior laser treatment. Groups: One eye of each patient was randomly assigned to immediate photocoagulation and the other to follow-up without treatment, regardless of the course followed by either eye. The eye chosen for photocoagulation was, in addition, randomly assigned to receive treatment from either argon laser or a xenon arc photocoagulator. 48

Argon laser protocol: • Treatment performed in one to two sittings; • 800-1,600 burns, 500 µm diameter, 0.1 s duration; • Laser performed up to, or anterior to the level of the vortex veins; • Laser was applied directly to NV and also to micro-aneurysms; • Follow-up treatment was applied as needed at four-month intervals. Primary endpoint: Rates of severe visual loss (< 5/200 at two consecutive visits). Secondary endpoints: Progression of retinopathy, risk factors for severe visual loss in untreated eyes and adverse events from photocoagulation. Follow-up: Patients were reviewed every four months.

DRS Results VA: Due to a highly statistically significant difference in severe visual loss at two months (treated eyes 6.4%, untreated eyes 16.3%), the protocol was changed to allow treatment to the control eyes based on the following ‘high-risk PDR’ criteria: • Moderate/severe NVD (within one DD); • Any NVD if associated with fresh vitreous or pre-retinal haemorrhage • Moderate/severe NVE (> ½ DD) if associated with fresh vitreous haemorrhage or pre-retinal haemorrhage; • Argon treatment was also preferred as the risks of loss of VA and constriction of visual field (VF) were less than with Xenon arc. With the revised protocol, PRP was shown to reduce the risk of severe visual loss by 50% over 24 months. In eyes with non-proliferative DR randomised to photocoagulation, rates of severe visual loss were decreased from 3.2% to 2.8% at two years. Risk factors: Four risk factors were identified as increasing the risk of severe VA loss in untreated eyes: • Presence of vitreous or pre-retinal haemorrhages; • Presence of new vessels;

• •

Location of new vessels on or near the disc (this had the strongest association); Severity of new vessels (i.e., moderate/severe).

Safety: Fifty percent of xenon-treated eyes suffered some loss of VF compared with 5% of the argon-treated eyes. It was also estimated that a persistent VA decrease of one line was attributable to treatment in 19% of xenon-treated eyes compared with 11% in the argon group.

Weaknesses The effect of macular oedema in terms of VA was not evaluated. It is likely that photocoagulation led to a transient increase in macular oedema with associated decrease in VA. This occurred especially prominently in eyes with pre-existing macular oedema. Control of blood glucose, hypertension and cholesterol would not be considered adequate by today’s standards. Therefore it is possible that risk of progression to high risk PDR would be even less likely today. The study did not establish when the most suitable time to apply PRP was; this provided the basis for the ETDRS study.

Key messages

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1. Xenon arc had greater rates of adverse events than argon laser and has since been abandoned. 2. Pan-retinal photocoagulation reduces severe vision loss from PDR by 50% at 24 months and was subsequently recommended for ‘high-risk’ PDR. 3. No significant benefit was found at two years from treating NPDR.

49

Early Treatment of Diabetic Retinopathy Study (ETDRS) Study design: RCT

Evidence level: 1b

Arch Ophthalmol 1985;103:1796-1806 | Ophthalmol 1987;94:761-74 | Ophthalmol 1991;98:766-785 | Ophthalmol 1991;98:741-756 | Am J Ophthalmol 1999;127:137-141.

Key questions 1. When is the best time to apply photocoagulation in diabetic retinopathy (DR)? 2. What is the role of laser in macular oedema? 3. Is aspirin effective in the treatment of diabetic retinopathy?

Aims The Diabetic Retinopathy Study had shown that pan retinal photocoagulation (PRP) was effective in the treatment of proliferative diabetic retinopathy in reducing the incidence of severe sight loss, but had not evaluated the best time to apply retinal photocoagulation or to investigate the management of macular oedema.

Methods

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Participants: Three thousand seven hundred eleven participants were recruited from 22 centres in the USA over a seven-year period. Fifty-six percent were male, 30% had Type 1 diabetes. Inclusion criteria: • DR in both eyes; • Age 18-70 years; • Each eye had to meet the following criteria, either: ᵒᵒ Macular oedema, visual acuity (VA) better than 20/200; ᵒᵒ No macular oedema, VA better than 20/40. Exclusion criteria: • High-risk proliferative diabetic retinopathy (PDR) at enrolment; • Significant ocular comorbidity; VA worse than 20/200; 50

•

Previous retinal laser.

Groups • One eye of each patient was randomly assigned to early photocoagulation and the other to deferral of photocoagulation (until development of high-risk PDR); • Furthermore, eyes receiving photocoagulation were randomised to receive ‘mild’ (400-650 burns in one session) or ‘full’ (1200-1600 burns in two sessions) treatment; • Eyes with macular oedema were randomised to receive immediate or delayed focal photocoagulation; • Each patient was randomised to receive aspirin 650 mg or placebo. Primary endpoint: Rates of severe visual loss (< 5/200 at two consecutive visits). Secondary endpoints: Rates of vitrectomy, macular oedema, moderate visual loss (defined as doubling of the visual angle). Follow-up: Patients were reviewed every four months.

ETDRS Results VA: Rates of severe visual loss were low at 2.6% in the early treatment group compared to 3.7% in the deferral group at five years, a 23% reduction in risk but this was not quite statistically significant (99% confidence interval (CI), 0.56-1.06). When vitrectomy and/or severe visual loss were considered together, there was a statistically significant benefit of early laser (relative risk (RR) 0.67) The most common causes of severe visual loss were vitreous haemorrhage (52%), macular oedema (14%), and retinal detachment (7%). Early full photocoagulation resulted in a significant reduction in the rate of developing high-risk proliferative retinopathy by 50% compared with deferral of photocoagulation. Macular oedema: The risk of moderate vision loss was reduced by up to 50% in eyes with ‘clinically significant macular oedema’. Clinically significant macular oedema was defined as: • Retinal thickening at or within 500 microns or 1/3 disc diameter of centre of macula;

• •

Hard exudates at or within 500 microns of the centre of the macula with adjacent retinal thickening; Retinal thickening > one disc diameter in size which is within one disc diameter from the centre of the macula.

Aspirin: Aspirin showed no effect on progression of diabetic retinopathy, VA or rates of vitreous haemorrhage.

Weaknesses Control of blood glucose, hypertension and cholesterol would not be considered adequate by today’s standards. Therefore it is possible that risk of progression to high-risk PDR would be even less likely today. The study did not evaluate the benefit of targeted retinal photocoagulation to areas of retinal ischaemia defined by fluorescein angiogram. Before the advent of OCT, macular oedema was diagnosed on slit-lamp examination. This would have a lower sensitivity for detection of macular oedema than by today’s standards.

Key messages

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1. Scatter laser should be deferred until at least severe non-proliferative or early PDR; at which point it should be considered. 2. Focal macular laser was recommended for ‘clinically significant macular oedema’ – the criteria developed are still used today. 3. There are no ocular contra-indications for aspirin therapy when required for other medical indications.

51

DRCR.NET Protocol I – Macular Laser Combined with Ranibizumab or Triamcinalone vs. Macular Laser Alone Study design: RCT

Evidence level: 1b

Am J Ophthalmol 2016;164: 57-68 | Ophthalmology 2015;122:375-381.

Key question 1.

Is ranibizumab or triamcinolone combined with focal/grid laser, performed either promptly or deferred more effective than treatment with focal/grid laser alone for diabetic macular oedema (DME)?

Aims To compare alternative treatment options for patients with centre involving DME, and determine if prompt or deferred laser is more effective in combination with anti-vascular endothelial growth factor (anti-VEGF) agents or steroids.

Methods

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Design: Randomised controlled trial initially including 828 eyes, with 558 completing the five-year visit. Inclusion criteria: • Type 1 or 2 diabetes mellitus (DM) with at least one eye with centre-involved DME; • Best corrected visual acuity (VA) at least 78 to 24 letters (20/32-20/320); • Age ≥ 18 years; • Retinal thickness ≥ 250 microns. Exclusion criteria: • Previous treatment for DME within the last four months; • Anticipated need for PRP laser within six months; • Major ocular surgery within the past four months.

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Trial protocol: • Patients were randomised to: ᵒᵒ Sham injection plus prompt focal/grid laser treatment; ᵒᵒ Ranibizumab plus prompt focal/grid laser treatment; ᵒᵒ Ranibizumab plus deferred laser treatment (≥ 24 weeks) if there was persistent DME involving the fovea on OCT that had not improved after at least two consecutive injections; ᵒᵒ Intravitreal triamcinolone plus prompt laser. • At one year, the patients in the sham and triamcinolone groups had worse outcomes and were allowed to initiate intravitreal ranibizumab (termed the very deferred ranibizumab groups). • Patients were reviewed four-weekly for 12 months, then four- to 16-weekly through year five (depending on protocol-defined criteria).

DRC.NET Protocol I Results •

•

VA: ᵒᵒ Mean improvement in VA from baseline to the five year visit was ten letters for ranibizumab and deferred laser, eight letters for ranibizumab and prompt laser, five letters for sham and laser, seven letters for triamcinolone and laser; ᵒᵒ The mean number of letters gained was 2.6 fewer in the prompt laser group than the deferred laser group; ᵒᵒ Controlling for baseline characteristics there were no significant differences between ranibizumab/deferred laser or ranibizumab/ prompt laser or triamcinolone/prompt laser; ᵒᵒ The percentage of patients with ≥ ten-letter gain from baseline was lower in the laser/very deferred ranibizumab groups. OCT thickness: ᵒᵒ Mean thickness was significantly lower in the laser/very deferred ranibizumab group despite worse visual outcomes.

• • • •

The median number of injections was four fewer in the prompt versus deferred laser group. The median number of follow-ups was 38 and 40 in the prompt and deferred laser groups respectively. Fifty-six percent of patients in the deferred laser group did not require laser. By year five, the median number of injections required in both groups was zero.

Weaknesses Over the five-year trial, there were a significant number of patients lost to follow-up (25%), these patients were statistically different and may have introduced confounding.

Key messages

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1. Prompt laser treatment combined with anti-VEGF therapy does not confer any benefit in the treatment of centre involving CSME and may result in worse visual acuity outcomes. 2. A significant proportion of patients treated with intravitreal anti-VEGF therapy will experience resolution of DME and not require further treatment. 3. Treatment with triamcinolone and deferred ranibizumab did not result in worse visual outcomes than ranibizumab ± laser alone 4. By four years, very few patients required ongoing ranibizumab therapy.

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DRCR.NET Protocol T - Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema Study design: RCT

Evidence level: 1b

New Engl J Med 2015;372:1193 | Ophthalmology 2016;123:1351.

Key question 1. Are intravitreal ranibizumab, bevacizumab and aflibercept equivalent for treatment of diabetic macular oedema (DME)?

Aims To determine the relative efficacy and safety for currently available anti-vascular endothelial growth factor (anti-VEGF) agents in the treatment of DME.

Methods Design: Randomised controlled trial including 660 adults at 89 clinical sites in the USA. Follow-up conducted over two years.

Copyright © 2017. Kugler Publications. All rights reserved.

Inclusion criteria: • Type 1 or 2 diabetes mellitus with least one eye with centre-involved DME; • Best corrected visual acuity (VA) at least 78 to 24 letters (20/32-20/320); • Age ≥ 18 years. Exclusion criteria: • Previous anti-VEGF therapy in the preceding 12 months; • Significant cataract; • PRP within four months of beginning trial.

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Trial protocol: • Patients randomised 1:1:1 to each anti-VEGF agent; • Intravitreal injections completed at baseline and four-weekly until: ᵒᵒ vision 20/20 or better and ᵒᵒ central subfield thickness on OCT less than a defined threshold; • From 24 weeks, injections were withheld if there was no improvement or worsening after two consecutive injections; • Treatment re-started if vision reduced five letters or OCT thickness increased 10%; • Macular laser applied (from 24 weeks) if persistent oedema; • If treatment failure (central macular thickness (CMT) above defined number, vision reduced > 10 letters, reduced vision caused by significant DME) a change of agent was permitted. Follow-up: Monthly follow-up over two years.

DRC.NET Protocol T Results •

•

•

•

At one year, then at two years, the median number of injections required was nine, then five for the aflibercept group and ten then six for both the bevacizumab and ranibizumab groups. Focal/grid laser was required by 41% of aflibercept patients, 64% of ranibizumab patients and 52% of bevacizumab patients at two years. VA after two years ᵒᵒ Mean improvement in VA at two years was 12.8 in the aflibercept group, 10.0 in bevacizumab group and 12.3 letters in the ranibizumab group. ᵒᵒ With better baseline acuity there were no significant differences between treatments groups, but with baseline acuity ≤ 20/50: the aflibercept group gained 18.1, bevacizumab gained 13.3 and ranibizumab group gained 16.1 letters (aflibercept statistically greater gains than bevacizumab). ᵒᵒ Gain of ≥ 15 letters occurred in 58% of aflibercept eyes, 52% of bevacizumab eyes and 55% of ranibizumab eyes (when initial VA < 20/50, NSS) Effect on retinal thickness (central subfield on OCT) ᵒᵒ Decreased on average at one year by 212, 143 and 177 μm for aflibercept, bevacizumab and ranibizumab respectively and remained very stable in the second year (aflibercept greater reduction than bevacizumab at two years, P = 0.01)

ᵒᵒ

•

There were no significant differences found between groups with respect to change in retinal thickness ᵒᵒ More patients on aflibercept and ranibizumab groups had CRT < 250 microns than in the bevacizumab group Safety: no significant differences were found in ocular or systemic complication rates between the groups, but a greater rate of vascular events occurred in the ranibizumab group (12% compared to 5% aflibercept and 8% bevacizumab groups, p = 0.047)

Weaknesses The ranibizumab dose of 0.3 mg was lower than the standard dose used outside USA (0.5 mg). This could lead to relative under-treatment in those with worse acuity. The 0.3 mg dose was not previously used in a PRN study of DME. Diabetic control was not controlled for (though would not be expected to be significantly different between groups) The patients included in this study who attended monthly appointments may be more likely to have good control and attain better outcomes than patients in clinical practice.

Copyright © 2017. Kugler Publications. All rights reserved.

Key messages 1. Patients with centre involving DME and acuity > 20/50 there was no difference in visual outcomes between aflibercept, ranibizumab and bevacizumab. 2. When vision was ≤ 20/50, patients treated with aflibercept had significantly better visual outcomes (however, four ETDRS letters may not be clinically significant). 3. Bevacizumab treated patients were less likely to attain an anatomically normal (< 250 microns) OCT CRT. 4. Each agent had equivalent safety profiles.

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DRCR.NET Protocol S - Panretinal Photocoagulation vs. Intravitreal Ranibizumab for Proliferative Diabetic Retinopathy Study design: RCT

Evidence level: 1b

JAMA 2015; 314: 2137-2146.

Key question 1.

Is intravitreal ranibizumab non-inferior to pan retinal photocoagulation (PRP) for treatment of proliferative diabetic retinopathy (PDR)?

Aims To demonstrate non-inferiority of ranibizumab compared to PRP for PDR.

intravitreal

Methods Design: Randomised controlled trial including 394 eyes of 305 patients enrolled at 55 sites in the U.S.A over two years. Mean age of participants was 42, with a gender split of 44% female and 56% male.

Copyright © 2017. Kugler Publications. All rights reserved.

Inclusion criteria: • Type 1 or 2 diabetes mellitus (DM) with least one eye with PDR; • Best corrected visual acuity (VA) 24 letters or better (6/96); • Age ≥ 18 years. Exclusion criteria: • Previous PRP; • Anti-vascular endothelial growth factor (aVEGF) treatment within four months; • Unstable medical status.

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Trial protocol: • Ranibizumab group: 0.5 mg monthly intravitreal ranibizumab then four-weekly for 12 weeks with injections given at 16 and 20 weeks unless neovascularization resolved completely; ᵒᵒ Further injections were given every 4 weeks unless investigators determined neovascularisation was stable or had resolved; ᵒᵒ PRP permitted for treatment failure or futility. • PRP group: baseline 1200-1600 burns (conventional laser) or 1800-2400 burns (pattern scanning laser) over one to three visits; ᵒᵒ Additional PRP if neovascularization worsened. Diabetic macular oedema (DME): • Eyes in both treatment groups could receive ranibizumab or macular laser for treatment at the investigators discretion. Follow-up: Monthly follow-up over two years.

DRC.NET Protocol S Results •

•

•

• •

Ranibizumab group: ᵒᵒ Average number of injections (at one and two years): »» Without baseline DME seven and ten injections; »» With baseline DME nine and 14 injections; ᵒᵒ 6% required PRP. PRP group: ᵒᵒ 45% required additional PRP; ᵒᵒ 35% required baseline ranibizumab for DME; ᵒᵒ 18% more required ranibizumab by two years for DME; ᵒᵒ Average number of injections required (one and two years): »» With baseline DME five and nine injections respectively; »» Without baseline DME three and four injections respectively. Visual outcomes (two years): ᵒᵒ +2.8 letters in the ranibizumab group and +0.2 in the PRP group; ᵒᵒ Visual field (VF) change: Ranibizumab group -23 dB vs. -422 dB for the PRP group. Risk of vitreous haemorrhage: 27% and 34% in the ranibizumab and PRP groups respectively. Risk of retinal detachment: Ranibizumab group 6% vs. 8% for the PRP group.

•

•

Risk of development of CME with visual impairment: 9% in the ranibizumab group vs. 28% in the PRP group. Percentage with regressed NVE at two years: 35% in the ranibizumab group vs. 30% in the PRP group.

Weaknesses Eyes in both groups received significant numbers of intravitreal ranibizumab (for DME), this is unavoidable in the current environment as it would be unethical to deny the gold-standard treatment for DME. The trial has only compared two-year data, PDR is a chronic condition and long-term data to show recurrence rates in the ranibizumab group (as the treatment effect may reduce with time) would be useful. The presence of active neovascularisation in around half of patients in both groups at the end of year two suggests under treatment in either group. Patients willing to engage in research and attend monthly appointments are more likely to be motivated and therefore have better glycaemic control. This may have implications for temporary anti-VEGF therapy such as ranibizumab compared to a more permanent therapy such as PRP.

Copyright © 2017. Kugler Publications. All rights reserved.

Key messages 1. Protocol S found intravitreal ranibizumab non-inferior to PRP for the treatment of proliferative diabetic retinopathy. 2. Visual field outcomes were unsurprisingly much better in the ranibizumab group. 3. Fewer patient in the ranibizumab group developed visual loss due to DME. 4. Both groups had very low rates of adverse reactions to treatment.

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Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study design: RCT

Evidence level: 1b

Lancet 2007;370:1687-1697.

Key question 1. Does treatment with addition of fenofibrate reduce the rate of diabetic retinopathy (DR) progression and need for laser treatment in patients with Type II diabetes mellitus (DM)?

Aims The main aim of the FIELD study was to assess the effect of the addition of fenofibrate on the rate of coronary events in patients with Type II diabetes. A tertiary study outcome was the effect of fenofibrate use on the need for laser treatment for diabetic retinopathy (DR). A sub-set of the patients were more closely studied to assess the effect of fenofibrate use on DR progression.

Methods Design: Multi-centre, prospective, randomised clinical trial.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Nine thousand seven hundred ninety-five patients from 63 centres in Australia, New Zealand and Finland were enrolled in main FIELD study. One thousand and twelve patients at 22 sites also underwent serial retinal photography. Inclusion criteria: • Type II diabetes mellitus; • Age 50-75 years; • Not taking statin therapy at study entry; • Initial plasma cholesterol 3.0-6.5 mmol/L PLUS total cholesterol/HDL ratio greater than 4.0 odds ratio (OR) plasma triglyceride concentration of 1.0-5.0 mmol/L.

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Exclusion criteria: • Blood creatinine > 130 mmol/L; • Chronic liver disease; • Cardiovascular event within three months of study enrolment. Groups: After a placebo and fenofibrate run-in phase, patients were randomly assigned to daily 200 mg micronised fenofibrates (n = 4895) or matched placebo (n = 4900). Retinal photography sub-study: One thousand and twelve patients underwent serial retinal photography and were graded according to standardised ETDRS criteria. Follow-up: Scheduled study visits every four to six months for five years.

FIELD Results Primary outcome: Fenofibrate did not significantly reduce the rate of coronary events. During the course of the study, 5.9% of patients in the placebo group and 5.2% of patients in the fenofibrate group had a coronary event (relative reduction 11%, p = 0.16). Need for laser for DR: There was a relative risk reduction in the need for laser treatment of 36% (p = 0.003) with fenofibrate treatment for diabetic maculopathy, and of 38% (p = 0.009) for proliferative retinopathy. There was also a relative reduction in the need for first laser with fenofibrate of 31% (p = 0.002) for maculopathy and 30% (p = 0.015) for proliferative retinopathy. Retinopathy progression: In the sub-study, patients with pre-existing retinopathy, the rate of two-step ETDRS criteria progression was 3.1% in fenofibrate vs. 14.6% on placebo (RR = 0.24, p = 0.004).

In the sub-study, patients without pre-existing retinopathy rate of two-step progression was unchanged at 11.4% in fenofibrate group and 11.7% in placebo group (p = 0.87).

Weaknesses The study excluded patients already taking statin therapy, which is now common in this patient population. Effects on diabetic retinopathy were only tertiary and sub-study outcomes of the main FIELD study. There were no objective measures of macular oedema such as optical coherence tomography (OCT), which is now standard. There was no demonstrated visual acuity (VA) benefit with the use of fenofibrate.

Key messages

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1. Addition of fenofibrate to standard diabetic care reduced the need for laser for both diabetic maculopathy and proliferative DR in this group of patients. 2. The rate of progression of DR was slowed with fenofibrate in patients with pre-existing diabetic retinopathy, but not without pre-existing retinopathy. 3. Fenofibrate was generally well-tolerated in the study and had a good overall safety profile. 4. Effects on retinopathy appear independent of serum lipid levels.

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Diabetic Retinopathy Vitrectomy Study (DRVS) Study design: RCT

Evidence level: 1b

Ophthalmology 1985;92:492-502 | Arch Ophthalmol 1985;103:1644-1652 | Ophthalmology 1988;95:13071320 | Arch Ophthalmol 1990;108:958-964.

Key question 1.

Is early vitrectomy, delayed vitrectomy or conventional management of diabetic vitreous hemorrhage due to severe proliferative diabetic retinopathy (PDR) a superior option?

Aims To determine the best management option for diabetic vitreous haemorrhage or severe fibro-vascular proliferation with useful vision caused by severe PDR.

Methods Design: Two randomised, controlled trials. Participants: Trial one (Vitreous haemorrhage): 616 patients; Trial two (Severe fibro-vascular proliferation with useful vision): 381 patients.

Copyright © 2017. Kugler Publications. All rights reserved.

Inclusion criteria: • Age 18-70 years; • Type 1 or 2 diabetes mellitus (DM); • Visual acuity (VA) < 5/200. Exclusion criteria: • Previous vitrectomy; • Previous pan retinal photocoagulation (PRP) within three months; • Severe neovascularisation (NVI), or intraocular pressure (IOP) > 29.

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Trial Groups/Protocols: • N: natural history study – severe PDR without vitreous haemorrhage: ᵒᵒ Six-monthly review for two years, then yearly review; ᵒᵒ Conventional management: PRP applied at the clinician’s discretion; ᵒᵒ If severe vitreous haemorrhage developed, could enter group H. • H: Severe vitreous haemorrhage, < 6 months, Best corrected VA (BCVA) < 5/200: ᵒᵒ Randomised to early vitrectomy or deferral; ᵒᵒ Vitrectomy goals: removal of vitreous opacity posterior to the equator, division of vitreous bands, division of elevated vitreo-retinal sheets; ᵒᵒ Deferred group: vitrectomy after 12 months if persistent vitreous haemorrhage AND BCVA < 5/200 or centre of macula detachment. • NR: Severe PDR, BCVA > 10/50.

DRVS Results •

•

•

DRVS report 1 (Group N): ᵒᵒ 32.7 to 51.6% of patients with severe proliferative diabetic retinopathy managed in a conventional manner lost two or more lines of vision over two years. DRVS report 2 (Group H): ᵒᵒ VA: early vitrectomy 10/20 or better in 34.5% vs. 15.2% in deferred group; ᵒᵒ No perception of light (NPL) vision was found in 24.9% of early vitrectomy patients and 19.3% of deferred patients; ᵒᵒ Type 1 diabetics did better with early vitrectomy: 35.6% 10/20 vision or better compared to 11.7% in the deferred group; ᵒᵒ Type 2 diabetics had higher rates of NVI with early vitrectomy (35.5% vs. 14.7%). DRVS report 3: ᵒᵒ The percentage of patients with VA ≥ 10/20 was significantly higher in the early vitrectomy group at two, three and four years.

•

DRVS report 5: ᵒᵒ The percentage of patients with VA ≥ 10/20 was significantly higher in the early vitrectomy group at two, three and four years; ᵒᵒ On subgroup analysis, these findings were significant for Type I, but not Type II diabetics.

Weaknesses When the DRVS was performed, vitrectomy had higher rates of complication than when performed with modern equipment which may result in worse outcomes than would be achieved in current practice. Patients who had vitrectomy did not have endolaser or PRP performed, which would be standard practice currently and again would result in worse outcomes.

Key messages

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1. Patients with severe PDR have high rates of visual loss. 2. Type 1 diabetics do better with early vitrectomy with regard to visual outcomes. 3. There were very high rates of NPL vision in both groups. 4. Vitrectomy and its role in diabetic retinopathy has changed significantly since the 1980s and 1990s.

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Ranibizumab for Diabetic Macular Oedema (RISE & RIDE) Study design: RCT

Evidence level: 1b

Ophthalmology 2012;119:789-801 | Ophthalmology 2013;120:2013-2022.

Key questions 1. How does intravitreal ranibizumab compare to sham injection for the treatment of diabetic macular oedema in terms of safety and efficacy? 2. Should 0.3 mg or 0.5 mg ranibizumab be used? 3. Is it worth treating diabetic retinal edema (DME) with ranibizumab even after a 12-month delay?

Aims These two methodologically-identical parallel studies aimed to assess whether intravitreal ranibizumab was safe and effective in the treatment of DME.

Methods Design: Phase III, randomised, multi-centre, double-masked, three-year trials, sham injection controlled for two years.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Seven hundred fifty-nine eyes of 759 adults with DME. Inclusion criteria: • Age ≥ 18 years; • Diabetes mellitus (DM) • Visual acuity (VA) 6/12 to 6/96; • Central macular thickness > 275 µm. Exclusion criteria: • Prior vitreoretinal surgery; • Scatter photocoagulation, macular laser, intraocular steroids or anti-angiogenic treatments within three months of enrolment.

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Groups: Patients were randomly assigned (on 1:1:1 basis) to receive either 0.3 mg or 0.5 mg ranibizumab or sham injections at monthly intervals for 24 months. From month three onwards, all patients were considered for macular laser according to protocol-specified criteria. At 24 months, the sham group were allowed to cross-over to 0.5 mg ranibizumab. Main outcome measure: Proportion of patients gaining 15 letters in BCVA from baseline at 24 months. Follow-up: Twenty-four months and 36 months.

RISE & RIDE Results Primary outcome (24 months): In RISE, 44.8% of patients receiving 0.3 mg ranibizumab and 39.2% of patients receiving 0.5 mg ranibizumab gained 15 letters compared with 18.1% of sham-treated patients (p < 0.001). In RIDE, corresponding proportions were 33.6%, 45.7%, and 12.3%, respectively (p < 0.0001).

Anatomical outcomes: After 12 months of monthly ranibizumab therapy, the sham/0.5 mg group experienced a reduction (SD) of 98.4 mm (142.8) compared with reductions of 237.9 mm (186.1) and 249.3 mm (194.8) in the 0.3 and 0.5 mg groups, respectively.

Primary outcome (36 months): At 36 months, the proportions of patients who gained 15 ETDRS letters from baseline in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, respectively, in RISE. After cross-over to one year of treatment with ranibizumab, average VA gains in the sham/0.5 mg group were lower compared with gains seen in the ranibizumab patients after one year of treatment (2.8 vs. 10.6 and 11.1 letters).

Safety: Rates of endophthalmitis were 0.06% per injection (n = 4). There were three cases of traumatic cataract and one case of rhegmatogenous retinal detachment in 10,584 injections.

Key messages

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1. Intravitreal ranibizumab is superior to sham injections in the treatment of patients with vision loss secondary to DME. 2. The improvement in visual acuity of ranibizumab was significantly less after a 24 month delay in the cross-over group, and may not be clinically significant. 3. Ranibizumab treatment was generally safe with low rates of serious adverse events.

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Ranibizumab Monotherapy or Combined with Laser versus Laser Monotherapy for Diabetic Macular Edema (RESTORE) Study design: RCT

Evidence level: 1b

Ophthalmology 2011;118:615-25 | Ophthalmology 2013;120:2004-12 | Ophthalmology 2014;121:1045-53.

Key questions 1.

2.

How does intravitreal ranibizumab alone compare to ranibizumab plus macular laser or macular laser alone for the treatment of diabetic macular oedema (DME) in terms of safety and efficacy? What are the results when the outcomes are monitored up to 36 months with individualised treatment given based on the investigators’ discretion?

Aims Both intravitreal ranibizumab and macular laser had been demonstrated to be effective in the treatment of DME. This trial aimed to compare the two treatments and also included a third group which permitted both treatments.

Methods Design: A 12-month, randomised, double-masked, multi-centre, laser-controlled Phase III study. An extension study reported outcomes at 36 months.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Three hundred and three eyes completed the 12-month study, 240 entered the extension study. Inclusion criteria: • Age ≥ 18 years; • Diabetes mellitus (DM); • Visual impairment due to focal or diffuse macular oedema which was eligible for laser treatment; • Visual acuity (VA) between 20/32 and 20/160.

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Exclusion criteria: • Decreased VA from other causes; • Active inflammation, infection in either eye or uncontrolled glaucoma; • Scatter photocoagulation within six months or macular laser, intraocular steroids or anti-angiogenic treatments within three months of enrolment; Groups: One eye of each patient was randomly assigned (on 1:1:1 basis) to receive either: • 0.5 mg ranibizumab + sham laser; • 0.5 mg ranibizumab + active laser; • Sham injections + active laser. Beyond 12 months, each group was permitted individualized treatment. Main outcome measure: Change in BCVA from baseline. Follow-up: Twelve months and 36 months.

RESTORE Results Primary outcome (12 months): The mean average change in the BCVA letter score from baseline to month 12 was significantly superior with ranibizumab (6.1; P < 0.0001) and ranibizumab + laser (5.9; P < 0.0001) than with laser treatment (0.8). There was no difference detected between the two ranibizumab treatment arms (P = 0.61). The mean CRT change from baseline to month 12 decreased significantly for ranibizumab (118.7 µm; P = 0.0002) and ranibizumab laser (128.3 µm; P = 0.0001) compared with laser (61.3 µm). The mean number of ranibizumab/ sham injections received was similar for all treatment groups (6.8-7.3 injections).

from +2.3 letters at month 12 to +6.0 letters at month 36. At month 36, 42.2% of patients in the prior ranibizumab group, 28.9% of patients in the prior ranibizumab + laser group, and 17.6% of patients in the prior laser group had a BCVA score > 78 letters (Snellen 20/40). CRT reduction was maintained in the ranibizumab groups, the prior laser group had an additional reduction of 79 µm, resulting in a total reduction of 142 µm at 36 months. The mean number of ranibizumab injections administered over two years of the extension study was similar across the three groups, ranibizumab (median six), ranibizumab + laser (median four), and prior laser (median four).

Primary outcome (36 months): Patients treated with ranibizumab in the first 12 months maintained their BCVA through months 12-36. Laser patients switched to ranibizumab improved their BCVA

Safety: There were no cases of endophthalmitis, retinal tear or detachment in any group over the three years. The most common serious adverse event was cataract (n =  8).

Key messages

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1. Both of the ranibizumab groups had better outcomes than the laser monotherapy group at 12 months. There was no difference between ranibizumab alone and ranibizumab + laser groups. 2. Combined ranibizumab + laser treatment did not reduce the number of injections required compared to ranibizumab alone. 3. Ranibizumab treatment maintained visual improvements from month 12-36. 4. Patients originally treated with laser monotherapy derived a significant benefit from ranibizumab therapy from months 12-36.

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Intravitreal Aflibercept for Diabetic Macular Edema (DA VINCI) Study design: RCT

Evidence level: 1b

Ophthalmology 2011;118:1819-1826 | Ophthalmology 2012;119:1658-1665.

Key questions 1. How does intravitreal aflibercept compare to macular laser for the treatment of diabetic macular oedema (DME) in terms of safety and efficacy? 2. Is there a difference between four different treatment regimens of aflibercept?

Aims This study aimed to assess whether intravitreal aflibercept was safe and effective in the treatment of DME.

Methods Design: Randomised, double-masked, multi-centre, Phase 2 clinical trial.


Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Two hundred nineteen eyes from 39 sites in US, Canada and Austria. Inclusion criteria: • Age >18 years; • Diabetes mellitus (DM); • Foveal involving DME with central foveal thickness > 250 µm; • Best corrected visual acuity (BCVA) between approximately 20/40 to 20/320. Exclusion criteria: • Significant ocular comorbidity which could confound the results; • Vitreoretinal surgery, pan-retinal or macular laser within three months of screening; • Previous intravitreal steroid injection or anti-vascular endothelial growth factor (anti-VEGF) treatment to the study eye within three months of screening. 66

Groups: Patients were randomly assigned to one of five treatment regimens: • 0.5 mg aflibercept, four-weekly; • 2 mg aflibercept, four-weekly; • 2 mg aflibercept, eight-weekly (after three-monthly loading doses); • 2 mg aflibercept, as needed (after three-monthly loading doses); • Macular laser photocoagulation. Main outcome measure: The change in VA at 24 weeks and at 52 weeks. The proportion of eyes that gained 15 ETDRS letters or more, and mean changes in foveal thickness from baseline. Follow-up: Six months and 12 months.

DA VINCI Results Primary outcome (six months): Patients in the four aflibercept groups experienced mean VA benefits ranging from 8.5 to 11.4 ETDRS letters vs. only +2.5 letters in the laser group (P = 0.0085 for each aflibercept group vs. laser). Gains from baseline of zero, ten, and 15 letters were seen in up to 93%, 64%, and 34% of VEGF Trap-Eye groups vs. up to 68%, 32%, and 21% in the laser group, respectively.

Anatomical outcomes: At six months, mean reductions in CRT in the 4 VEGF Trap-Eye groups ranged from 127.3 to 194.5 m compared with only 67.9 m in the laser group (P = 0.0066 for each aflibercept group vs. laser). At 12 months, the mean reductions in CRT in the aflibercept groups were between 165-227µm vs. 58.4 µm for laser (P = 0.0001 vs. laser).

Primary outcome (12 months): Mean improvements in BCVA in the aflibercept groups at one year were between 9.7 and 13.1 letters compared with 1.3 letters for the laser group (P = 0.0001 vs. laser). Proportions of eyes with gains in BCVA of 15 or more ETDRS letters at week 52 in the aflibercept groups were between 23.8% and 45.5%, vs. 11.4% for laser.

Adverse outcomes: Injection related endophthalmitis occurred in two eyes from approximately 1,625 injections.

Different treatment regimens: Mean number of injections required varied from 7.2 in the 2 mg/eight-weekly group to 11.7 in the 0.5 mg/ four-weekly group. No significant differences were observed between the aflibercept groups.

Weaknesses The study was not powered to assess the significance of differences in adverse events among the treatment arms.

Key messages

Copyright © 2017. Kugler Publications. All rights reserved.

1. Intravitreal aflibercept is superior to macular laser in the treatment of patients with vision loss secondary to DME. 2. There were no statistically significant differences between the outcomes of the four aflibercept treatment groups.

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Intravitreal Aflibercept for Diabetic Macular Edema (VIVID & VISTA) Study design: RCT

Evidence level: 1b

Ophthalmology 2015;122:2044-2052.

Key question 1. What are the safety and efficacy profiles of two dosing regimens of intravitreal aflibercept when compared to macular laser for diabetic macular oedema (DME).

Aims To compare the safety and efficacy of q4 and q8 weekly aflibercept to macular laser treatment.

Methods Design: Randomised controlled trial including 872 patients with Type 1 and 2 diabetes mellitus (DM) over 54 states in the U.S.A (VISTA) and 73 sites across Europe, Japan and Australia (VIVID).

Copyright © 2017. Kugler Publications. All rights reserved.

Inclusion criteria: • Type 1 or 2 DM with centre-involved DME; • Visual acuity (VA) 20/40 to 20/320; • Retinal thickness ≥ 300 microns (VIVID only); • Only one eye per patient was included. Exclusion criteria: • Concurrent pathology in the study eye likely to influence outcomes; • Previous anti-vascular endothelial growth factor (anti-VEGF) therapy or two or more macula laser treatments; • Previous vitreoretinal surgery; • Laser photocoagulation within 90 days.

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Study protocol: • Patients were randomised 1:1:1 to either Aflibercept 2 mg four-weekly (Aq4), Aflibercept 2 mg eight-weekly following five loading doses of 2 mg four-weekly (Aq8), or macular laser treatment: ᵒᵒ Patients in the Aq8 group received sham injections between visits; ᵒᵒ Patients in the laser group received sham injections at each visit; ᵒᵒ Re-treatment with laser starting at 12 weeks was permitted if ETDRS criteria were met; ᵒᵒ Rescue therapy was allowed for all groups if there was significant vision loss (10-15 letters over one to two visits). • Patients were assessed at each visit with BCVA and OCT. • Fluorescein angiogram and fundus photography were performed at baseline, weeks 24 and 52. Follow-up: Monthly follow-up over 100 weeks.

VIVID&VISTA Results Average number of injections: • Patients in VISTA received a mean of 21.3 and 13.5 in the Aq4 and Aq8 groups respectively; • Patients in VIVID received a mean of 22.6 and 13.6 in the Aq4 and Aq8 groups respectively; • Rescue laser was required in 3.2% and 7.4% of eyes in the Aq4 group, and 8.6% and 11.4% of eyes in the Aq8 groups in VISTA and VIVID respectively; • Rescue treatment was required in 34.6% of the laser group. Efficacy outcomes: • Both the Aq4 and Aq8 groups showed significant and sustained gains in VA through 100 weeks: ᵒᵒ VISTA: Mean gain of 11.5, 11.1 and 0.9 letters in the Aq4, Aq8 and laser groups respectively; ᵒᵒ VIVID: Mean gain of 11.4, 9.4 and 0.7 letters for the Aq4, Aq8 and laser groups respectively. • The number of eyes gaining ≥15 letters of BCVA were higher in the Aflibercept groups: ᵒᵒ VISTA: 38.3%, 33.1% and 13.0% gained ≥15 letters in the Aq4, Aq8 and laser groups respectively; ᵒᵒ VIVID: 38.2%, 31.1% and 12.1% gained ≥15 letters in the Aq4, Aq8 and laser groups respectively.

•

Diabetic retinopathy scores improved more in the Aflibercept groups (≥ two category improvements in > 30% of patients).

Safety outcomes: • There were low incidences of both ocular and non-ocular adverse events and no significant differences between groups.

Weaknesses These trials did not directly compare the outcomes of four- and eight-weekly ranibizumab to each other, but compared them independently to macular laser. The control group was macular laser which has been shown to be inferior to intravitreal ranibizumab and is no longer the gold standard treatment for DME.

Key messages

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1. Intravitreal aflibercept treatment both four- and eight-weekly (after five monthly loading doses) for DME is superior in efficacy to macular laser. 2. Intravitreal aflibercept treatment may result in improvements in diabetic retinopathy scores 3. Intravitreal aflibercept treatment is safe in DME.

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Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema (BOLT) Study design: RCT

Evidence level: 1b

Retina 2010; 20:781-786 | Ophthalmol 2010;117:1078-1086 | Arch Ophthalmol 2012;130:972-979 | PLoS One 2013;8:e72755-7 | Br J Ophthalmol 2013;97:1177-1180.

Key question 1. How do intravitreal bevacizumab injections compare to macular laser therapy (MLT) in the treatment of persistent diabetic macular oedema (DME)?

Aims The BOLT study aimed to compare the effects of two available therapies (laser and anti-VEGF) for DME.

Methods Design: Prospective, randomised, masked, two-arm, two-year clinical trial.

single-centre,

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Eighty eyes of 80 patients. Inclusion criteria: • Age ≥ 18 years; • Diabetes mellitus (DM); • Visual acuity (VA) 6/12 to 6/60; • Central macular thickness (CMT) > 270 µm; • Media clarity, pupil dilatation, etcetera adequate for fundus imaging; • At least one prior macular laser therapy; • Fellow eye VA > 3/60; • Fellow eye has not received anti-VEGF treatment within three months. Exclusion criteria: • Macular ischaemia, or macular oedema from other causes; • Co-existent ocular pathology; • Treatment for DME within previous three months;

70

•

Pan-retinal photocoagulation (PRP) within three months before enrolment or anticipated within next six months.

Groups: Subjects were randomised to intravitreal bevacizumab (ivB) (six-weekly; minimum of three injections and maximum of nine injections in the first 12 months) or MLT four- monthly; minimum of one treatment and maximum of four treatments in the first 12 months). Primary outcome measure: VA (loss of 15 letters, gain of 15 letters). Secondary outcomes: CMT, number/frequency of treatments, macular perfusion determined by fundus fluorescein angiogram. Follow-up: Two years.

BOLT Results VA: At 12 months, The bevacizumab arm had a mean gain of 8.6 letters vs. a mean loss of 0.5 letters for MLT (p = 0.0002). At two years, mean BCVA was 20/50 in the bevacizumab arm and 20/80 in the MLT arm (P = 0.005). The bevacizumab arm had a mean gain of 8.6 letters vs. a mean loss of 0.5 letters for MLT. Forty-nine percent of patients gained ten or more letters (P = .001) and 32% gained at least 15 letters (P = 0 .004) for bevacizumab vs. 7% and 4% for MLT. Percentage who lost fewer than 15 letters in the MLT arm was 86% vs. 100% for bevacizumab (P = 0.03). Central macular thickness: At 12 months, the mean reduction in CMT was 130 ± 122 µm in the bevacizumab arm and 68 ± 171µm in the laser group (P = 0.06). At 24 months, mean reduction in central macular thickness was 146 μm in the bevacizumab arm vs. 118 μm in the MLT arm (non-significant; P = 0.62). Treatment frequency: The median number of treatments over 24 months was 13 for bevacizumab and four for MLT.

Macular perfusion studies: There was no difference in macular perfusion between the two groups, based on greatest linear dimension of the foveal avascular zone, area of the foveal avascular zone and the grade of perifoveal capillary loss. Safety: In the bevacizumab group, eight eyes suffered with pain/irritation after injection and four eyes had transient increase of IOP > 30 mmHg (one case > 45 mmHg). One eye in the laser group lost more than 30 ETDRS letters and one eye developed vitreo-macular traction requiring surgery.

Weaknesses The study was not powered to detect differences in adverse outcomes. The study did not examine whether there was a benefit from combining laser with anti-VEGF therapy. This was later investigated by the RESTORE trial.

Key messages

Copyright © 2017. Kugler Publications. All rights reserved.

1. Visual acuity was better in the bevacizumab group at 12 and 24 months. 2. Other than central macular thickness at 12 months, there was no significant difference in the anatomical outcomes between the two groups. 3. Safety outcomes were good.

71

Fluocinolone Acetonide Vitreous Inserts for Diabetic Macular Edema (FAME A & B) Study design: RCT

Evidence level: 1b

Ophthalmology 2010;117:1393-1399 | Ophthalmology 2011;118:626-635 | Ophthalmology 2011;118:15801587 | Ophthalmology 2012;119:2125-2132.

Key questions 1. How does intravitreal fluocinolone acetonide compare to sham injection for the treatment of diabetic macular oedema (DME) in terms of safety and efficacy? 2. Should 0.2 µg/day or 0.5 µg/day implants be used?

Aims Iluvien (Alimera Sciences, Alpharetta, GA) is a 3.5 x 0.37 mm non-biodegradable, cylindrical tube that is inserted into the vitreous cavity through a 25-gauge needle. It provides an initial release rate of 0.5 or 0.2 µg/day of fluocinolone acetonide (FAc) for two to three years. These two methodologically-identical parallel studies aimed to assess whether intravitreal FAc was safe and effective in the treatment of diabetic macular oedema.

Methods Design: Two randomised, sham injection-controlled, double-masked, multi-centre clinical trials.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Nine hundred fifty-three subjects were recruited from the US, India, and four European countries. Inclusion criteria: • Age ≥ 18 years; • Visual acuity (VA) 20/50-20/400; • Persistent or recurrent DME despite one macular laser treatment; • Central macular thickness > 250 µm. Exclusion criteria: • Patients with glaucoma, ocular hypertension (OHT), or using intraocular pressure (IOP)-lowering medication. 72

Groups: A total of 953 subjects were randomised in a 2:2:1 ratio to 0.2 µg/day FAc intravitreal insert (n = 375), 0.5 ­µg/­day FAc intravitreal insert (n = 393), or sham injection (n = 185). After month 12, patients who met re-treatment criteria were allowed to receive repeat administration of their assigned study treatment at the investigators discretion. In addition, after six weeks in the study, patients were allowed to have additional laser treatments, and subsequently treatments were allowed as frequently as every three months for persistent or recurrent DME. Main outcome measure: Best corrected VA. Follow-up: Clinical outcomes to 36 months and safety outcomes to 48 months.

FAME A&B Results Primary outcome: At month 36, the mean improvement from baseline BCVA letter score was 8.1 (low dose) and 7.1 (high dose) compared with 3.1 for the sham group (P = 0.007 for difference between low dose and sham). A final BCVA of > 20/40 was attained at month 36 in 35.1% and 34.9% of patients in the FAc insert groups compared with 26.5% in the sham group (sham vs. low dose, P = 0.016). Anatomical outcomes: At month 24, the mean FTH was significantly lower in the FAc groups (low dose, 293 µm [P = 0.005]; high dose, 308 µm [P < 0.001]) compared with the sham group (340 µm). There was no statistically significant difference in macular thickness at 36 months, sham group (309 µm) compared with the low-dose (280 µm) and high-dose (300 µm) groups.

Re-treatments and rescue treatments: The percentage of patients who received two, three or four study treatments was 19.5%, 2.7%, and 1.6%, respectively, in the sham group; 21.3%, 1.9%, and 0.3%, respectively, in the low-dose group; and 22.6%, 2.5%, and 0.3%, respectively, in the high-dose group. Significantly more patients in the two FAc insert groups did not receive focal/grid laser therapy after study entry than in the sham group (63.3% and 64.8% vs. 41.1%; P  26; • Chronic use of medications known to be toxic to the retina.

Groups: Subjects were randomised via a 2x2 matrix to receive Methods one of the following supplements in addition to the Design: original AREDS formula: Prospective, multi-centre, randomised, double­ - • Control; masked, placebo-controlled phase-3 study with a 2x2 • Lutein + Zeaxanthin; factorial design. • DHA + EPA (Omega-3 fatty acids); • Lutein + Zeaxanthin + DHA + EPA. Participants: Four thousand two hundred and three participants Seventy-two percent of participants agreed to ranacross 82 sites in the USA. domisation to receive variants of the original AREDS formulation: Inclusion criteria: • AREDS supplement; • Age 50-85 years; • AREDS supplement (no ß-carotene); • Sufficiently clear media for fundus photographs; • AREDS supplement (low zinc); • Either bilateral large drusen, or unilateral large • AREDS supplement (no ß-carotene and low zinc). drusen with advanced AMD in the other eye. 76

AREDS-2 Primary outcome measure: Time to progression to advanced AMD (GA involving the fovea or nAMD). Follow-up: Five years.

Results Primary outcomes: Over five years, 1940 study eyes progressed to advanced AMD. Kaplan-Meier probabilities of progression to advanced AMD by five years were 31% for placebo, 29% for lutein + zeaxanthin, 31% for DHA + EPA, and 30% for lutein + zeaxanthin + DHA + EPA. None of the supplements had statistically significant reduction in change of progression over placebo. Secondary randomisation: Lowering zinc dose and removing ß carotene had no sta-

tistically significant effect on progression to advanced AMD. Comparing the two groups of lutein + zeaxanthin + AREDS formulation (without ß carotene) versus the original AREDS supplement alone demonstrated a hazard ratio of 0.82 for progression to advanced AMD (p = 0.02). VA: There was no difference in proportion of patients losing > 15 letters between the groups. Safety: There was no statistically significant difference in rates of serious adverse effects between the four groups, including rates of development of neoplasms. Secondary randomisation, which excluded smokers from receiving any formulation containing ß carotene, still demonstrated a statistically significant increase in lung cancer in the ß carotene groups.

Key messages

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1. Adding either lutein + zeaxanthin or omega-3 fatty acids or both to the original AREDS formulation incurred no additional benefit. 2. Lutein + zeaxanthin can be an appropriate substitute for ß carotene as when added to the AREDS formula without β carotene they conferred a protective benefit. 3. It is still efficacious to give a lower, more tolerable dose of zinc. 4. Following this trial, the recommended supplement includes: Vitamin C (500 mg), Vitamin E (400 IU), Lutein (10 mg), Zeaxanthin (2 mg), Zinc (25 mg) and Copper (2 mg).

77

Ranibizumab vs. Verteporfin for Predominantly Classic Choroidal Neovascularisation in AgeRelated Macular Degeneration (ANCHOR) Study design: RCT

Evidence level: 1b

New Engl J Med 2006;355:1432-1444.

Key question 1.

How do intravitreal ranibizumab injections compare to photodynamic therapy with verteporfin in predominantly classic neovascular macular degeneration (MD)?

Aims Ranibizumab is a recombinant, humanized monoclonal antibody Fab that neutralises all active forms of vascular endothelial growth factor A (VEGF-A). The anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization (CNV) in Age-Related Macular Degeneration (ANCHOR) trial was a two-year, phase-3 study, which compared the efficacy and safety of monthly intravitreal injections of ranibizumab with that of photodynamic therapy with verteporfin in patients with predominantly classic neovascular lesions associated with age-related macular degeneration.

Methods

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Design: Multi-centre, randomised, double-blind, active-treatment controlled trial. Participants: Four hundred twenty-three patients were enrolled from 83 sites in six countries. Inclusion criteria: • Age ≥ 50 years; • Visual acuity (VA) 6/12 to 6/96; • Choroidal neovascularisation (CNV) ≤ 5400 μm diameter.

78

Exclusion criteria: • Permanent structural damage to the fovea; • Previous treatment. Groups: Patients were randomly assigned 1:1:1 to receive 0.3 mg or 0.5 mg ranibizumab injections with sham verteporfin (i.e., low fluence laser after saline infusion), or sham injections with verteporfin photodynamic therapy. Injections were administered monthly, verteporfin administered at day 0 then at the investigators’ discretion based on angiograms at three, six, nine and 12 months. Primary outcome measure: VA (loss of 15 letters, gain of 15 letters). Secondary outcomes: Structural outcomes on fluorescein angiography. Follow-up: Two years.

ANCHOR Results VA: The ranibizumab groups both showed an average increase in VA in the first few months to a stable plateau with average gain of 8.5 letters in the 0.3 mg group and 11.3 letters in the 0.5 mg group at 12 months, compared to a steady decline in average acuity in the verteporfin group with average loss of 9.5 letters at 12 months. Twelve-month outcomes: All VA outcomes strongly favoured ranibizumab. The proportion who lost fewer than 15 letters was 94.3% of patients in the 0.3 mg group and 96.4% in the 0.5 mg group and 64.3% in the verteporfin group (P < 0.001). The proportion who gained 15 letters was 35.7% in the 0.3 mg group and 40.3% in the 0.5 mg group, as compared with 5.6% in the verteporfin group (P  20/40) or very good vision (20/20) and fewer patients with poor vision (< 20/200) or severe loss of vision (loss of 30 letters) in both ranibizumab groups (P < 0.001 all comparisons). Twenty-four-month outcomes: VA differences at 12 months were largely sustained through to 24 months in all groups. That is, with ongoing

injections, the ranibizumab groups maintained their improvements of around ten letters and the verteporfin group stabilized with an average loss of 15 letters. Structural outcomes: In the verteporfin group, the lesions grew in area and leakage over the course of the study. In the ranibizumab groups the classic lesion and area of leakage decreased, and the total lesion area and total neovascular lesion grew very marginally (P < 0.001 all comparisons). Safety: Serious ocular adverse events were rare: two endophthalmitis, one uveitis, two retinal detachments (one in verteporfin group) and one vitreous haemorrhage. Cataract was more common in the ranibizumab groups, but generally mild and were not due to lens trauma. Total deaths and non-ocular adverse events were similar between groups. Back pain was more common in the verteporfin group, a recognized side effect.

Weaknesses The study was not powered to detect safety differences in non-ocular adverse events.

Key messages

Copyright © 2017. Kugler Publications. All rights reserved.

1. The ANCHOR study revolutionised treatment of neovascular macular degeneration, demonstrating hugely better visual outcomes from ranibizumab compared to the standard care with verteporfin photodynamic therapy. 2. The protocol of monthly ranibizumab injections resulted in improved vision of ~10 letters on average, which was sustained through two years. 3. Safety outcomes were good.

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Ranibizumab for Minimally Classic or Occult Neovascular Age-Related Macular Degeneration (MARINA) Study design: RCT

Evidence level: 1b

New Engl J Med 2006;355:1419-1431.

Key question 1.

In minimally classic and occult neovascular lesions of macular degeneration (MD) (for which no effective treatment existed), do monthly intravitreal injections of ranibizumab improve visual outcomes?

Aims MARINA was a two-year, phase-3 study to evaluate the safety and efficacy of monthly intravitreal ranibizumab injections (against sham injections), in patients with minimally classic or occult with no classic choroidal neovascularization (CNV) associated with age-related MD.

Methods Design: Multi-centre, randomised, double-blind, sham-controlled study.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Seven hundred sixteen patients were enrolled across 96 sites in the USA. Inclusion criteria: • Age ≥ 50 years; • Visual acuity (VA) 6/12 to 6/96; • Primary or recurrent minimally classic or occult CNV involving foveal centre; • Subjective or objective evidence of recent progression. Exclusion criteria: • Lesions larger than 12 disc areas. 80

Groups: Patients were randomly assigned 1:1:1 to receive 0.3 mg or 0.5 mg ranibizumab injections or sham injections. Injections were administered monthly. Verteporfin photodynamic therapy was allowed if the lesion changed to become classic, and after an amendment in 2004 when the use of PDT was expanded to certain small minimally classic or occult lesions with severe documented vision loss of 20 letters. Primary outcome measure: VA (loss of 15 letters, gain of 15 letters). Secondary outcomes: Structural outcomes on fluorescein angiography. Follow-up: Two years.

MARINA Results VA: The ranibizumab groups both showed an average increase in VA in the first few months to a stable plateau with average gain of 6.5 letters in the 0.3 mg group and 7.2 letters in the 0.5 mg group at 12 months, compared to a steady decline in average acuity in the sham injection group with average loss of 10.4 letters at 12 months. Twelve-month outcomes: All VA outcomes strongly favoured ranibizumab. The proportion who lost fewer than 15 letters was 94.5% of patients in the 0.3 mg group and 94.6% in the 0.5 mg group and 62.2% in the sham group (P < 0.001). The proportion who gained 15 letters was 24.8% in the 0.3 mg group and 33.8% in the 0.5 mg group, as compared with 5.0% in the sham group (P < 0.001). After 12 months here were more patients with good vision (> 20/40) or very good vision (20/20) and fewer patients with poor vision (< 20/200) or severe loss of vision (loss of 30 letters) in both ranibizumab groups (P < 0.001 all comparisons). Twenty-four-month outcomes: VA differences at 12 months were largely sustained through to 24 months in all groups. That is, with ongoing injections, the ranibizumab groups maintained their improvements of around six letters and the sham group stabilized with an average loss of 15 letters.

Structural outcomes: In the sham group, the lesions grew in area and leakage over the course of the study. In the ranibizumab groups, the lesion area was stable and leakage decreased (P < 0.001 all comparisons). Safety: In ranibizumab groups, there were five cases of severe inflammation after injection (only one proven infection), with a rate of 1.0% patients or 1:2000 injections. IOP rises were common after injection, but rarely severe. Cataract surgery was more common in the ranibizumab groups (around 6%) compared to sham group (0%). Non-ocular adverse events (including serious adverse events) were similar between groups, but non-ocular haemorrhage appeared to be more common in ranibizumab groups (sham 5.5%, 0.3 mg 9.2%, 0.5 mg 8.8%) although the study was not powered to detect differences in these uncommon events.

Weaknesses The study was not powered to detect safety differences in non-ocular adverse events.

Copyright © 2017. Kugler Publications. All rights reserved.

Key messages 1. The MARINA study revolutionized treatment of neovascular MD, demonstrating hugely better visual outcomes from ranibizumab than control. 2. The protocol of monthly ranibizumab injections resulted in improved vision of seven letters on average, which was sustained through two years. 3. Safety outcomes were good.

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Randomised, Double-Masked, Sham-Controlled Trial of Ranibizumab for Neovascular Age-related Macular Degeneration (PIER) Study design: RCT

Evidence level: 1b

Am J Ophthalmol 2008;145:239-248 | Am J Ophthalmol 2010;150:315-324.

Key questions 1.

2.

How do intravitreal ranibizumab injections (three-monthly loading doses followed by quarterly injections) compare to sham injection in the treatment of neovascular age-related macular degeneration (nAMD) (with or without classic features)? Should 0.3 mg or 0.5 mg ranibizumab be used?

Aims The ANCHOR and MARINA studies used a monthly dosing regimen of ranibizumab. The PIER study investigated if less frequent dosing of ranibizumab would prevent loss of visual acuity (VA) in nAMD (three-monthly loading doses, followed by quarterly injections). It included all forms of choroidal neovascularisation (CNV).

Methods Design: Multi-centre, randomised, double-masked, sham-controlled two- year trial in nAMD patients with subfoveal CNV with or without classic features.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: One hundred eighty-four patients were enrolled from 43 sites in the USA. Inclusion criteria: • Age ≥ 50 years; • VA 6/12 to 6/96; • Classic lesions: CNV area comprising > 50% of the AMD lesion; • Minimally classic or occult lesions: Evidence of presumed recent disease progression.

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Exclusion criteria: • Permanent structural damage to the fovea; • Previous treatment with verteporfin, anti-angiogenic drug therapy, or other AMD treatments. Groups: Patients were randomly assigned 1:1:1 to receive 0.3 mg (n = 60) or 0.5 mg ranibizumab (n = 61) injections or sham injections (n = 63). Injections were administered monthly, for the first three doses, followed by three-monthly intervals. Verteporfin photodynamic therapy (vPDT) was permitted at the investigators’ discretion. After the results of ANCHOR and MARINA were published, the sham injection group were allowed to cross-over to 0.5 mg ranibizumab quarterly for the remainder of the study. Furthermore, a later amendment moved patients from all groups to ranibizumab 0.5 mg monthly. Primary outcome measure: Best corrected VA. Follow-up: One and two years.

PIER Results Twelve-month outcomes: Best corrected visual acuity (BCVA) had decreased by 16, two and zero letters in the sham, 0.3 mg and 0.5 mg groups respectively (p < 0.0001). 27%, 1.7% and 1.6% of patients in the sham, 0.3 mg and 0.5 mg groups respectively received vPDT rescue therapy. Forty-one percent, 83% and 90% of patients had lost less than 15 EDTRS letters in the sham, 0.3 mg and 0.5 mg groups respectively (p < 0.0001). On average, there was 4.5-letter decline in VA between month 3-12 for both ranibizumab dose groups, reflecting the effect of quarterly dosing; these declines were statistically significant. Twenty-four-month outcomes: BCVA had decreased by 21, two and two letters in the sham, 0.3 mg and 0.5 mg groups respectively (p < 0.0001). Forty-one percent, 78% and 82% of patients had lost less than 15 EDTRS letters in the sham, 0.3 mg and 0.5 mg groups respectively (p < 0.0001).

Cross-over outcomes: Thirty-nine patients crossed-over from sham injections to ranibizumab 0.5 mg quarterly. There was an average loss of 3.5 letters between cross-over to an average of ten months follow-up. Amendment to 0.5 mg ranibizumab monthly outcomes: Thirty-four, 43, and 44 eligible patients in the sham, 0.3 mg, and 0.5 mg groups, respectively, rolled over to receive monthly 0.5 mg ranibizumab, beginning month 19. There was an average change of -2, +2 and +4 letters in the sham, 0.3 mg and 0.5 mg groups four months after roll-over, respectively.

Weaknesses As 80% of patients had minimally classic or occult lesions, the results should be interpreted with caution when applying to patients with classical CNV lesions. The number of patients enrolled in this study is comparably smaller than most wet AMD trials and therefore often prevented subgroup analyses. The results may be difficult to interpret given the number of amendments to the protocol.

Key messages

Copyright © 2017. Kugler Publications. All rights reserved.

1. Both bevacizumab groups had superior outcomes than sham injections. 2. There was a reduction in VA in the bevacizumab groups when their treatments were switched from monthly to quarterly, suggesting this is an insufficient frequency of treatments. This is further confirmed when the outcomes in this study are compared to the results of the MARINA and ANCHOR trials.

83

Safety and Efficacy of a Flexible Dosing Regimen of Ranibizumab in Neovascular Age-Related Macular Degeneration (SUSTAIN) Study design: Non-controlled trial

Evidence level: 2b

Ophthalmology 2011;118:663-671

Key question 1.

Is an individualized ranibizumab treatment regimen safe and effective in patients with neovascular age-related macular degeneration (AMD)?

Aims To determine the safety and efficacy of an individualized ranibizumab treatment regimen in wet AMD.

Methods Design: Multi-centre, open label, phase III, single-arm study.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Five hundred thirteen patients from ten European countries and Australia. Only one eye per patient received treatment (the better eye was chosen if both involved). Inclusion criteria: • Age ≥ 50 years; • Active primary or recurrent subfoveal choroidal neovascularisation (CNV) secondary to AMD (classic, predominantly classic, minimally classic and occult lesions included); • Total area of CNV (including classic and occult) ≥ 50% of lesion area; • Total lesion ≤ 12 disc diameters; • Best corrected visual acuity (VA) 6/12 to 6/96. Exclusion criteria: • Use of systemic vascular endothelial growth factor (VEGF) agents or other anti-angiogenic drugs; • Previous photodynamic therapy (PDT) treatment, vitrectomy, radiotherapy, trans-pupillary thermo84

• •

therapy in the study eye; Other ocular disorders that may confound results (i.e., vitreous haemorrhage) Secondary causes of choroidal neovascular membrane (CNVM) (i.e., angioid streaks).

Study protocol: • Patients were reviewed monthly for 12 months: ᵒᵒ Best corrected VA (BCVA) and optical coherence tomography (OCT) scanning were performed at all visits; ᵒᵒ Vital signs, ophthalmic examination and tonometry were performed at baseline, day 8, at months 1, 2, 3 and 12, and optionally at visits from months 4 to 11; ᵒᵒ Fluorescein angiogram was performed at baseline, months 3 and 12; ᵒᵒ All patients were observed two days post-injection to document complications and visual loss. • Study phases: ᵒᵒ ‘Loading phase’: three consecutive monthly injections (0.5 mg or 0.3 mg which was given prior to approval of 0.5 mg); ᵒᵒ ‘PRN phase’: Treatment given as per PRN criteria: »» Loss of BCVA ≥ five letters; »» Increase in central retinal thickness (CRT) ≥ 100 microns; »» Option to not treat if VA ≥ 79 letters or CRT ≤ 225 microns.

SUSTAIN Results

Weaknesses

Safety: The adverse event profile of this regimen was mild and as expected.

There was no control group of monthly dosing to compare to. The dose of ranibizumab varied between 0.3 and 0.5 mg which may impact results given 0.5 mg is now given as standard. Not all patients were examined monthly – this may have underestimated the number of PRN injections ideally needed as early signs of active wet AMD such as haemorrhage would not have triggered an injection.

Efficacy: • VA: ᵒᵒ Mean change BCVA from baseline to month 3 and 12 were 6.3 and 4.4 letters respectively; ᵒᵒ At one year, 92.5% of patients had lost < 15 letters BCVA; ᵒᵒ 19.3% of patients gained ≥ 15 letters BCVA. • CRT: ᵒᵒ Mean change from baseline of -101.1 microns at 3 months, and 915.5 microns at 12 months; • Resolution of angiographic signs of CNVM was seen in 41.2% of patients; • Number of treatments required: ᵒᵒ Mean of 5.6 over 12 months (2.7 injections from month 4-11); ᵒᵒ 20.5% did not require further dosing after the loading phase.

Key messages

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1. The sustain study found an individualised dosing regimen to be safe. 2. A significant percentage of patients may not require more than the initial three doses of medication given in this study. 3. In this PRN regimen, visual acuity outcomes at one year were inferior to monthly outcomes reported in ANCHOR/MARINA. 4. PRN dosing regimens result in fewer injections being given than standard monthly dosing regimens.

85

PrONTO Studies: An Optical Coherence Tomography-Guided Variable Dosing Regimen with Intravitreal Ranibizumab (Lucentis) for Neovascular Age-related Macular Degeneration Study design: Non-controlled trial

Evidence level: 2b

Am J Ophthalmol 2007;143:566-583 | Am J Ophthalmol 2009;148:43-58.

Key question 1.

Is a variable (PRN) dosing regimen for intravitreal ranibizumab in wet age-related macular degeneration (AMD) effective, and are outcomes similar to those for a monthly dosing regimen used in landmark phase III trials?

Aims The primary aim of the PrONTO study was to assess the effect of a variable dosing regimen in patients with choroidal neovascular membrane secondary to AMD.

•

Methods

•

Design: Open-label, single-centre, domised, uncontrolled trial.

prospective,

non-ran-

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Forty patients enrolled at the Bascom-Palmer Eye Institute in Miami, FL for year one, 37 patients completed year 2 of the study. Inclusion criteria: • Age ≥ 50 years, with active primary or recurrent macular neovascularization secondary to AMD involving the central fovea; • OCT CRT ≥ 300 microns; • Best corrected visual acuity (BCVA) 20/40 to 20/400 (Snellen equivalent). Exclusion criteria: • More than three prior treatments with verteporfin photodynamic therapy; 86

•

Participation in a prior clinical trial (either eye) of antiangiogenic drugs; Previous subfoveal focal laser photocoagulation in the study eye; Subfoveal fibrosis or atrophy in the study eye.

Trial protocol: • VA testing, fundus photography, OCT and ocular examinations were performed at least at baseline, day 14, day 30, day 45, day 60, then monthly for two years. • Fluorescein angiography was performed at baseline, month 1, month 2, month 3, then three-monthly. • All patients received intravitreal injections of ranibizumab (0.5 mg) at baseline, month 1, and month 2; • Additional reinjections of ranibizumab (0.5 mg) were given PRN if: • VA loss of at least five letters with fluid on OCT at the macula; • Increase in CRT ≥ 100 microns; • New macular hemorrhage; • New area of classic CNVM; • Persistent fluid on OCT at least one month after the previous injection;

PrONTO Studies •

If an unplanned injection was required all visits continued but the patient was not eligible for a further injection for one month.

Results One-year outcomes: • Eleven unscheduled visits – for symptomatic worsening of vision; • Mean and median number of injections were 5.6 and 5.0, respectively; • Thirty-nine eyes became fluid-free; 37 of these eyes developed recurrent by one year; • Mean and median VA scores improved by 9.3 letters and 11 letters, respectively. Two-year outcomes: • Mean and median number of injections of 9.9 and 9.0 over two years; • 97.5% of patients did not lose 15 or more letters;

•

•

Mean and median VA scores improved by 11.1 letters and 14 letters, respectively: ᵒᵒ 43% gained at least three lines of vision, with 8.1% gaining at least six lines; ᵒᵒ 78% avoided any loss of letters. OCT: ᵒᵒ Mean thickness decreased by 212 microns which was found to be significantly correlated to VA.

Weaknesses This was a relatively small study. There was no control group or comparison to a matched population receiving a monthly or treat and extend regimen to allow direct comparisons. Conclusions on comparison of regimens were drawn from ANCHOR and MARINA whose populations may not be directly comparable. OCT scanning used only six radial scans, which may miss retinal fluid, and newer OCT scanners may result in a larger number of repeat injections required.

Key messages

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1. PRN treatment is effective for CNVM in patients with AMD. 2. The average number of injections required per patient was reduced markedly using a PRN treatment regimen. 3. The number of patients losing > 15 letters was comparable to monthly treatment regimens (used in ANCHOR and MARINA).

87

Efficacy and Safety of Monthly versus Quarterly Ranibizumab Treatment in Neovascular Agerelated Macular Degeneration (EXCITE) Study design: Non-controlled trial

Evidence level: 1b

Ophthalmology 2011;118:831-839.

Key question 1.

Is a quarterly treatment regimen inferior to a monthly regimen of intravitreal ranibizumab for subfoveal choroidal neovascular membrane secondary to age-related macular degeneration (AMD)?

Aims To demonstrate non-inferiority of a quarterly treatment regimen compared to a monthly regimen of intravitreal ranibizumab for subfoveal choroidal neovascular membrane secondary to age-related macular degeneration.

• • •

Methods Design: Multi-centre, randomised, double-masked, active-controlled, phase IIIb study.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Two hundred ninety-three patients were recruited from 59 centres in 16 European countries, Australia, Brazil, Israel and Turkey. Inclusion criteria: • Age ≥ 50 years; • Active primary or recurrent subfoveal choroidal neovascular membrane (CNVM) with fluorescein subtypes of predominantly classic, minimally classic or occult (but not classic CNVM); • Best corrected visual acuity (VA) between 73 and 24 letters (20/40-20/320). Exclusion criteria: • Best corrected VA < 34 letters in both eyes; 88

• • •

Participation in a prior clinical trial (either eye) of antiangiogenic drugs; Use of other investigational drugs at the time of screening; Prior treatment in the study eye with verteporfin, external beam radiotherapy, vitrectomy or other surgery for ARMD, transpupillary thermotherapy, or subfoveal focal laser photocoagulation; Laser photocoagulation (juxtafoveal or extrafoveal) in the study eye within one month; Angioid streaks or other precursors of CNVM; Clinically significant sub-retinal haemorrhage.

Study assessments: • VA (ETDRS chart) and OCT were performed at baseline and each monthly visit; • Fluorescein angiograms were performed at baseline and months 6 and 12. Study protocol: • Groups: ᵒᵒ Ranibizumab 0.3 mg monthly for three months, then quarterly injections; ᵒᵒ Ranibizumab 0.5 mg monthly for three months, then quarterly injections; ᵒᵒ Monthly injection of ranibizumab 0.3 mg from baseline to month 11. Patients randomly assigned 1:1:1 to each group.

EXCITE Sham injections were given at monthly visits (when injections not due) for those in the quarterly groups.

•

Follow-up: Monthly follow-up over one year.

•

Results Primary outcomes: • VA: ᵒᵒ At three months, the increase observed was 6.8, 6.6 and 7.5 letters, respectively; ᵒᵒ At 12 months, a mean increase was observed of 4.9, 3.8 and 8.3 letters in the 0.3 mg, 0.5 mg and monthly groups, respectively; ᵒᵒ The VA results for the 0.5 mg quarterly group were inferior, however, despite poorer outcomes the 0.3 mg quarterly group was non-inferior. • OCT thickness: ᵒᵒ Mean change in retinal thickness was reduced by 105.6, 105.3 and 96.0 microns in the 0.3 mg quarterly, 0.5 mg quarterly and 0.3 mg monthly groups, respectively.

Fluorescein findings: ᵒᵒ No significant difference was found in reduction in area of CVNM between the groups. Adverse events: ᵒᵒ No specific dosing regimen had a significantly higher rate of adverse events; ᵒᵒ Pain was the most common (11.9-20%); ᵒᵒ Increased IOP – (quarterly 0.3 mg 5.0%, 0.5 mg 5.9%, monthly 14.8%).

Weaknesses Non-inferiority studies must be regarded with caution as they do not prove equivalence. Follow-up was only for one year, during the later stages of this the visual outcomes began to decline in the quarterly groups, but not in the monthly group. A longer trial may have shown inferiority for both quarterly groups.

Key messages

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1. While non-inferior (for the 0.3 mg quarterly group) the outcomes of quarterly dosing were worse (significantly so in the 0.5 mg group). 2. Best VA declined with time in the quarterly group. 3. Quarterly dosing after three loading doses is not an ideal treatment option for CVNM from AMD. 4. There were no significant differences in rates of ADRs in any group.

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SAILOR Study: Safety Assessment of Intravitreal Lucentis for AMD Study design: RCT

Evidence level: 1b

Ophthalmology 2009;116:1731-1739.

Key question 1. Is intravitreal ranibizumab a safe and efficacious treatment for patients with wet age related macular degeneration (AMD)?

Aims To determine the safety profile and efficacy of intravitreal ranibizumab treatment for neovascular age related macular degeneration (AMD).

Methods Design: Randomised (cohort one) and open-label (cohort two) clinical trial.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: A total of 4300 patients across multiple centres in the USA. Inclusion criteria: • Age ≥ 50 years; • Best corrected visual acuity (BCVA) 6/12 to 6 6/120; • Angiographically determined subfoveal choroidal neovascular membrane (CNVM) secondary to AMD; • Evidence of recent disease progression: ᵒᵒ Loss of ≥ five letters BCVA within six months; ᵒᵒ Increase in angiographic CNVM size over six months pre-trial; ᵒᵒ Subretinal haemorrhage associated with CNVM within one month; ᵒᵒ Classic CNVM comprising > 50% of CNVM lesion area.

90

Exclusion criteria: • Previous photodynamic therapy (PDT), pegaptanib or other AMD therapy/surgery within 30 days; • Use of systemic anti-vascular endothelial growth factor (aVEGF) agents; • Fibrosis or atrophy involving the foveal centre in the study eye; • CNVM due to other cause in either eye. Study protocol: • One eye per subject was included; • Full ophthalmic examination, BCVA, and OCT performed at all visits • Cohort One: ᵒᵒ Randomised 1:1 to receive 0.3 or 0.5 mg intravitreal ranibizumab; ᵒᵒ Intravitreal injections given at baseline, month 1 and 2 and pro re nata (PRN): »» Decrease in BCVA ≥ 5 letters; »» Increase in central retinal thickness (CRT) on OCT ≥ 100 microns. ᵒᵒ Scheduled visits at months 1, 2, 3, 6, 9 and 12; ᵒᵒ Physician determined ‘unscheduled’ visits allowed at their discretion. • Cohort Two: ᵒᵒ Received open label 0.5 mg intravitreal ranibizumab; ᵒᵒ Injection at baseline then at the physicians discretion (no more frequently than every 30 days).

SAILOR Study Results Primary outcomes: • Cohort One: Mean of 8.8 visits requiring 4.6 injections; • Cohort Two: Mean of 4.9 visits requiring 3.6 injections; • Ocular safety: Key ocular adverse events occurred in < 1% of patients: ᵒᵒ 0.2% and 0.4% patients developed endophthalmitis in the 0.3 mg and 0.5 mg groups, respectively; ᵒᵒ Ocular inflammation rates were 1.0% in the 0.3 mg group, 1.5% in the 0.5 mg group and 0.5% in cohort two. • Non-ocular safety: ᵒᵒ 0.7% and 1.2% of patients had cerebrovascular accidents in the 0.3 mg and 0.5 mg groups, respectively; ᵒᵒ The incidence of other arterial thrombotic events was low and similar across groups; ᵒᵒ Rates of non-ocular side effects were lower in cohort two – likely due to under reporting and withdrawal from the trial.

•

Efficacy: ᵒᵒ In cohort one, VA was improved at three months in all groups, but declined from months 3 to 12; ᵒᵒ Gain of ≥ 15 letters BCVA: »» Cohort one at three months: 19.4% and 20.1% in the 0.3 and 0.5 mg groups, respectively; »» Cohort one at 12 months: 14.6% and 19.3% in the 0.3 and 0.5 mg groups, respectively.

Weaknesses This study has no control arm to compare visual outcomes to. As CVA is a relatively rare adverse event within a study, numbers were compared to epidemiological data which may not be equivalent population-wise (in fact the CVA rates in this trial were lower than untreated patients). This trial had relatively high rates of discontinuation (18% in cohort one and 50% in cohort two).

Key messages

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1. Intravitreal ranibizumab is safe for the treatment of neovascular AMD. 2. The risk of stroke was higher with 0.5 mg dosing regimens than with 0.3 mg regimens, though the number of events was small. 3. VA was improved in patients receiving ranibizumab at month 3 (when monthly injections have been given), but tended to decline to month 12 on a PRN regimen without scheduled monthly review.

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Ranibizumab vs. Bevacizumab for Neovascular Age-Related Macular Degeneration Inhibition of VEGF in Age-related Neovascularisation (IVAN) Study design: RCT

Evidence level: 1b

Ophthalmology 2012;119:1399-1411 | Lancet 2013;382:1258-1267.

Key questions 1. 2.

In the treatment of neovascular age-related macular degeneration (nAMD), is bevacizumab non-inferior to ranibizumab? Can a discontinuous regimen with careful regular observation and treatment when required result in non-inferior outcomes?

Aims Bevacizumab and ranibizumab are both monoclonal antibodies against vascular endothelial growth factor A (VEGF-A). Bevacizumab is a full-sized humanised immunoglobulin molecule, while ranibizumab is a high-affinity antibody fragment. Bevacizumab offered major cost savings compared to ranibizumab. This study, conducted in parallel with the Comparison of Age-related macular degeneration Treatments Trial (CATT) in the USA, aimed to collect robust data on the safety and efficacy of bevacizumab as compared to ranibizumab for nAMD, and compare a continuous and discontinuous regimen.

Copyright © 2017. Kugler Publications. All rights reserved.

Methods Design: Multi-centre, randomised, 2x2 factorial non-inferiority trial. Participants: Six hundred twenty-eight participants from 23 teaching hospitals in the United Kingdom. Inclusion criteria: • Age ≥ 50; 92

• • •

Previously untreated nAMD in study eye (confirmed with fluorescein angiogram (FA)); Visual acuity (VA) ≥ 25 letters on ETDRS chart (~20/320 Snellen); Subfoveal neovascularisation, subretinal fluid, or serous pigment epithelial detachment.

Exclusion criteria: • Lesions comprising > 50% fibrosis or blood. Groups: Drug allocation was masked. Participants were randomly assigned equally into four groups: 0.5 mg ranibizumab continuous, 0.5 mg ranibizumab discontinuous, 1.25 mg bevacizumab continuous, and 1.25 mg bevacizumab discontinuous. All participants had monthly assessment with optical coherence tomography. The continuous groups had monthly intravitreal injections, the discontinuous groups had 3x monthly intravitreal injections and had a further 3x monthly injections if there was subretinal fluid, intra-retinal fluid increasing or new blood, or if VA dropped ≥ ten letters or 25% circumference leakage or expansion on FA.

IVAN Primary outcome measure: VA. Secondary outcomes: Adverse events, quality of life, structural measures, others. Follow-up: Two years.

Results Primary outcome: In total, 610 received treatment, 525 reached the two-year visit. VA was similar between ranibizumab (67.8 letters) and bevacizumab (66.1), and between continuous (66.6) and discontinuous regimens (67.3), but the confidence interval included zero and the pre-specified margin of 3.5 letters so neither inferiority nor non-inferiority were demonstrated. Pooled data with CATT indicated a small but significant improvement in acuity with continuous regimen, and also confirmed non-inferiority of bevacizumab. Anatomical outcomes: Lesion thickness was greater in the discontinuous groups, and there was a greater likelihood of fluid

and persisting neovascularisation in the discontinuous groups. On the other hand, the risk of geographic atrophy was lower in the discontinuous group. Safety analysis: Ocular adverse events were rare in this study, with no endophthalmitis. The risk of death or arterial thrombosis or heart failure admission did not differ between groups. The discontinuous regimen was associated with a greater risk of death (OR 0.47, CI 0.22-1.03, P 0.05). Pooled analysis with CATT indicated a small but significant increased risk of death in the discontinuous group. Other outcomes: Amongst other outcomes, near vision and contrast sensitivity were worse in the discontinuous regimen. Quality-of-life measures did not differ by drug or regimen.

Weaknesses As in CATT, the assessment of geographic atrophy was suboptimal, using colour photography and FA, rather than current approach which uses both fundus autofluorescence and spectral-domain optical coherence tomography.

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Key messages 1. In the treatment of nAMD, intravitreal injections with bevacizumab are noninferior to ranibizumab. 2. A discontinuous regimen, treating with 3x monthly injections when needed, results in small deteriorations in the structural and functional outcomes. 3. Continuous regimens are associated with development of more geographic atrophy. 4. In general, there were no differences in safety between groups, but an unexplained small increased risk in death was observed in the discontinuous groups on meta-analysis with CATT.

93

Ranibizumab vs. Bevacizumab for Neovascular Age-related Macular Degeneration Comparison of Age-related macular degeneration Treatments Trial (CATT) Study design: RCT

Evidence level: 1b

New Engl J Med 2011;364:1897 | Ophthalmology 2012;119:1388.

Key questions 1. 2.

In the treatment of neovascular age-related macular degeneration (nAMD), is bevacizumab non-inferior to ranibizumab? Can an as-needed regimen with careful regular observation and treatment when required result in non-inferior outcomes?

Aims

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Monthly intravitreal injections of ranibizumab were shown to greatly improve outcomes in nAMD (ANCHOR, MARINA) but represented a costly and intensive new intervention for a common condition. Bevacizumab offered substantial cost savings, and it was felt that perhaps monthly injections were not always required. This study, conducted in parallel with the Inhibition of VEGF in Age-related Neovascularisation (IVAN) study, set out to assess the relative efficacy and safety of ranibizumab and bevacizumab and to determine whether an as-needed regimen would compromise long-term visual acuity (VA), as compared with a monthly regimen.

Methods Design: Multi-centre, randomised, non-inferiority trial. Participants: One thousand two hundred and eight participants were enrolled across 44 sites in the USA. Due to protocol deviations, all patients from one centre (23) were excluded (n = 1185). 94

Inclusion criteria: • Age ≥ 50; • Previously untreated nAMD in study eye (confirmed with fluorescein angiogram, FA), one eye enrolled; • VA 20/25 to 20/320 in study eye; • Subfoveal neovascularisation, subretinal fluid, blood, or serous pigment epithelial detachment. Groups: Drug allocation was masked. Participants were randomly assigned equally into four groups: 0.5 mg ranibizumab monthly, 0.5 mg ranibizumab as-needed, 1.25 mg bevacizumab monthly, and 1.25 mg bevacizumab as-needed. After 12 months, participants in the monthly groups were randomised to have their second year of treatment monthly or as-needed. All participants had monthly assessment with optical coherence tomography. The monthly groups had monthly intravitreal injections, the as-needed groups had intravitreal injections only if there was subretinal or intra-retinal fluid, new or persistent blood, decreased acuity, or leakage/lesion growth on FA. Primary outcome measure: VA.

CATT Secondary outcomes: Adverse events, quality of life, structural measures, others. Follow-up: Two years.

Results Treatment: In total, 1185 were enrolled received treatment, 1030 reached the two-year visit. The OCT reading centre detected fluid more often than treating ophthalmologists, resulting in some under treatment. VA: In those treated the same way for two years, final VA was similar. Improvements in acuity were greater with monthly regimen: ranibizumab monthly (+8.8 letters), bevacizumab monthly (+7.8), ranibizumab as-needed (+6.7) and bevacizumab as-needed (+5.0) (ranibizumab better by 1.4 letters, P = 0.21, monthly better by 2.4 letters, P = 0.046). Those who switched from monthly to as-needed injections at one year had intermediate outcomes at two years. The proportions with good vision and three-line improvements were very similar between all groups. Anatomical outcomes: Retinal thickness and FA leakage were less with monthly injections, and lesion area and persistent fluid were both less with both ranibizumab and monthly injection.

On the other hand, the risk of geographic atrophy was higher in the monthly treatment group. Safety analysis: Severe ocular inflammation (presumed endophthalmitis) occurred in in four (0.7%) ranibizumab- and seven (1.2%) bevacizumab-treated patients (P = 0.38) and ten of these 11 cases were monthly treated. The risk of death or arterial thrombosis did not differ between groups, but there was a significant difference in all serious systemic adverse events in the bevacizumab-treated groups (39.9% c.f. 31.7% ranibizumab, P = 0.004). This difference persisted after excluding all known adverse events associated with anti-VEGF treatment. Other outcomes: The mean number of injections received were 12.6 in the ranibizumab as-needed and 14.1 in the bevacizumab as-needed groups and 26 in monthly groups. The cost per patient varied from $705 in the bevacizumab as-needed group to $44 800 in the ranibizumab monthly group.

Weaknesses Assessment of geographic atrophy was made using colour photography and fluorescein angiography, when fundus autofluorescence and spectral domain optic coherence tomography are now optimal technologies: this may have resulted in confounding by other lesion components.

Copyright © 2017. Kugler Publications. All rights reserved.

Key messages 1. In the treatment of nAMD, intravitreal injections with bevacizumab are noninferior to ranibizumab. 2. An as-needed regimen, with monthly review, results in small deteriorations in the structural and functional outcomes. 3. Monthly regimens are associated with development of more geographic atrophy. 4. In general, there were no differences in safety between groups, but an unexplained increase in serious systemic adverse events was observed in the bevacizumab groups. 95

Intravitreal Afliberept (VEGF Trap-Eye) in Wet Agerelated Macular Degeneration (VIEW 1&2) Study design: RCT

Evidence level: 1b

Ophthalmology 2012;119: 2537-2548 | Ophthalmology 2014;121:193-201.

Key question 1. Is intravitreal aflibercept equivalent in efficacy to intravitreal ranibizumab therapy for wet age related macular degeneration (AMD) with regard to visual outcomes and safety profiles, and what is the optimal dosing regimen for aflibercept?

Aims To investigate the efficacy and safety of treatment with a monthly or two-monthly dosing regimen of aflibercept in eyes with neovascular AMD and compare this with monthly ranibizumab dosing.

Methods Design: Double-masked, multi-centre, randomised controlled trial.

parallel-group,

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Participants: Two thousand sixty-three patients completed 96 weeks of the trial across 362 sites including multiple countries (USA, Canada, Europe, the Middle East, Asia-Pacific and Latin America). Inclusion criteria: • Age ≥ 50 years; • Active subfoveal or juxtafoveal (with fluid at the fovea) choroidal neovascular membrane (CNVM) secondary to AMD; • CNVM comprising of at least 50% of the lesion of fluorescein angiogram; • Best corrected visual acuity (BCVA) 6/12 to 6/96; • Only one eye included per patient. Exclusion criteria: • Prior treatment for CNVM in the study eye. 96

Trial protocol: • Patients randomised 1:1:1:1 to groups: ᵒᵒ 0.5 mg Aflibercept four-weekly (0.5q4); ᵒᵒ 2 mg Aflibercept four-weekly (2q4); ᵒᵒ 2 mg Aflibercept eight-weekly (2q8); ᵒᵒ 0.5 mg Ranibizumab four-weekly (Rq4). • Patients were reviewed at baseline, then four-weekly including: BCVA, examination and OCT scanning. • Fundus photography and fluorescein angiogram were performed at baseline, 24 weeks and 52 weeks. • From 52 to 96 weeks – ongoing monthly review: ᵒᵒ Capped PRN dosing regimen – minimum 12-weekly injections; ᵒᵒ Re-treatment criteria: new or persistent fluid on OCT, increased central thickness of 100 microns, loss of five ETDRS letters, new onset classic CNVM or haemorrhage. Follow-up: Monthly follow-up over 96 weeks.

VEGF Trap-Eye | VIEW 1&2 Results

Weaknesses

•

1. The VIEW studies only included predominantly classic CNVM, which may behave differently to other subtypes which are commonly encountered in clinical practice 2. Weeks 52-96 were a capped PRN treatment regimen which is likely less effective than the bimonthly monthly regimen used in year 1.

•

•

Efficacy ᵒᵒ Both monthly and 2 monthly aflibercept non-inferior to monthly ranibizumab ᵒᵒ 91.5% to 92.4% of patients across all groups maintained stable VA (no significant differences) ᵒᵒ 28.1 to 33.4% of patients gained 15 letters or more across all groups (no significant differences) ᵒᵒ Mean increase BCVA was 7.9, 7.6, 6.6 and 7.6 letters in the Rq4, 2q4, 0.5q4 and 2q8 groups respectively ᵒᵒ At 96 weeks a significantly higher percentage of 2q4 patients had no fluid on OCT (5.7%) compared to 2q8 patients (10.4%) Number of injections (weeks 52-96) ᵒᵒ On post-hoc analysis patients in the 2q4 and 2q8 groups received fewer injections than the Rq4 group (4.1, 4.2 and 4.7 injections respectively) Safety: no significant differences were found between groups.

Key messages

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1. Aflibercept treatment dose of 2 mg is non-inferior to ranibizumab treatment with respect to visual outcomes. 2. Aflibercept treatment 2 mg four- or eight-weekly resulted in better OCT retinal thickness than four-weekly ranibizumab treatment. 3. The safety profiles of ranibizumab and aflibercept are similar, and both have low rates of significant adverse reactions.

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The Central Vein Occlusion Study - CVOS Study design: RCT

Evidence level: 1b

Arch Ophthalmol 1993;111:1087-1095 | Trans Am Ophthalmol Soc 1994;92:203 | Ophthalmology 1995;102:1425-1433 | Ophthalmology 1995;102:1434-1444 | Arch Ophthalmol 1997;115:486-491.

Key questions 1. 2. 3.

Does early pan-retinal photocoagulation (PRP) prevent iris neovascularisation in eyes with ischemic central retinal vein occlusion (CRVO)? How effective is PRP if it is delayed until significant anterior segment neovascularisation develops? Does argon macular grid laser improve visual acuity compared to control in CRVO?

Aims The BVOS study demonstrated the benefits of macular laser in the treatment of CMO secondary to BRVO. This study aimed to investigate whether laser could also be beneficial in CRVO. In addition, the role of PRP as prophylaxis for anterior segment neovascularisation was investigated.

Methods Design: Multi-centre, prospective, randomised clinical trial.

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Participants: Two concurrent trials were run: those at risk of vision loss from macular oedema (155 eyes), those with ischaemic CRVO at risk of developing anterior segment neovascularisation (ASNV) defined as two clock-hours of iris involvement or any angle involvement (181 eyes in total). Inclusion criteria (CMO): • BCVA between 20/50 and 5/200; • Angiographic evidence of centre-involving macular oedema; • CRVO of at least three months duration. Inclusion criteria (PRP): • CRVO duration less than 12 months; • No neovascularisation present on enrolment into the study; 98

•

Angiographic evidence of at least ten disc areas of retinal non-perfusion.

Exclusion criteria: • Absence of other ocular disease threatening visual acuity (VA); • Previous retinal vascular disease or retinal laser treatment; • Patients using systemic anticoagulants. Groups: In the CMO arm, patients were randomised to receive macular grid laser or observation. In the PRP group, patients were randomised to receive early PRP, or else close observation. Both groups would receive further or initial PRP if significant neovascularisation occurred. Re-treatment criteria: CMO was re-treated if there was angiographic leakage at the four-month visit and the patient had gained less than nine letters from baseline. Outcome measures (CMO): Change in VA from baseline at one, two and three years. Outcome measures (PRP): Percentage developing ASNV, or percentage of those whose ASNV regressed after PRP was applied.

CVOS Follow-up: Mean follow-up was three years in both groups.

Results Percentage achieving primary outcome (CMO): Grid macular laser did reduce angiographic leakage, however, there was no statistical difference in VA between the treatment and control groups at any time. Baseline VA was 20/160 in the treatment group and 20/125 in the control group. At three years, final VA was 20/200 and 20/160, respectively. Percentage achieving primary outcome (NV): Baseline characteristics of the two groups in the PRP side of the study featured statistically worse VA, more non-perfusion and more venous tortuosity. Of those receiving early treatment, 18/90 (20%) developed ASNV

compared with 32/91 (35%) of the observation group. Once baseline differences were adjusted for, this was not statistically significant (OR = 0.6; p = 0.17). In those who were treated with PRP subsequent to NV, observations at one month showed the NV regressed in 4/18 (22%) of the early treated group compared to 18/32 (56%) of the observation group (p = 0.02). A further 11% in each group regressed during the remainder of the study, leaving four patients in each group with persistent NV. Risk factors for NV: The most important risk factor identified was the total area of retinal non-perfusion at baseline. Of those with 10-29 disc areas of ischaemia, 16% developed NV compared to 52% of those with > 75 disc areas of ischaemia. Male sex, extensive haemorrhages and short duration of CRVO were other risk factors identified.

Key messages

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1. Prophylactic PRP decreased the risk of NV compared to observation. 2. However, there was no advantage to prophylactic PRP in the long term. 3. This study did not find evidence of benefit for macular gird laser in CMO secondary to CRVO.

99

The Branch Vein Occlusion Study - BVOS Study design: RCT

Evidence level: 1b

Am J Ophthalmol 1984;98:271-282 | Arch Ophthalmol 1986;104:34-41.

Key questions 1. 2.

Can macular grid argon laser improve visual acuity versus control when used in the treatment of macular oedema secondary to branch retinal vein occlusion (BRVO)? How does sectoral argon pan-retinal photocoagulation (PRP) compare with controls in preventing neovascularisation (NV) or vitreous haemorrhage (VH)?

Aims Visual morbidity from BRVO arises from cystoid macular oedema (CMO), macular ischaemia or later, vitreous haemorrhage. If prolonged, the macular oedema may cause permanent structural damage to the fovea persisting after the resolution of the vein occlusion. Prior to this study, no proven treatment existed for CMO secondary to BRVO.

Methods Design: Multi-centre, prospective randomised clinical trial

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Participants: Patients were enrolled into three groups: those at risk of vision loss from macular oedema (139 eyes), those at risk of developing NV and those with NV at risk of VH (401 eyes in total). Inclusion criteria (CMO): • Best corrected visual acuity (BCVA) less than 20/40; • Angiographic evidence of centre-involving macular oedema; • BRVO duration between three and 18 months. Inclusion criteria (sectoral PRP): • BRVO duration between three and 18 months; • Either five disc areas of retinal haemorrhages with no NV, or BRVO of any size with NV.

100

Exclusion criteria: • Absence of other ocular disease threatening VA; • Patients using systemic anticoagulants. Groups: Patients were eligible to participate in the sectoral PRP and CMO groups if they met both sets of criteria. In each part of the study, groups were randomised to receive active treatment (sectoral PRP, or macular grid laser) or control. Re-treatment criteria: CMO was re-treated if leaking was identified on repeat FFA four months after the initial treatment. Outcome measures (CMO): Those gaining at least two lines of Snellen VA. Outcome measures (sectoral PRP): Percentage developing NV, or % of those with existing NV who developed VH. Follow-up: Mean follow-up was three years in the CMO trial and 3.7 years in the sectoral PRP. study.

BVOS Results Percentage achieving primary outcome (CMO): Those who gained two or more lines at two consecutive visits were 65% in the treated group compared to 37% in the control group. Of those treated, 60% had VA of 20/40 or better at the three-year follow-up compared to 34% in the control group. Both of these were statistically significant at the 5% level. Percentage achieving primary outcome (NV): Of those treated, 19/160 (12%) subsequently developed NV as compared with 35/159 (22%) in the control group. In those who already had NV before randomisation, 12/41 (29%) of those treated developed a VH compared to 25/41 (61%) in the control group. Both of these were statistically significant at the 5% level.

Safety outcomes: The authors report a complication of sectoral retinal photocoagulation in only one case, i.e., pre-retinal fibrosis causing traction on the macula.

Weaknesses The study was not developed to determine suitable timings for treatment of macular oedema. Those presenting with vision > 20/40 were not studied, and the results of this trial are therefore not applicable for this group of patients. The study was not designed to evaluate VA in those treated with sector laser for the prophylaxis of NV or VH.

Key messages

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1. Argon grid macular laser is effective in improving VA in CMO secondary to BVRO. 2. The authors recommended observation in the first three months following BRVO as some patients’ CMO may improve spontaneously. 3. Sectoral PRP was established as the gold standard for preventing NV/VH in BRVO patients. 4. Despite its proven efficacy in preventing NV, the authors recommend that sectoral argon laser is only applied once NV is identified.

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The Standard Care vs. cOrticosteroid for Retinal vEin Occlusion (SCORE) - CRVO Study design: RCT

Evidence level: 1b

The SCORE Study Research Group, Study Report 5. Arch Ophthalmol 2009;127:1101-1114.

Key questions 1. How does intravitreal triamcinolone compare to observation for the treatment of macular oedema due to central retinal vein occlusion in terms of safety and efficacy? 2. Should 1 mg triamcinolone or 4 mg triamcinolone be used?

Aims The main aim was to assess whether intravitreal steroid injection (triamcinolone) was safe and effective in the treatment of macular oedema due to central retinal vein occlusion, compared to the previous standard of care (observation).

Methods Design: Multi-centre, prospective, randomised clinical trial.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Two hundred seventy-one eyes of 271 patients were randomised. Inclusion criteria: • Best corrected visual acuity (BCVA) between approximately 6/12 to 6/120; • Centre-involving macular oedema secondary to central retinal vein occlusion (CRVO); • Mean central retinal thickness (CRT) > 250 µm. Exclusion criteria: • Substantial cataract that estimated would decrease VA by three or more lines; • Previous macular laser within past 3.5 months; • Foveal atrophy; • Prior treatment with intravitreal corticosteroids.

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Groups: Patients were randomly assigned to receive 1 mg triamcinolone or 4 mg triamcinolone or standard care (observation). Re-treatment criteria: Patients in both triamcinolone groups could be re-treated at four-monthly intervals according to their original randomization. Main outcome measure: Gain in VA letter score of 15 or more from baseline to follow-up at 12 months. Follow-up: Thirty-six months.

SCORE - CRVO Results Percentage achieving primary outcome: At 12 months, the percentage of patients achieving 15 or more letters was 6.8% in the observation group, 26.5% in the 1 mg triamcinolone and 25.6% in the 4 mg triamcinolone group. Other results: At four months, the median decrease in OCT measured CRT was significantly greater in the 4mg triamcinolone group (196 μm) than the 1mg triamcinolone group (77 μm) and the observation group (125 μm). However by 12 months the percentage of patients with less than 250 μm central thickness was similar between the three groups. After month 24, a loss of 15 or more letters was noted in 48% of the observation group, compared to 30% in the combined triamcinolone groups. Number of treatments: The average number of injections in first 12 months were 2.2 for the 1 mg triamcinolone group and 2.0 in the 4 mg triamcinolone group.

Safety outcomes: The need for IOP lowering medication in the first 12 months was significantly higher in the 4 mg triamcinolone group (35%) compared to the 1 mg triamcinolone group (20%) and the observation group (8%). Among phakic eyes at baseline, the estimate of new lens opacity or progression of existing opacity at 12 months was 33% in the 4 mg intravitreal triamcinolone group, 26% in the 1 mg triamcinolone group and 18% in the observation group. Conclusion: At 12 months, there was a greater percentage of patients achieving the primary outcome in both triamcinolone groups compared to observation.

Weaknesses Follow-up in all groups beyond 12 months was low. At 24 months, the rate of follow-up was 50% in the observation group, 60% in the 1 mg triamcinolone group and 55% in the 4 mg triamcinolone group. At 36 months, the rates of follow-up were only 28%, 28% and 33%, respectively.

Copyright © 2017. Kugler Publications. All rights reserved.

Key messages 1. Intravitreal triamcinolone is superior to observation in the treatment of patients with vision loss secondary to macular oedema from CRVO. 2. At 12 months, the percentage of patients achieving 15 or more letters improvement was similar between the 1 mg and 4 mg triamcinolone groups. 3. One mg triamcinolone had a lower rate of IOP rise and cataract progression than the 4 mg triamcinolone group. 4. When using Kenalog formulation 40 mg/mL in clinical practice, it can be difficult to accurately measure and administer 1 mg (0.025 mL). Many clinicians compromise by administering 2 mg (0.05 mL) per injection.

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The Standard Care vs. cOrticosteroid for Retinal vEin Occlusion (SCORE) - BRVO Study design: RCT

Evidence level: 1b

The SCORE Study Research Group, Study Report 6. Arch Ophthalmol 2009;127:1115-1128.

Key questions 1. How does intravitreal triamcinolone compare to macular grid laser for the treatment of macular oedema due to branch retinal vein occlusion in terms of safety and efficacy? 2. Should 1 mg triamcinolone or 4 mg triamcinolone be used?

Aims The main aim was to assess whether intravitreal steroid injection (triamcinolone) was safe and effective in the treatment of macular oedema due to branch retinal vein occlusion, compared to the previous standard of care (macular grid laser).

Methods Design: Multi-centre, prospective, randomised clinical trial.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Four hundred eleven eyes of 411 patients were randomised. Inclusion criteria: • Best corrected visual acuity (BCVA) between approximately 6/12 to 6/120; • Centre-involving macular oedema secondary to branch retinal vein occlusion (BRVO); • Mean central retinal thickness (CRT) > 250 µm. Exclusion criteria: • Substantial cataract that estimated would decrease VA by three or more lines; • Previous macular laser within past 3.5 months; • Foveal atrophy; • Prior treatment with intravitreal corticosteroids.

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Groups: Patients were randomly assigned to receive 1 mg triamcinolone or 4 mg triamcinolone or standard care. Standard care consisted of grid photocoagulation if there was no dense macular haemorrhage or observation at 4 monthly intervals until the haemorrhages had cleared sufficiently to permit macular laser. Re-treatment criteria: Patients in all three groups could be re-treated at four-monthly intervals according to their original randomization. Main outcome measure: Gain in VA letter score of 15 or more from baseline to follow-up at 12 months. Follow-up: Thirty-six months.

SCORE - BRVO Results Percentage achieving primary outcome: At 12 months, there was no statistical difference in the percentage of patients achieving 15 or more letters between standard care (28.9%), 1 mg triamcinolone (25.6%) and 4 mg triamcinolone (27.2%). Other results: At 12 months, the decrease in OCT measured CRT was similar between all three groups. After month 12 through to month 36, the mean improvement in VA and improvement in OCT thickness was greater in the standard care group compared to both triamcinolone groups, although numbers were low. Number of treatments: The average number of treatments in first 12 months for the macular laser group was 1.5, 2.2 injections for the 1 mg triamcinolone group and 2.1 injections in the 4 mg triamcinolone group. Safety outcomes: The need for intraocular pressure (IOP)-lowering medication in the first 12 months was significantly higher in the 4 mg triamcinolone group (41%) compared to the 1 mg triamcinolone group (7%) and the standard care group (2%).

Among phakic eyes at baseline, the estimate of new lens opacity or progression of existing opacity at 12 months was significantly higher in the 4 mg intravitreal triamcinolone group (35%) than the 1 mg triamcinolone group (25%) which was significantly higher than the standard care group (13%). Conclusion: At 12 months, there was no significant difference between the three treatment groups in the primary outcome of 15 or more letter VA gain. Rates of IOP rise and cataract were highest in the 4 mg triamcinolone group.

Weaknesses Follow-up in all groups beyond 12 months to the end of the study was low. At 24 months, the rate of follow-up was 60% in the standard care group, 62% in the 1 mg triamcinolone group and 52% in the 4 mg triamcinolone group. At 36 months, the rates of follow-up were only 34%, 32% and 28%, respectively.

Key messages

Copyright © 2017. Kugler Publications. All rights reserved.

1. There is no benefit in using intravitreal triamcinolone in patients with macular oedema secondary to BRVO compared to the previous standard of care (macular grid laser). 2. The rates of IOP rise and cataract progression were highest in the 4 mg triamcinolone group.

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Dexamethasone for the treatment of Macular Edema following Retinal Vein Occlusion (GENEVA) Study design: RCT

Evidence level: 1b

Ophthalmology 2010;117:1134 | Ophthalmology 2011;118:2453.

Key questions 1. What are the effects of a single slow-release dexamethasone intravitreal implant compared to sham injection for the treatment of macular oedema due to retinal vein occlusion (RVO) in terms of rate of improvement, duration of effects, and safety? 2. Should 0.35 mg or 0.7 mg dexamethasone implant be used? 3. Is it worth treating cystoid macular oedema (CMO) with dexamethasone even after a six-month delay?

Aims Intravitreal injection of triamcinolone was shown to be effective for RVO in the SCORE studies. The drug-copolymer complex offers a slow release preparation of dexamethasone and was evaluated for its effects.

Methods Design: Two multi-centre, randomised, masked, sham injection-controlled studies.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: One thousand two hundred sixty-seven eyes were enrolled across 167 sites in 24 countries. Inclusion criteria: • Foveal involving macular oedema secondary to BRVO diagnosed within 12 months before study initiation or CRVO diagnosed within nine months before study initiation; • Best corrected visual acuity (BCVA) between approximately 20/50 to 20/200; • Mean central retinal thickness (CRT) > 300 µm. Exclusion criteria: • Significant ocular comorbidity (e.g., age-related macular oedema (AMD), diabetic retinopathy (DR)); 106

• • •

Active neovascularisation; Aphakia or anterior chamber intraocular lens; Ocular hypertension (OHT) or glaucoma requiring more than one medication to control intraocular pressure (IOP).

Groups: Patients were randomly assigned to receive one 0.35 mg or 0.7 mg dexamethasone implant or one sham injection at baseline and then all were observed for six months, followed by a six-month open-label extension. Main outcome measure: Time to reach a three or more EDTRS lines improvement. Follow-up: Six and 12 months.

GENEVA Results Primary outcome: There were no significantly significant differences between dexamethasone 0.35 mg and 0.7 mg at any time point. The treatment groups gained a > 15 letter improvement significantly faster than the sham group (p < 0.001). The peak effects of dexamethasone were seen at day 60, with 29% achieving a 15-letter improvement from baseline compared with 11% in the sham group, mean gain in letters was approximately ten letters (dexamethasone) compared to three letters (sham). At six months, this had fallen to 22% (0.7 mg), 19% (0.35 mg) and 18% (sham). Anatomical outcomes: The mean decrease in CRT was 208 µm ± 201 (dexamethasone 0.7 mg), 177 µm ± 197 (dexamethasone 0.35 mg) and 85 µm ± 173 (sham) at three months (p < 0.001), but failed to be statistically significant at six months. Safety analysis: There was significantly more OHT in the dexamethasone groups compared with sham (p < 0.002) and more neovascularisation in the sham group (p = 0.03). Differences in IOP were maximal at day 60 (> 15%

having > 10 mmHg increase in IOP) and had resolved by six months. In the 0.7 mg and 0.35 mg groups, 7.3% and 4.1% of eyes developed cataracts compared to 4.5% in the sham group (p = 0.08). Twelve-month outcomes: At the six-month stage, 997/1256 met the requirements for a dexamethasone implant injection. The proportions in each group were not significantly different. The peak improvement was similar with re-treatment with mean BCVA was approximately +10 letters and occurred at two months post-injection. In the sham-crossover group, mean improvement was +7 letters at two months.

Weaknesses The effects of the dexamethasone implant do not last six months and the VA of patients enrolled in this study began to deteriorate after two months post-injection which creates a ‘saw-toothed’ pattern of visual acuities over time. In modern clinical practice, dexamethasone implants are often required at three-monthly intervals, however, this may result in more cataract formation and raised IOP than in this study.

Copyright © 2017. Kugler Publications. All rights reserved.

Key messages 1. Intravitreal slow release dexamethasone implants are superior to sham injections in the treatment of patients with vision loss secondary to macular oedema from RVO. 2. Average improvement per injection was ten letters and the effect was maximal at two months post-injection. 3. There were no significant differences between the 0.35 mg and 0.7 mg groups. 4. Patients in the sham treatment group did receive a benefit when they were switched to dexamethasone, but the improvement was less pronounced.

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Ranibizumab for the treatment of Macular Edema after Central Retinal Vein Occlusion Study (CRUISE) Study design: RCT

Evidence level: 1b

Ophthalmology 2010;117:1124; Ophthalmology 2011;118:2041.

Key questions 1. How does intravitreal ranibizumab compare to sham injection for the treatment of macular oedema due to central retinal vein occlusion (CRVO) in terms of safety and efficacy? 2. Should 0.3 mg or 0.5 mg ranibizumab be used? 3. Is it safe to give ranibizumab on an as-needed basis? 4. Is it worth treating cystoid macular oedema (CMO) with ranibizumab even after a six-month delay?

Aims Elevated intraocular levels of vascular endothelial growth factor (VEGF) had been demonstrated in patients with retinal vein occlusion (RVO). The main aim was to assess whether intravitreal anti-VEGF was safe and effective in the treatment of macular oedema due to CRVO.

Methods Design: Multi-centre, randomised, double-masked, sham injection-controlled study.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Three hundred ninety-two eyes of 392 patients were enrolled across 95 centres in the USA. Inclusion criteria: • Foveal involving macular oedema secondary to CRVO diagnosed within 12 months before study initiation; • Best corrected visual acuity (BCVA) between approximately 20/40 to 20/320; • Mean central retinal thickness (CRT) > 250 µm.

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Exclusion criteria: • Significant ocular comorbidity (e.g., age-related macular oedema (AMD), diabetic retinopathy (DR)) or brisk afferent pupillary defect; • Previous scatter photocoagulation or macular laser within past three or four months; • Previous intravitreal steroid injection within past three months; • Prior VEGF-related treatment within six months. Groups: Patients were randomly assigned to receive 0.3 mg, 0.5 mg of ranibizumab or sham injection at monthly intervals for six months, followed by a period of observation for six months, during which ranibizumab could be given to either group ‘as-needed’. Each group was eligible for ‘rescue’ macular laser treatment, from months three and nine onwards. Main outcome measure: Mean change from baseline in best corrected VA. Follow-up: Six and 12 months.

CRUISE Results Primary outcome: After six months of treatment, gain in number of letters was 0.8 in the sham injection group compared to 12.7 and 14.9 letters in the 0.3 mg and 0.5 mg ranibizumab groups, respectively (p < 0.001). Other results: After treatment, 46.2% and 47.7% of patients receiving ranibizumab 0.3 mg and 0.5 mg gained > 15 letters compared to 16.9% in the sham injection group (p  20/40 were 43.9%, 46.9% and 20.8%, respectively.

Twelve-month outcomes: Mean number of ranibizumab injections during the six-month observation period was 3.8, 3.3 and 3.7 in the 0.3 mg, 0.5 mg and sham groups, respectively. There was no significant change in the VA of the original ranibizumab groups. The sham group had a significant improvement of VA gain of 7.3 letters from baseline and 33.1% achieving > 15 letter improvement, however, these remained significantly less than the other two groups.

Anatomical outcomes: After treatment, mean reduction in CRT was 167 µm in the sham injection group compared to 433 µm and 452 µm in the ranibizumab 0.3 mg and 0.5 mg respectively (p < 0.001). The percentage of those with a CRT of less than 250 µm at month 6 was 23.1% (sham) compared to 75.0% (0.3 mg) and 76.9% (0.5 mg).

Key messages

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1. Intravitreal ranibizumab is superior to sham injections in the treatment of patients with vision loss secondary to macular oedema from CRVO. 2. The 0.5 mg group consistently fared better than the 0.3 mg group, but the difference was neither statistically nor clinically significant. 3. VA did not decline significantly when patients were switched from receiving monthly ranibizumab to PRN treatment. 4. Patients in the sham treatment group did receive a benefit when they were switched to PRN ranibizumab, but the improvement was less pronounced.

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Ranibizumab for the treatment of Macular Edema following Branch Retinal Vein Occlusion (BRAVO) Study design: RCT

Evidence level: 1b

Ophthalmology 2010;117:1102; Ophthalmology 2011;118:1594.

Key questions 1. How does intravitreal ranibizumab compare to sham injection for the treatment of macular oedema due to branch retinal vein occlusion in terms of safety and efficacy? 2. Should 0.3 mg or 0.5 mg ranibizumab be used? 3. Is it safe to give ranibizumab on an as-needed basis? 4. Is it worth treating cystoid macular oedema (CMO) with ranibizumab even after a six-month delay?

Aims Elevated intraocular levels of vascular endothelial growth factor (VEGF) had been demonstrated in patients with retinal vein occlusion (RVO). The main aim was to assess whether intravitreal anti-VEGF was safe and effective in the treatment of macular oedema due to branch RVO (BRVO).

Methods Design: Multi-centre, randomised, double-masked, sham injection-controlled study.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Three hundred ninety-seven eyes of 397 patients were enrolled across 93 sites in the USA. Inclusion criteria: • Foveal involving macular oedema secondary to BRVO diagnosed within 12 months before study initiation; • Best corrected visual acuity (BCVA) between approximately 20/40 to 20/400; • Mean central retinal thickness (CRT) > 250 µm.

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Exclusion criteria: • Significant ocular comorbidity (e.g., age-related macular oedema (AMD), diabetic retinopathy (DR)) or brisk afferent pupillary defect; • Previous scatter photocoagulation or macular laser within past three or four months; • Previous intravitreal steroid injection within past three months; • Prior VEGF-related treatment within six months. Groups: Patients were randomly assigned to receive 0.3 mg, 0.5 mg of ranibizumab or sham injection at monthly intervals for six months, followed by a period of observation for six months, during which ranibizumab could be given to either group ‘as-needed’. Each group was eligible for ‘rescue’ macular laser treatment, from months 3 and 9 onwards. Main outcome measure: Mean change from baseline in BCVA. Follow-up: Six and 12 months.

BRAVO Results Primary outcome: After six months of treatment, gain in number of letters was 7.3 ± 13.0 in the sham injection group compared to 16.6 ± 11.0 and 18.3 ± 13.2 letters in the 0.3 mg and 0.5 mg ranibizumab groups, respectively (p < 0.001). Other results: After treatment, 55.2% and 61.1% of patients receiving ranibizumab 0.3 mg and 0.5 mg gained > 15 letters compared to 28.8% in the sham injection group (p < 0.001). Anatomical outcomes: After treatment, mean reduction in CRT was 157 µm ± 224 in the sham injection group compared to 522 µm ± 201 and 551 µm ± 223 in the ranibizumab 0.3 mg and 0.5 mg respectively (p < 0.001). The percentage of those with a CRT of less than 250 µm at month 6 was 45.5% (sham) compared to 91.0% (0.3 mg) and 84.7% (0.5 mg).

Twelve-month outcomes: Mean number of ranibizumab injections during the six-month observation period was 2.8, 2.7 and 3.6 in the 0.3 mg, 0.5 mg and sham groups, respectively. There was no significant change in the VA of the original ranibizumab groups. The sham group had a significant improvement of VA gain of 12.1 letters from baseline and 43.9% achieving > 15 letter improvement, however these remained significantly less than the other two groups.

Weaknesses Macular grid laser had already been established as standard of care for CMO secondary to BRVO by the BVOS study, and should have been used for the control group rather than sham injections.

Key messages

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1. Intravitreal ranibizumab is superior to sham injections in the treatment of patients with vision loss secondary to macular oedema from BRVO. 2. The 0.5 mg group consistently fared better than the 0.3 mg group, but the difference was neither statistically nor clinically significant. 3. VA did not decline significantly when patients were switched from receiving monthly ranibizumab to PRN treatment. 4. Patients in the sham treatment group did receive a benefit when they were switched to PRN ranibizumab, but the improvement was less pronounced.

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Intravitreal Aflibercept for Macular Edema following Central Retinal Vein Occlusion (COPERNICUS & GALILEO) Study design: RCT

Evidence level: 1b

Ophthalmology 2012;119:1024 | A J Ophthalmol 2013;155:429 | Ophthalmology 2014;121:1414 | Br J Ophthalmol 2013;97:278 | A J Ophthalmol 2014;158:1032 | Ophthalmology 2014;121:202.

Key questions 1. 2. 3.

How does intravitreal aflibercept compare to sham in the treatment of macular oedema due to central retinal vein occlusion (CRVO) in terms of safety and efficacy? Is it safe to give aflibercept on an as-needed basis? Is it worth treating CMO with aflibercept even after a six- or 12-month delay?

Aims These two parallel studies aimed to assess whether intravitreal aflibercept was safe and effective in the treatment of macular oedema due to CRVO.

Methods Design: Multi-centre, randomised, double-masked, sham injection-controlled study.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: Copernicus: 187 eyes across 70 sites in US, Canada, Israel, Argentina, India and Columbia. Galileo: 177 eyes across 63 sites in Austria, France, Germany, Hungary, Italy, Latvia, Australia, Japan, Singapore and South Korea. Inclusion criteria: • Foveal involving macular oedema secondary to ischaemic/non-ischaemic CRVO diagnosed within nine months before study initiation; • Best corrected visual acuity (BCVA) between approximately 20/40 to 20/320; • Mean central retinal thickness (CRT) > 250 µm. Exclusion criteria: • Significant ocular comorbidity (e.g., age-related 112

• •

macular oedema (AMD), diabetic retinopathy (DR)) causing decreased VA; Previous scatter photocoagulation or macular laser; Previous intravitreal steroid injection or anti-vascular endothelial growth factor (aVEGF) treatment to the study eye.

Groups: Patients were randomly assigned (on 3:2 basis) to receive 2 mg of aflibercept or sham injection at monthly intervals for six months. Main outcome measure: Proportion of patients gaining three or more EDTRS lines. Follow-up: Six months (methodology identical between two studies), subsequently the studies were extended. Copernicus introduced PRN aflibercept to the sham group from six months onwards and reported on outcomes at 12 and 24 months; Galileo continued sham until 12 months and then allowed PRN aflibercept. Outcomes were reported at 12 and 18 months. The treatment groups continued to receive aflibercept PRN, but at less-than-monthly observation.

COPERNICUS & GALILEO Results Primary outcome: After six months of treatment, those gaining three or more lines of letters in the treatment groups (Copernicus = 57.9%, Galileo = 60.2%) was significantly more than the sham groups (12.3% and 22.1% respectively). Mean change in VA in the treatment groups (Copernicus = +17.3, Galileo = +18.0) was significantly more than in the sham groups (-4 letters and +3.3 letters, respecti­ vely). Other results: The outcomes for perfused vs. non-perfused CRVO treated with aflibercept were very similar, letters gained in the perfused group (Copernicus = +17.1, Galileo = +17.8) compared with the non-perfused group (Copernicus = +17.8, Galileo = +19.6).

Extended outcomes: In the Copernicus trial, change in VA from baseline in the treatment group was +16.2 at one year and +13.0 at two years compared with +3.8 and +1.5 in the shamcross-over group. In Galileo, change in VA from baseline in the treatment group was +16.9 at one year and +13.7 at 18 months compared with +3.8 and +6.2 in the sham/ sham-cross-over group.

Weaknesses By the time of this study, aVEGF treatment was established for RVO. Sham injections did not represent a standard of care.

Anatomical outcomes: At six months, mean difference in CRT between treatment and sham groups was 312 µm (Copernicus) and 279 µm (Galileo) (p < 0.001).

Key messages

Copyright © 2017. Kugler Publications. All rights reserved.

1. Intravitreal aflibercept is superior to sham injections in the treatment of patients with vision loss secondary to macular oedema from CRVO. 2. VA did not decline significantly when patients were switched from receiving monthly aflibercept to less-than-monthly PRN treatment, but did start to decline slightly from one year onwards. 3. Patients in the sham treatment group did receive a benefit when they were switched to PRN aflibercept, but the improvement was less pronounced.

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Intravitreal Aflibercept Injection for Macular Edema following Branch Retinal Vein Occlusion (VIBRANT) Study design: RCT

Evidence level: 1b

Ophthalmology 2015;122:538.

Key question 1.

How does intravitreal aflibercept compare to macular grid laser for the treatment of macular oedema due to branch retinal vein occlusion (BRVO) in terms of safety and efficacy?

Aims This study aimed to assess whether intravitreal aflibercept was safe and effective in the treatment of macular oedema due to BRVO or hemi-retinal vein occlusion (HRVO) compared to macular grid laser.

Methods Design: Multi-centre, randomised, double-masked, controlled study.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: One hundred eighty-three eyes of 183 patients were enrolled across 58 centres in North America and Japan. Inclusion criteria: • Foveal involving macular oedema secondary to BRVO or HRVO diagnosed within 12 months before study initiation; • Best corrected visual acuity (BCVA) between approximately 20/40 to 20/320. Exclusion criteria: • Significant ocular comorbidity (e.g., age-related macular oedema (AMD), diabetic retinopathy (DR)) causing decreased VA; • Previous scatter photocoagulation or macular laser;

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•

•

Previous intravitreal steroid injection or anti-vascular endothelial growth factor (aVEGF) treatment to the study eye; Intraocular surgery within three months or vitreoretinal surgery within 12 months.

Groups: Patients were randomly assigned to receive 2 mg of aflibercept on a four-weekly basis from baseline to week 20 and a sham laser treatment. The control group received macular laser at baseline and sham injections every four weeks. From week 12 onwards, both groups were permitted rescue treatment of further laser. Main outcome measure: Proportion of patients gaining three or more EDTRS lines. Follow-up: Six months.

VIBRANT Results Primary outcome: After six months of treatment 26.7% of the last group gained three lines of EDTRS letters compared to 52.7% in the aflibercept group (p < 0.001). Mean change in letters from baseline was +6.9 letters in the laser group compared to 17.0 letters in the aflibercept group (p  26 mm; ᵒᵒ SE > -6D; ᵒᵒ Presence of posterior changes consistent with pathological myopia; ᵒᵒ Active leakage from CNV; ᵒᵒ Increase in central retinal thickness (CRT), intraor sub-retinal fluid. 116

Involvement of the central macular area by subfoveal/juxtafoveal/extrafoveal/peripapillary CNV; Best corrected visual acuity (BCVA) between approximately 20/32 to 20/320; Vision loss only due to the presence of myopia related CNV.

Exclusion criteria: • Presence of CNV secondary to any other cause than pathological myopia; • Previous pan-retinal or focal/grid macular laser; • Previous anti-vascular endothelial growth factor (aVEGF) or verteporfin photodynamic therapy (vPDT) to the study eye at any time; • Intraocular steroids or surgery within three months. Groups: Patients were randomly assigned (2:2:1 protocol) to receive 0.5 mg of ranibizumab guided by either VA stabilization criteria (group 1) or disease activity criteria (group 2), compared with vPDT with ranibizumab allowed from month 3 onwards (group 3). All patients received sham injections or sham PDT in conjunction with the study treatment.

RADIANCE Main outcome measure: Mean change from baseline in BCVA. Follow-up: Three, six and 12 months.

Results Primary outcome: After three months of treatment, both ranibizumab groups demonstrated significantly greater gain in number of EDTRS letters: group 1 = +10.5 letters ± 8.2; group 2 = +10.6 letters ± 7.3; group 3 = +2.2 letters ± 9.5 (p < 0.001).

Other results: The mean number of injections given over 12 months to the VA-guided treatment arm was higher than the disease activity guided group (4.6 injections vs. 3.5), this was not statistically tested. Anatomical outcomes: Mean reduction in CRT at three months was 61 µm in group 1 (66 µm at 12 months), 77 µm in group 2 (71.3 µm at 12 months), 12 µm in group 3 (61 µm at 12 months). Twelve-month outcomes: After 12 months of treatment, both ranibizumab groups demonstrated significantly greater gain in number of EDTRS letters: group 1 = +13.8 letters ± 11.4, group 2 = +14.4 letters ± 10.2, group 3 = +9.3 letters ± 11.3 (not statistically tested).

Key messages

Copyright © 2017. Kugler Publications. All rights reserved.

1. Intravitreal ranibizumab is superior to vPDT in the treatment of patients with myopic macular choroidal neovascular membranes. 2. There were no differences in efficacy between the two ranibizumab dosing regimens. The authors suggest that basing re-treatment decision on OCT findings is a more sensitive approach and may provide similar benefit, with fewer injections. 3. Patients in the vPDT group did receive a benefit when they were switched to PRN ranibizumab, but the improvement was less pronounced.

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Intravitreal Aflibercept in Myopic Choroidal Neovascularization (MYRROR) Study design: RCT

Evidence level: 1b

Ophthalmology 2015;122:1220.

Key questions 1. How does intravitreal aflibercept 2 mg compare to sham injections for the treatment of macular choroidal neovascularisation in terms of safety and efficacy? 2. Should ranibizumab re-treatment decisions be guided by visual acuity (VA) or OCT findings? 3. Is it worth treating myopic choroidal neovascularisation (CNV) with aflibercept even after a six-month delay?

Aims Myopic CNV develops in 5-10% of those with pathological myopia. Aflibercept was evaluated for its efficacy in CNV secondary to myopia subsequent to its use in AMD becoming well-established.

Methods Design: Multi-centre, randomised, double-masked, sham-controlled study.

Copyright © 2017. Kugler Publications. All rights reserved.

Participants: One hundred twenty-two eyes of 122 patients were enrolled across 20 centres across Hong Kong, Japan, South Korea, Singapore and Taiwan. Inclusion criteria: • Diagnosis of active CNV secondary to pathological myopia, based on: ᵒᵒ Axial length (AL) >26.5 mm; ᵒᵒ spherical equivalent (SE) > -6D; ᵒᵒ Active leakage from CNV; ᵒᵒ Increase in central retinal thickness (CRT), intraor sub-retinal fluid. • Involvement of the central macular area by subfoveal/juxtafoveal CNV; • Best corrected visual acuity (BCVA) between approximately 20/40 to 20/200; 118

•

Vision loss only due to the presence of myopia related CNV.

Exclusion criteria: • Only eye; • Recurrent myopic CNV; • Aphakic or pseudophakic eyes; • Presence of CNV secondary to any other cause than pathological myopia. Groups: Patients were randomly assigned (3:1 protocol) to receive 2 mg of aflibercept or sham injections. Additional aflibercept injections were given to the treatment arm in case of CNV persistence or recurrence at monthly evaluations. All patients in the sham arm received one injection of aflibercept at 24 weeks, thereafter receiving monthly sham injections (if no disease activity) or aflibercept (if disease activity). Main outcome measure: Mean change from baseline in BCVA. Follow-up: Twenty-four and 48 weeks.

MYRROR Results Primary outcome: At week 24, the treatment group had gained 12.1 letters compared to the sham group losing 2 letters (p < 0.001). At week 48, the treatment group were 13.5 letters better than baseline compared to a gain of 3.9 letters in the sham-crossover group (p < 0.001). Other results: The treatment group had on average two injections within the first eight weeks. Thereafter an average of 2.2 further injections were given. Once the sham group were started on aflibercept, they received on average three injections in 24 weeks.

Anatomical outcomes: Mean reduction in CRT at 24 weeks was 80 µm in the treatment group compared to 14 µm in the sham group (p < 0.001). At week 48, these became 86 µm and 74 µm respectively (p = 0.39).

Weaknesses Unlike the RADIANCE study, in this case aflibercept was compared to sham injections rather than verteporfin. The authors state that PDT was not an established therapy for myopic CNV in Japan which was the principle country of this study. This study investigated an east Asian population, where myopia and its sequelae are especially prevalent.

Key messages

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1. Intravitreal aflibercept is superior to sham in the treatment of patients with myopic macular choroidal neovascular membranes (CNVM). 2. Patients in the sham group did receive a benefit when they were switched to aflibercept, but the improvement was less pronounced.

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Efficacy and Safety of Verteporfin Photodynamic Therapy in Combination with Ranibizumab or Alone Versus Ranibizumab Monotherapy in Patients with Symptomatic Macular Polypoidal Choroidal Vasculopathy (EVEREST) Study design: RCT

Evidence level: 1b

Retina 2012;32:1453-1464.

Key question 1.

What are the effects of intravitreal ranibizumab monotherapy vs. verteporfin photodynamic therapy (vPDT) vs. combined therapy in the management of symptomatic macular polypoidal choroidal vasculopathy (PCV?)

Aims To determine the optimal management of PCV. VPDT and anti-vascular endothelial growth factor (aVEGF) agents had previously been trialled in small studies, but this was the first randomised controlled trial to investigate the effects of each.

Methods

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Design: Multi-centre, randomised, double-masked, sham-controlled, six-month trial in Asian patients with symptomatic macular PCV. Participants: Sixty-one patients were enrolled from seven sites across Hong Kong, Singapore, South Korea, Taiwan and Thailand. Inclusion criteria: • Age ≥ 18 years; • Visual acuity (VA) 6/12 to 6/96; • Greatest linear dimension of the lesion < 5400 µm; • PCV confirmed by indocyanine green (ICG) angiography. 120

Exclusion criteria: • Previous treatment with verteporfin, anti-angiogenic drug therapy, or other age-related macular oedema (AMD) treatments; • History of angioid streaks, presumed ocular histoplasmosis syndrome (POHS), pathological myopia, retinal pigment epithelium (RPE) tear, retinal detachment or macular hole. Groups: Patients were randomly assigned 1:1:1 to receive vPDT (6 mg/m2) + ranibizumab 0.5 mg, vPDT (6 mg/m2) + sham injection, or ranibizumab 0.5 mg + sham PDT. Both vPDT and ranibizumab were administered as per protocol-specific re-treatment criteria. Primary outcome measure: Polyp regression as determined by ICG angiography. Follow-up: Six months.

EVEREST Results Primary outcomes: The proportion of patients with complete regression of polyps at six months were 78%, 71% and 28% in the combined group, PDT-only and aVEGF-only groups respectively. Both the PDT groups were statistically significant compared with the aVEGF-only group. VA: The mean change in BCVA over the six months were +11, +7.5 and +9 in the combined group, PDT only and aVEGF only groups respectively. The proportion of patients gaining > 15 letters were 21%, 19% and 33%, respectively. The study was not sufficiently powered to detect a statistically significant difference in VA outcomes.

Anatomical outcomes: The mean change in CRT over the six months were -145 µm, -98 µm and -66 µm in the combined group, PDT-only and anti-VEGF-only groups, respectively. Safety outcomes: No patient lost more than 15 letters. The most common ocular adverse event was retinal haemorrhage which occurred in 10%, 14% and 0% in the combined group, PDT-only and aVEGF-only groups, respectively.

Weaknesses The study was not powered to detect differences in VA. The long-term outcomes are uncertain as the results were collected at six months.

Key messages

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1. Verteporfin therapy was more successful than ranibizumab monotherapy in regression of choroidal polyps. 2. The visual outcomes were comparable between the three groups at six months.

121

Microplasmin for Intravitreous Injection – Traction Release without Surgical Treatment (MIVI-TRUST) Study design: RCT

Evidence level: 1b

N Eng J Med 2012;367:606.

Key questions 1. Can ocriplasmin intravitreal injections induce posterior vitreous detachment? 2. Can ocriplasmin intravitreal injections treat vitreo-macular traction and macular holes? 3. What are the side effects of ocriplasmin?

Aims Ocriplasmin is a recombinant protease which degrades fibronectin and laminin which are molecular components of the vitreoretinal interface. This study aimed to examine whether ocriplasmin would provide a non-surgical alternative to inducing posterior vitreous detachment (PVD), and furthermore whether this could treat diseases of vitreo-macular traction (VMT) and macular hole (MH).

Methods

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Participants: Two multi-centre, double-masked, randomised, placebo-controlled trials were conducted. Inclusion criteria (unless stated otherwise): • Age > 18 years; • Vitreous adherence to the central 6 mm of the macula as demonstrated on OCT with focal elevation of the retina; • Best corrected visual acuity (BCVA) of 20/25 or less in the study eye; • BCVA of 20/800 or more in the other eye. Exclusion criteria: • Clinical conditions including: proliferative diabetic retinopathy, neovascular age related macular degeneration (nAMD), retinal vascular occlusion (RVO), aphakia, myopia < -8D, uncontrolled 122

• •

glaucoma, macular hole > 400 µm in diameter, vitreous opacification, lenticular or zonular instability or a history of retinal detachment; Prior vitrectomy, laser photocoagulation of the macular; Ocular surgery, intravitreal injection or retinal laser photocoagulation within the previous three months.

Groups: Six hundred fifty-two patients were randomised to receive ocriplasmin (125 ug in 0.1 ml) or 0.1 ml of saline. Primary endpoint: Percentage of eyes with resolution of VMT by 28 days (determined by OCT). Secondarily, percentage of eyes with PVD at 28 days (determined by B-scan ultrasonography), number of patients requiring vitrectomy, change in baseline BCVA, and closure of macular holes.

MIVI-TRUST Results Resolution of VMT: At 28 days, 26.5% of ocriplasmin patients had resolution of their VMT compared to 10.1% in the placebo group (p < 0.001).

Pars plana vitrectomy: At six months, 17.7% of ocriplasmin patients had required a pars plana vitrectomy compared to 26.6% in the placebo group (p = 0.02).

Resolution of PVD: At 28 days, 13.4% of ocriplasmin patients had resolution of PVD compared to 3.7% in the placebo group (p <  .001).

Epiretinal membrane: A subgroup analysis based on the presence or absence of epiretinal membrane showed resolution of VMT in 37.4% (ocriplasmin) vs. 14.3% (placebo) when epiretinal membrane was absent, compared with 8.7% vs. 1.5% when epiretinal membrane was present.

Closure of MH: At 28 days, 40.6% of ocriplasmin patients had resolution of their MH compared to 10.6% in the placebo group (p  6 D or hypermetropia or astigmatism > 3 D in affected eye; IOP > 30 mmHg at any stage or angle closure; Medications that might cause retinal or optic nerve toxicity (e.g., ethambutol); Hypertension, diabetes, or corticosteroid treatment within six months.

Groups: Participants were randomised to receive one of three treatments in 1:1:1 ratio: (1) the IVMP group received intravenous methylprednisolone 250 mg every six hours for three days followed by 11 days of oral prednisone at 1 mg per kg body weight; (2) the oral group received 14 days of oral prednisone at 1 mg per kg body weight; (3) the placebo group received 14 days of placebo in equivalent tablets to the oral group. After the 14 days, the prednisone dose was tapered to 20 mg for day 15 and 10 mg for day 16 and 17. Primary endpoint: VF, contrast sensitivity at six months (15 years reported).

ONTT Secondary endpoints: Visual acuity (VA), colour vision, complications of treatment, recurrent optic neuritis and development of MS.

Results Presenting features: Ninety-two percent had ocular pain, and 35% had optic disc swelling. There was a wide range of presenting VA and field defects. Approximately one third were at least 20/40 and one third were 20/200 or worse. Median logMAR acuity was 0.56, and 11% had normal acuity (at least 20/20). The great majority (over 95%) had abnormal colour or contrast sensitivity. Field defects were diffuse in 45% and any pattern of defect was observed (a central or centrocecal scotoma was observed in only 15%). Only 6% had an existing diagnosis of MS. Recovery of vision: All groups improved well, but the IVMP group improved faster than placebo (by acuity, field, colour or contrast sensitivity). At six months, subtle differences in the final field defect or likelihood of normal visual function were of borderline statistical significance but unlikely to be of clinical significance. The oral group had no difference in recovery to the placebo group.

Recurrent optic neuritis: At two years, 13% of the IVMP group had a recurrence, compared to 16% of the placebo group and 30% of the oral group. Unexpectedly, the oral group had a significantly higher rate of recurrence than the other two groups (RR 1.9, p = 0.02). Development of MS: At two years, 7.5% of the IVMP group had definite MS, compared to 16.7% of the placebo group and 14.7% of the oral group. The IVMP group had a temporarily reduced rate of definite MS at two years (RR 0.34, P = 0.006), but the effect was lost at four years. The MRI findings at baseline were strongly predictive of the risk of developing further neurological symptoms and clinically definite MS. At all-time points the number of white matter lesions ≥ 3 mm predicted MS risk. At 15 years the overall risk of MS was 50% and those with no lesions at baseline had a risk of 25% while those with ≥ 3 lesions had a risk of 78%. Final disability was mild in 68% and baseline MRI findings did not predict disability. No other baseline characteristics were major predictors of MS but in those with no MRI lesions, women had a greater risk of developing MS, especially in the absence of disc oedema.

Weaknesses The study design was strong, however, the study was not designed to test the most important post-hoc findings: that IVMP reduces the development of MS while oral steroids increase the risk of recurrence.

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Key messages 1. Intravenous steroids accelerate recovery but do not affect final visual outcome in optic neuritis. Intravenous steroids have a temporary effect in reducing further demyelination symptoms (clinical MS) within two years. 2. Oral steroids at 1 mg/kg should not be used as there was an unexpected increase in recurrent optic neuritis in the first two years. 3. Baseline MRI findings predict the risk of developing MS in future.

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Interferon-β1a for Optic Neuritis: The Controlled High-risk subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) Study design: RCT

Evidence level: 1b

All demyelination ‒ New Engl J Med 2000;343:898 | Optic neuritis ‒ Am J Ophthalmol 2001;132:463.

Key question 1. In people presenting with typical optic neuritis and MRI findings indicating a risk of multiple sclerosis (MS), will early disease-modifying treatment with interferon β-1a prevent or delay development of definite MS?

Aims The CHAMPS was conducted to determine whether treatment with weekly intermuscular injections of interferon β-1a in patients with their first demyelinating event and MRI evidence of prior subclinical demyelination in the brain reduced the incidence of further symptoms and clinically defined MS. The half of the participants who presented with isolated optic neuritis, were reported separately.

Methods

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Participants: Of 383 CHAMPS participants, 192 presented with acute optic neuritis at 50 centres in the USA and Canada. Mean age was 34 years, 80% were female, and 85% were white. Inclusion criteria: • Acute unilateral optic neuritis; • Age 18-50 years; • Relative afferent pupil defect (RAPD) and visual field (VF) defect present; • ≥ 2 clinically silent brain MRI lesions ≥ 3 mm typical of MS. Exclusion criteria: • Visual symptoms > 14 days before steroid treatment; 128

• •

History or evidence of recurrent optic neuritis (disc pallor); Ocular findings suggesting another cause (vitreous cells 1+, macular exudates, iritis).

Groups: All participants received intravenous methylprednisolone 1 g/d for three days followed by 11 days of oral prednisone at 1 mg/kg/d and a rapid 4 day taper to stop. During steroid treatment, participants were randomised to receive weekly intramuscular injections of interferon β-1a 30μg or placebo, starting within 27 days of symptoms and treatment was planned to continue for three years. Primary endpoint: Clinically definite MS by the Poser criteria. Secondary endpoints: Brain MRI findings at six, 12 and 18 months. Follow-up: The study was stopped early, 22 months after the final enrolment, because treatment efficacy had been demonstrated in the larger study.

CHAMPS Results Baseline differences: The two groups were well-balanced in demographic factors, but there was a greater volume of MRI lesions and more gadolinium enhancing lesions in the interferon β-1a group. This would have biased the findings against the treatment, so the adjusted statistics gave a more favourable effect to the treatment group. Completion of follow-up was similar. Effect of interferon β-1a on development of clinically definite MS: After an average of 31 months follow-up (minimum 22 months), the rate of clinically definite MS was 28% in the interferon β-1a group and 37% in the placebo group (adjusted rate ratio 0.58, p = 0.05). The secondary outcome combining MRI findings with clinical MS occurred in 61% of the interferon β-1a and 75% of the placebo group (adjusted rate ratio 0.50, p < 0.001). The effect of treatment was very similar in subgroups of gender, age, and MRI findings. Effect of interferon β-1a on brain MRI lesions: Noting that those patients who converted to clinical MS departed from the study protocol to receive necessary investigation and other treatments, there was an additional benefit of interferon β-1a amongst those who did not develop MS. Increments in lesion volume as well as the number of new lesions, were both reduced by treatment with interferon β-1a compared to placebo (p = 0.02 and p < 0.001, respectively).

Safety: Interferon β-1a was associated with a influenza-like syndrome in 54% during the first six months (compared to 26% in placebo group, p < 0.001). These were typically off-set by giving oral steroid, paracetamol (ace­ taminophen) and non-steroidal anti-inflammatories. Depression was also more common in the interferon β-1a group (20%, compared to 13%, p = 0.05). Serious adverse events occurred in 12 interferon β-1a participants and 19 placebo participants (none related to treatment), and discontinuation of treatment occurred in one interferon β-1a participant and seven placebo participants.

Weaknesses The study was terminated early following positive results as assessed by the Independent Data Monitoring Committee. Therefore, though it was powered for the larger patient group, the early closure meant that the outcomes in the optic neuritis subgroup were of borderline significance and shortened follow-up. The study was not powered to detect benefits to overall function or quality of life from interferon β-1a, which is important given that treatment involved weekly injections and flu-like side effects.

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Key messages 1. Amongst patients presenting with acute optic neuritis and MRI evidence of demyelination, weekly intramuscular interferon β-1a resulted in a lower rate of clinically definite MS and lower burden of brain MRI lesions. 2. A prognostic MRI scan and discussion about early treatment to prevent MS is now warranted in patients presenting with typical isolated acute optic neuritis.

129

Interferon-β1a for Optic Neuritis: The Early Treatment of Multiple Sclerosis Study (ETOMS) Study design: RCT

Evidence level: 1b

Lancet 2001;357:1576 | Lancet 2004;364:1489.

Key question 1. In people presenting with typical optic neuritis and MRI findings indicating a risk of multiple sclerosis (MS), will early disease-modifying treatment with interferon β-1a prevent or delay development of definite MS?

Aims The ETOMS study was a double-blind, placebo-controlled trial to determine whether low dose interferon β-1a treatment for patients with their first demyelination event and MRI evidence of prior subclinical demyelination in the brain reduced the conversion to clinically definite MS. The main differences to CHAMPS were: (1) participants did not receive high-dose steroid treatment; (2) the interferon β-1a dose was lower; and (3) the presenting syndrome was more often multifocal and with more MRI lesions, suggesting greater risk of MS.

Methods

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Participants: Three hundred and nine participants were recruited from 57 centres in 14 European countries. Ninety-eight (32%) had optic neuritis, although 39% had multifocal symptoms at presentation. The mean age was 28 years, 64% were female. Inclusion criteria: • First neurological episode consistent with MS within the last three months; • Age 18-40 years; • Neurological abnormality on examination; • ≥ 4 white matter MRI lesions typical of MS (three lesions if one infra-tentorial or enhancing with gadolinium). 130

Exclusion criteria: • Steroid treatment was only allowed if the event was functionally moderate or severe; • Other immunomodulatory treatments; • Intercurrent illnesses, experimental procedures, or psychiatric disorders; • Pregnancy, or unwilling to use contraception. Groups: Participants were randomised to receive weekly subcutaneous injections of interferon β-1a 22 μg or placebo for two years. Around 70% had received some steroids at presentation. Primary endpoint: Clinically definite MS (development of new symptoms or exacerbation of old symptom after stability, lasting 24 hours, without a fever, accompanied by a neurological abnormality on examination). Follow-up: Two years.

ETOMS Results Effect of interferon β-1a on development of clinically definite MS: After two years follow-up, the rate of clinically definite MS was 34% in the interferon β-1a group and 45% in the placebo group (adjusted odds ratio 0.61, p = 0.045). Only multifocal presentation and MRI with > eight lesions indicated an increased risk of MS within this high-risk cohort. The time for 30% of the cohort to develop MS was also prolonged in interferon β-1a group (569 days, compared to 252 days in the placebo group, p = 0.034). Effect of interferon β-1a on brain MRI lesions: The great majority of participants had development of a 10 mm white matter lesion, or three smaller lesions on MRI, which were the criteria for radiological conversion to MS, but the number of new lesions was smaller in the interferon β-1a group (2.0 compared to 3.0 in placebo group, p < 0.001) and the proportion without MRI activity was higher (16% compared to 6% in placebo group, p = 0.005). The volume of MRI lesions increased 8% in the placebo group and decreased 13% in the interferon β-1a group (p = 0.002).

Safety: Interferon β-1a was associated with more injection site inflammation (60% vs. 12%), fever (28% vs. 12%), myalgia (17% vs. 9%), and chills (11% vs. 5%). Serious adverse events occurred in < 2% of the interferon β-1a group and 2% of the placebo group.

Weaknesses The study did not present optic neuritis patients separate to the main group, and included patients at higher risk of MS than most who present with typical optic neuritis. That only 64% were females raises the issue of recruitment bias. The initial treatment for optic neuritis was not controlled or clearly reported. However, taken with the ONTT and CHAMPS findings these data support the use of interferon β-1a to reduce the likelihood of MS, but do not indicate a clear benefit for quality of life or function (including visual function).

Key message

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1. Amongst patients presenting with a clinically isolated syndrome and MRI evidence of demyelination, weekly intramuscular interferon β-1a resulted in a lower rate of clinically definite MS and lower burden of brain MRI lesions.

131

Interferon-β1b for Optic Neuritis: Betaferon/ Betaseron in Newly Emerging Multiple Sclerosis For Initial Treatment (BENEFIT) trial Study design: RCT

Evidence level: 1b

2y results ‒ Neurology 2006; 67:1242 | 3y disability ‒ Lancet 2007;370:389 | 5y open label extension ‒ Lancet Neurol 2009;8:987.

Key question 1. In people presenting with their first neurological event suggesting multiple sclerosis (MS) (a clinically isolated syndrome, including typical optic neuritis) with MRI findings of silent demyelination, will early disease-modifying treatment with interferon β-1b prevent or delay development of definite MS?

Aims CHAMPS and ETOMS demonstrated a protective benefit from interferon β-1a treatment for patients with a clinically isolated syndrome. The BENEFIT trial was conducted to investigate whether interferon β-1b given every other day was comparable.

Methods

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Participants: Four hundred sixty-eight participants were recruited from 98 hospitals in 18 European countries, Israel and Canada. Eighty (22%) had optic neuritis, although 47% had multifocal symptoms at presentation. The mean age was 30 years, 71% were female, 98% were white. Inclusion criteria: • First neurological episode consistent with MS in the last 60 days; • Age 18-45 years; • ≥ 2 clinically silent white matter T2 MRI lesions ≥ 3 mm (at least one infra-tentorial, ovoid or periventricular).

132

Exclusion criteria: • Severe disability at onset; • Other explanatory causes, history of possible previous demyelination, transverse myelitis or bilateral optic neuritis, or previous immunosuppressive treatment. Groups: Participants were randomised 5:3 to receive subcutaneous injections of interferon β-1b 250 μg or placebo every other day for two years. About 70% were on steroids at presentation. A dose-escalation protocol was used and paracetamol and ibuprofen were given in the first three months to minimize side effects. After two years, patients were offered an open-label extension on interferon β-1b out to five years, to investigate effects of delayed vs. early treatment. Primary endpoint: Time to clinically definite MS (modified Poser criteria: a new neurological event, progressive disability), or time to MS defined by the MacDonald criteria which uses paraclinical data to improve sensitivity of diagnosis.

BENEFIT Results Effect of interferon β-1b on development of clinically definite MS: After two years follow-up, the rate of clinically definite MS was 28% in the interferon β-1b group and 45% in the placebo group (hazard ratio 0.50, p < 0.0001). Using MacDonald criteria for MS, the rate was 69% in the interferon β-1b group and 85% in the placebo group (p < 0.00001). The effect was similar in all subgroups, but suggested more effect for those with active inflammation at presentation. After the prolonged open label extension (five years) the risk of clinical MS was 46% in the early treatment group and 57% in the delayed treatment group (HR 0.63, p = 0.003). That is, nine patients treated would prevent one case of clinically definite MS. The risk and disability scores appeared to converge during the extension phase when all participants were treated, but a benefit of early treatment remained. Effect of interferon β-1b on brain MRI lesions: There were fewer new or newly-active lesions in the interferon β-1b group, and the volume of enhancing lesions was less in the interferon β-1b group compared to the placebo group. The number of lesions declined in both groups from screening, but declined more in the interferon β-1b group.

Effect of interferon β-1b on disability: The likelihood of worsening disability was reduced by early treatment with interferon β-1b, as follow-up continued into the open label extension. The mean disability score did not change significantly in either group, because there was low disability at first event and a highly skewed distribution. Safety: Interferon β-1b was associated with more injection site inflammation (48% vs. 8.5%), and flu-like symptoms (44% vs. 18%). Both of these adverse events were much less common in the second year of treatment. Serious adverse events occurred in 6.8% of both groups. Five interferon β-1b recipients discontinued because of liver test abnormalities.

Weaknesses The study did not present optic neuritis patients separate to the main group, and included patients at higher risk of MS than most of those who present with typical optic neuritis. It is difficult to weigh the side effects of treatment against the low disability scores in the majority of patients; that is, even those who develop definite MS were not disabled by it.

Key message

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1. Amongst patients presenting with a clinically isolated syndrome and MRI evidence of demyelination, subcutaneous interferon β-1b every other day resulted in a lower rate of clinically definite MS and lower burden of brain MRI lesions.

133

International Optic Nerve Trauma Study (IONTS) Study design: Non-randomised comparison

Evidence level: 3

Ophthalmology 1999;106:1268.

Key question 1.

Does treatment with a very high dose of corticosteroids, extracranial optic canal decompression, or observation alone lead to better outcomes in indirect traumatic optic neuropathy (TON)?

Aims The IONTS was organized to investigate the optimal treatment for indirect TON. Although initially planned as a randomised trial between steroids and optic canal decompression with steroids, the IONTS had slow recruitment and was changed to an observational study, described as a comparative non-randomised intervention study with concurrent groups. The aim was to evaluate which treatment paradigm best improved visual function in indirect TON.

Methods

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Participants: Data were collected on 206 patients with optic nerve injuries from 16 countries, of whom 127 participants met the inclusion criteria. Mean age was 34 years (SD 18y), and 85% were male. Motor vehicle or bicycle accidents were the most common cause. Inclusion criteria: • Indirect (non-penetrating) optic nerve injury; • First visual assessment within three days of injury; • A minimal ocular examination was performed. Exclusion criteria: • The six bilateral cases were considered separately as numbers were too few. Groups: No protocol was enforced, the usual practice was followed and thus no consent was obtained. Treatment 134

group was defined as treatment received within seven days of injury. Nine had no treatment, 85 had steroids (of whom five had surgery after seven days) and 33 had optic canal decompression surgery (of whom 32 also received steroids). Steroid doses were categorized as mega-dose (≥ 5.4 g/day), very high dose (2.00-5.39 g­ ­ /­ day), high dose (500-1999 mg/day), moderate (100-499 mg/day) or low dose (< 100 mg/day). Primary endpoint: Visual acuity (VA) (arbitrary LogMAR values when vision off chart). Follow-up: Six months (but only 33% of each group achieved this follow-up).

IONTS Results Visual loss at presentation: Severe visual loss (acuity of hand movements or worse) was present in two thirds of patients. As expected, patients who received surgical decompression were more often NPL (no perception of light) (67% compared to 31% in steroid group) or PL (15% compared to 9% in steroid group).

group, 57% untreated, and 52% in steroid group (P = 0.22). Adjusting for baseline acuity there were no statistical differences in outcome, or in the likelihood of improvement, between groups. The likelihood of improving three lines was similar between steroid doses, or between patients receiving treatment earlier or later after the injury.

Treatment given: In the steroid group, 40% received mega-dose, 18% very high dose, 19% high, 9% moderate, and 6% low dose (8% dose unknown). Treatment was received within 24 hours of injury in 62%. In the surgical group, surgery included external ethmoidectomy (12, 36%), medial orbitotomy (four, 12%), endonasal (13, 39%) and craniotomy (three, 9%). Surgery was performed between 48 hours and seven days of injury in 63%. In addition, 32 surgical patients received steroids, at a similar dose distribution to the medical group.

Risk factors: In multiple subgroup and risk factor analyses, only baseline acuity predicted the likelihood of visual improvement or visual outcome. In those presenting with NPL the likelihood of improvement was 45% compared to 76% of those with vision.

VA outcome: The initial acuity predicted final acuity. A few patients improved from HM or worse to ≥ 6/12 with over one month of follow-up (one of three untreated, seven of 34 steroid group, none of 23 surgical group). With at least one month of follow-up, the proportion achieving a three-line improvement were 32% in the surgical

Weaknesses The study was obviously limited by the observational retrospective design, which would likely have resulted in some bias. The effect may have been to mask a benefit or a harmful effect of surgery or steroids by the selection the worst patients for surgical treatment. By retrospective design, this study could not show a causal effect. Having found no effect this may have reflected a ‘wash’ of two or more opposite factors. The study authors conclude that while randomised trials are needed, they are not feasible.

Key messages

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1. Choice of initial treatment was not strongly associated with visual outcome in this observational study. 2. Baseline acuity was the strongest predictor of outcome from indirect TON. The likelihood of improvement is low when the initial vision is very poor.

135

Corticosteroid Randomisation After Significant Head injury trial (CRASH) Study design: RCT

Evidence level: 1b

Two weeks ‒ Lancet 2004;364:1321 | Six months ‒ Lancet 2005;365:1957 | Prognostic models ‒ BMJ 2008;336:425.

Key question 1. In patients with significant head injury, does early treatment with intravenous steroids improve survival and long-term disability?

Aims Previous randomised trials of corticosteroids in spinal cord injury suggested a potential neuroprotective effect in CNS trauma (NASCIS 2 and 3 trials). The CRASH trial was a large international randomised placebo-controlled trial of the effect of early administration of 48-hour infusion of methylprednisolone on risk of death and disability after head injury. This is a common and serious clinical problem with substantial scientific uncertainty. Finding a change in outcomes would have the potential to decrease mortality and morbidity worldwide. Thus the study planned to recruit 20,000 participants to detect small benefits or harms. For ophthalmologists, this study was important for management of traumatic optic neuropathy (TON) as steroids are often used on a similar basis. The optic nerve is part of the central nervous system and TON commonly occurs in the context of a significant head injury.

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Methods Participants: Ten thousand and eight participants were recruited from 239 hospitals in 49 countries. Ethically approved local consent rules were followed in each hospital. Mean age was 37 years, 81% were men, and 40% had a severe head injury with GCS ≤ 8. The most common cause was road traffic accident (65%) and the most common CT scan findings were subarachnoid blood (31%), petechial haemorrhages (29%), non-evacuated haematoma (27%), and cortical contusion > 1 cm (23%). 136

Inclusion criteria: • Age > 16 years; • Presentation within eight hours of head injury; • Glasgow coma score (GCS) ≤ 14; • Substantial uncertainty of treating doctor if corticosteroids were indicated. Exclusion criteria: • Fair certainty that corticosteroids were indicated; • Fair certainty that corticosteroids were contra-indicated. Groups: Participants were randomised 1:1 to a masked treatment with intravenous methylprednisolone 2 g in 100 mL in one hour followed by 0.4 g/h infusion for 48 hours, or a placebo infusion. Primary endpoint: Death from any cause within two weeks of injury. Secondary endpoint: Death or disability at six months after injury. Follow-up: Six months.

CRASH Results Recruitment was terminated at 10,008 when the data safety monitoring committee detected a significant increase in risk of death in the steroid group. Effect of steroids on death within two weeks after head injury: Two weeks after injury, 21% of the steroid group had died, compared to 18% of the placebo group. The relative risk of death from any cause in the steroid group was 1.18 (95% CI 1.09-1.27, p = 0.0001). The relative effect of steroids on risk of death did not differ by injury severity or by duration from injury to randomization, or by CT-scan findings, or by the presence or absence of major extracranial injury. Effect of steroids on death or disability six months after head injury: Very few patients were lost to follow-up. In the steroid group 25.7% died, compared to 22.3% in the placebo group (RR 1.15, p = 0.0001), and the risk of death or severe disability was also possibly higher in the steroid group (38.1% vs. 36.3%, RR 1.05, p = 0.079). The risk of death, or severe disability, was not associated with steroids when stratified by injury severity or time to treatment.

Prognostic factors for death or disability after head injury: Risk factors predicting death at 2 weeks or death or disability at six months, were stratified by high or low-middle income country as there were some differences between those countries as to injury type and risk of death at two weeks. In all countries, risk factors predicting a poor outcome were: age, GCS on presentation, one or both pupils unreactive, and the presence of a major extracranial injury. Safety: There was no large rise in infection or gastrointestinal haemorrhage associated with steroid treatment. The mechanism by which steroids led to increased death risk remains unknown.

Weaknesses The study did not measure cause of death as it was believed to be too complex in this setting of multiple injuries and medical interventions. The mechanism behind the increased risk from steroids remains speculative and debated. It is possible that there was a selection bias insofar as exclusion criteria included physician certainty as to the suitability of corticosteroids. Traumatic optic neuropathy was not part of this study so conclusions for treatment of the optic nerve cannot be drawn from CRASH, notwithstanding certain implications.

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Key messages 1. Amongst patients with head injury and reduced GCS, steroids should not be used routinely as they may increase the risk of death. 2. Ophthalmologists should keep this in mind when assessing patients with traumatic optic neuropathy, for which there is scant evidence that steroids are beneficial.

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Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) Study design: RCT

Evidence level: 1b

Baseline ‒ JAMA Neurol 2014;71:693 | Results ‒ JAMA 2014;311:1641.

Key question 1. Does acetazolamide, when added to a low-salt weight-reduction diet, improve visual outcomes in patients with idiopathic intracranial hypertension (IIH)?

Aims The major neurological disability resulting from IIH is optic neuropathy, and up to 10% of patients may develop some permanent bilateral blindness, so evidence-based treatment strategies are required. The purpose of this trial was to determine the effect of acetazolamide in reducing or reversing visual loss after six months of treatment when added to a weight-reduction program.

• • • • •

•

Methods

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Participants: One hundred sixty-five participants were recruited from 38 academic and private practices in North America. Only four participants were male, mean age was 29 years, 65% were white and 25% were black. Mean body mass index was 39.9 kg/m2 (range 25 to 71). Inclusion criteria: • Diagnosis of IIH by modified Dandy criteria; • Age 18-60 years at diagnosis; • Reproducible visual field (VF) defect with mean deviation (MD) -2dB to -7dB in worst eye and bilateral papilledema; • Opening lumbar cerebrospinal fluid (CSF) pressure >25 cmCSF or 20-25 cmCSF if other highly specific signs and symptoms of IIH were present. Exclusion criteria: • Treatment for IIH longer than two weeks, including any surgical treatment; 138

Previous gastric bypass surgery; Abnormal CSF analysis; Other disorders causing visual loss, or optic disc drusen; Untreated obstructive sleep apnoea; Treatment with medication known to cause increased ICP, or need for treatment with diuretics, steroids or topiramate for other reasons; Unwillingness to use contraception if potentially childbearing.

Groups: All participants were offered a supervised low-salt weight-reduction dietary plan and lifestyle modification program, and were randomised 1:1 to acetazolamide 250 mg tablets or placebo. The dose of acetazolamide or placebo increased from two tablets twice daily up to a maximum of four tablets four times daily (4 g/day) as tolerated until papilledema was minimal, or was reduced to maximum tolerable levels. Treatment failure was reproducible decrease in MD of 3 dB. Primary endpoint: Change in MD in worst eye at six months. Secondary endpoints: Change in papilledema grade, quality of life, headache, weight, and treatment failures at six months.

IIHTT Results VF and VA: In both groups, the MD of the worst eye improved, but there was a greater improvement in the acetazolamide group (from -3.53 dB to -2.10 dB, change +1.43 dB) compared to the placebo group (from -3.53 dB to -2.82 dB, change +0.71 dB, difference p = 0.05). A similar effect of smaller magnitude was seen in the better eye (acetazolamide change +0.87, placebo change +0.42, difference p = 0.045). Acuity did not change in either group (p = 0.99).

group than the placebo group (P values all ≤ 0.03). Both groups had mildly reduced headache, to a similar extent between groups.

Papilledema grade and CSF pressure: There were significant differences between acetazolamide and placebo groups in the improvement of papilledema. In the acetazolamide group the papilledema grade improved by an average of 1.14 to 1.75 depending on the grader or which eye, and in the placebo group the grade improved by 0.62 to 0.91 (all comparisons p < 0.001). Half of participants had a lumbar puncture at six months, with a reduction of CSF pressure of -11.2 cmH2O in acetazolamide group and -5.2 cmH2O in the placebo group (p = 0.002).

Safety: Adverse events were more common in the acetazolamide group, specifically paraesthesia, dysguesia, fatigue, nausea, vomiting, diarrhoea, and tinnitus. Two in the placebo group had treatment failure requiring optic nerve sheath fenestration, and a third had pneumonia. There were six hospitalizations in the acetazolamide group for renal impairment, elevated transaminases, pancreatitis, diverticulitis, unknown allergic reaction, and hypokalemia.

Quality of life and headache disability: Vision-related quality of life and both physical and mental health related quality of life scores all improved to a significantly greater extent in the acetazolamide

Weight: Weight reduced more in the acetazolamide group (107.7 kg to 100.2 kg, difference -7.5 kg) than the placebo group (107.7 kg to 104.3 kg, difference -3.4 kg, p < 0.001) but mediation analysis indicated that the weight effect was not responsible for the visual benefit.

Weaknesses A 2-dB VF benefit is very small. The clinical significance of this improvement in visual function remains to be determined.

Key message

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1. In patients with IIH and mild visual loss, acetazolamide in addition to a low-salt weight reduction diet results in modest improvements to visual function and quality of life compared to placebo.

139

Idebenone for Leber Hereditary Optic Neuropathy – the Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) Study design: RCT

Evidence level: 1b

Brain 2011:134;2677-2686.

Key question 1. Is idebenone effective in recovering vision in patients with Leber hereditary optic neuropathy (LHON)?

Aims Idebenone is a short-chain synthetic benzoquinone that crosses mitochondrial membranes and the blood-brain barrier. There was anecdotal evidence of effectiveness in LHON from small open label retrospective uncontrolled studies. The RHODOS was conducted to evaluate idebenone effectiveness in recovering vision with a prospective, randomised, controlled, double-masked study design.

Methods

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Participants: Eighty-five participants with typical LHON were recruited from Germany (44), England (30) and Canada (11). All three common mtDNA mutations were included. Sixty-five percent had visual loss for more than one year, 85% had best logMAR acuity ≥ 1.0 (6/60), 37% had significant discordance of acuity between their eyes. Inclusion criteria: • Age 14-64 years; • Cardinal LHON mutations (m.3460G>A or m.11778G>A or m.14484T>C); • Visual loss from LHON within the last five years. Exclusion criteria: • Recreational drug use, pregnancy or breastfeeding.

140

Groups: Participants were randomised to receive idebenone 300 mg three times daily or placebo in a 2:1 ratio. Randomization was stratified by mutation and disease history. Primary endpoint: Change in visual acuity (VA) was measured as: (1) change in the eye with best recovery or least worsening; (2) change in best acuity; (3) change in acuity of best eye at baseline; (4) total change in acuity of both eyes. Secondary endpoints: Responder analyses, optical coherence tomography (OCT) of retinal nerve fibre layer (RNFL), colour sensitivity. Follow-up: Six months.

RHODOS Results VA: The primary endpoint of best recovery of VA did not reach significance between groups. The placebo group improved by -0.071 logMAR and the idebenone group improved by -0.135 logMAR (approximately half a line difference, or logMAR difference of 0.064, p = 0.291). However, subgroup analysis in the group with discordant VA had significantly better recovery on idebenone (p = 0.011). In secondary analyses such as change in best VA or change in best eye or change in all eyes, the pattern was for acuity to deteriorate in the placebo group and remain stable in the idebenone group. Responders: In counting the eyes or patients with improvement by 0.2 logMAR, the idebenone group had 26-37% improving and 17% worsening, compared to 17-24% improving and 29% worsening in the placebo group (NS). In the subgroup with discordant vision, the differences were more marked and statistically significant. In those who were ‘off chart’ at baseline, 28% of participants and 19% of eyes were able to read one full line at six months in the idebenone group, compared to 0% participants or eyes in the placebo group (p = 0.008 and 0.072).

Nerve fibre layer and colour sensitivity: The numbers of patients with OCT data were too few for meaningful statistical analyses, but there was an impression that those with < six months of visual loss had preservation of their RNFL thickness on idebenone, but continued thinning in the placebo group. Colour sensitivity was improved in the tritan domain in the idebenone group compared with placebo. Safety: Compliance was high. Adverse events were few and were indistinguishable between groups. Four of 30 placebo group and three of 55 idebenone group discontinued. Serious adverse events were not thought to relate to treatment.

Weaknesses Although the study was prospective, the only statistically significant change were in post-hoc subgroup analysis. This must be viewed with circumspect caution. VA is a limited outcome measure in this disease, and VF data would give a better assessment of functional limitation (but not reported). The duration of the follow-up was only six months and there is good evidence that idebenone treatment may require longer for full benefits to be appreciated.

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Key messages 1. Although the primary end-point was not reached with statistical significance, this study appeared to show that idebenone resulted in a clinically meaningful improvement in visual acuity outcomes among patients with LHON. 2. Subgroup analyses and structural analyses indicate that those with new onset disease, or asymmetric disease have the greatest potential for benefit. 3. Idebenone appears to be safe and well-tolerated.

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Idebenone for Leber Hereditary Optic Neuropathy – Carelli retrospective study Study design: Retrospective interventional cohort

Evidence level: 2

Brain 2011:134;1-5.

Key question 1. Is idebenone effective in recovering or protecting vision in patients with Leber hereditary optic neuropathy (LHON)?

Aims Idebenone is a short-chain synthetic benzoquinone that crosses mitochondrial membranes and the blood-brain barrier. This large retrospective interventional cohort study was published in conjunction with the RHODOS trial to demonstrate the clinical experience of using idebenone in LHON.

Methods

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Participants: One hundred and three participants were described from clinics across Italy. Seventy-seven were male, mean age of onset was 25 years. All had one of the cardinal LHON mutations: 73 had m.11778G>A, 18 had m.3460G>A and 12 had m.14484T>C. Inclusion criteria: • Treatment offered within one year of second eye involvement, or before; • Age > ten years at onset of visual loss; • Follow-up of > five years available. Groups: From the early 1990s idebenone treatment was offered to all patients (n = 44 treated), and no patients declined. Patients before this period were considered as a control group (n = 59 controls). In the early years of the treatment phase, treated participants were offered 270 mg/day, but as other studies were published the dose offered was increased to 540-675 mg/day. 142

Of the treated group, six were treated before loss of vision in the second eye. Primary outcome: Recovery of vision (eyes or patients gaining two Snellen lines or moving from off the chart to seeing something on chart)

Results In this retrospective un-randomised study, the treated and untreated groups did not differ in gender proportions, age of onset, mutation, or VA in best or worst eye at the nadir of visual loss. Recovery of visual acuity (VA): The proportion of patients or eyes with visual recovery was higher in the idebenone-treated than untreated group (45% vs. 32%). Recovery occurred earlier in the idebenone group than the untreated group (17 months vs. 25 months). The age of the untreated patients who recovered vision was less than the other groups. The benefit of treatment seen in the m.11778G>A patients increased for about three years. The m.11778G>A subgroup: Patients with the m.14484T>C mutation did well regardless of treatment. Those with the m.3460G>A mutation had a poor prognosis with or without treatment. Only patients with the most common, m.11778G>A mutation, showed statistically significant benefit from treatment. Amongst m.11778G>A, the likelihood of recovery was 47% in the idebenone group and 23% in the untreated group.

Predictors of recovery: In two Cox proportional-hazards models, the main predictor of visual recovery was mutation type, with m.14484T>C mutation associated with a greater chance of recovery (hazard ratio 2.9 or 3.1). In the second model, an earlier introduction of therapy was also associated with a greater chance of recovery. Amongst the m.11778G>A subgroup, treatment with idebenone was associated with a greater chance of recovery (HR 2.46, p = 0.031). As a whole, the early start of treatment in m11778G>A patients was the only predictor of recovery.

Weaknesses Duration of follow-up was not clearly reported but all had a minimum of five years. Retrospective analysis such as this is subject to selection bias, but this was deemed to be unlikely as treatment was offered and accepted by all patients after the introduction of idebenone. A cohort bias is possible as there may have been changes in the environment around the time of idebenone introduction that made recovery more likely.

Key messages

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1. Although not prospective or randomised, and subject to all the pitfalls of retrospective data, this study indicated a trend toward improved likelihood of visual recovery with idebenone. This trend reached statistical significance in the m.11778G>A subgroup, who had an intermediate chance of recovery. 2. Early treatment appeared to be associated with recovery. 3. Treatment effects became more apparent after three years.

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North American Symptomatic Carotid Endarterectomy Trial (NASCET) Study design: RCT

Evidence level: 1b

New Engl J Med 1998;339:1415 | New Engl J Med 2001;345:1084.

Key questions 1. In patients with transient monocular visual loss (TMVL, amaurosis fugax) and ipsilateral carotid stenosis, what is the benefit of carotid endarterectomy (CEA) in preventing death or stroke? 2. Which patients will benefit most from CEA?

Aims Initial randomised trials of CEA had negative results due to the high peri-operative morbidity. As both medical care for atherosclerosis and surgical technology were improving in the 1980s, major randomised trials were conducted in both symptomatic and asymptomatic patients. The European Symptomatic Carotid Trial and NASCET demonstrated a benefit of CEA in reducing ipsilateral stroke in patients with symptomatic carotid stenosis, especially those with carotid stenosis ≥ 70%. In the small subgroup of participants in NASCET presenting with TMVL, the risk of stroke and benefit of CEA was analysed separately.

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Methods Participants: A total of 2,885 participants were recruited from 50 centres in the USA and Canada, with demonstrated peri-operative stroke or death rates of < 6%. Mean age was 66 years, 70% were male, and 93% were white. Of all 2885 participants, 1583 had transient ischemic attack (TIA, rather than stroke), and of these 496 had TMVL. Inclusion criteria: • Transient ischaemic attach (TIA) (including transient monocular vision loss (TMVL)) or non-disabling stroke, occurring within the preceding 120 days, in the same carotid territory; 144

•

Angiography within 120 days showing ≥ 30% stenosis, suitable for CEA, without total occlusion.

Exclusion criteria: • Unable to consent; • Worse carotid stenosis or occlusion distal to the accessible segment; • Age > 79 years; • Kidney, liver, heart, or lung failure, or potentially fatal cancer; • Stroke sufficient to prevent all useful function from the affected area; • Symptoms of other disease, or other embolic sources, or previous CEA; • Temporary exclusion was applied for uncontrolled diabetes, ischemic heart disease, progressive neurological signs or recent major surgery. Groups: Participants were randomised 1:1 to receive best medical care alone or best medical care plus CEA. Best medical care was aspirin with antihypertensive, antilipid, and antidiabetic medication as indicated. Primary endpoint: Ipsilateral stroke. Secondary endpoint: Death from any cause, all strokes.

NASCET Follow-up: Two years initially, eight years reported.

Results Effect of CEA on risk of stroke or death for symptomatic carotid stenosis: Recruitment of participants with high-grade stenosis (70-99%) was stopped after 659 participants. A small short-term increase in absolute risk of around 2% was outweighed by a larger medium term reduction in risk of 10% at two years. At two years, the rate of ipsilateral stroke was 26% in the medical group and 9.0 % in the CEA group (p < 0.001). The moderate stenosis group was followed longer. In the 50-69% stenosis group the five-year risk of ipsilateral stroke was 22.2% in the medical group and 15.7% in the CEA group (p = 0.045). With stenosis < 50%, the five-year risk was 18.7% in the medical group and 14.9% in the CEA group (p = 0.16). These patterns were echoed for other definitions of treatment failure.

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TMVL versus hemispheric TIA, and the subsequent risk of stroke: Comparing the 397 participants with TMVL to the 829 who had a hemispheric TIA (excluding those with stroke or overlapping symptoms), the patients with TMVL were younger, with less diabetes and hypertension, more often smokers, twice as likely to have high-grade stenosis and more than three times more likely to have collateral circulation. In the medical group (but not the surgical group), the three-year risk of stroke after TMVL was approximately

half that of participants with hemispheric TIA (HR 0.53). One third of the strokes in the TMVL group were retinal and 18 % were disabling or fatal, while only 6% of the strokes in the hemispheric TIA group were retinal and 28% were disabling or fatal. Predictors of stroke after TMVL: Amongst the medical group with TMVL, six risk factors each doubled the risk of stroke: (1) age ≥ 75 years; (2) male gender; (3) history of hemispheric TIA; (4) history of intermittent claudication; (5) stenosis 80-94%; and (6) no collateral filling on angiography. The relative risk for each factor was between 2.2 and 2.9. Severity of stenosis was not a risk factor for stroke after TMVL. Effect of CEA after TMVL: In the 360 patients with TMVL, the relative benefit of CEA was dependent on the number of risk factors. With zero or one factor, surgery increased the risk of stroke from 1.8% to 4.0% at three years. With two factors, surgery decreased the risk of stroke from 12.3 to 7.4% at three years. With ≥ three factors, surgery decreased the risk of stroke from 24.2% to 9.9% at three years. That is, surgery was of benefit to patients with TMVL and ipsilateral carotid stenosis only when they also had three risk factors for stroke.

Weaknesses NASCET provided a large and robust study for the effects of CEA in general but, as always, post-hoc subgroup analysis of the participants with TMVL may be susceptible to erroneous chance findings.

Key messages 1. In patients with TMVL and ipsilateral carotid stenosis, CEA is a potentially helpful treatment if the patient also has three or more risk factors for stroke. 2. TMVL may involve smaller emboli such that the risk of stroke is lower and the potential to benefit from carotid surgery is less.

145

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146

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Paediatric Ophthalmology Section editor: Prof. Anthony Moore

Cryotherapy for Retinopathy of Prematurity (CRYOROP) Study design: RCT

Evidence level: 1b

Arch Ophthalmol 1988;106:471 | Arch Ophthalmol 1990;108:195 | Arch Ophthalmol 1990;108:1408 | Arch Ophthalmol 2001;119:1110 | Arch Ophthalmol 2002;120:595.

Key questions 1. What is the most suitable threshold for deciding to treat retinopathy of prematurity? 2. Does cryotherapy reduce the incidence of unfavourable outcomes in eyes with significant retinopathy of prematurity? 3. What are the risk factors for an unfavourable anatomical outcome?

Aims Until the CRYOROP study, the treatment of ROP was highly variable. This study aimed to provide an evidence based framework for the management of ROP.

Methods

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Participants: Four thousand ninety-nine premature infants with a birthweight less than 1251 g from 23 study centres prospectively screened between January 1986 to November 1987. Inclusion criteria: • These infants were examined every fortnight beginning at four to six weeks of age; • Those developing ‘pre-threshold ROP’ were then examined weekly: »» Zone 1, Any stage; »» Zone 2, Stage 2 with plus disease; »» Zone 2, Stage 3. • Threshold ROP was defined as: »» Five continuous or eight cumulative clock hours of stage-3 disease in zones 1 or 2 in the presence of plus disease. Exclusion criteria: • Co-existence of a fatal anomaly where the infant was not predicted to survive; 148

• • • •

Co-existence of an eye anomaly likely to confound results of prevent suitable study of the eye; Infants transferred to a non-participating hospital; Monocular patients or those with > Stage 4 ROP in either eye; In cases where initially unilateral threshold ROP was randomised to be observed, and subsequently the second eye developed ROP, this second eye would be treated with cryotherapy but was not included in the study.

Groups: The 291 infants who developed unilateral threshold ROP were randomised to receive peripheral retinal ablation using cryotherapy or observation alone. Where threshold ROP was bilateral, one eye was randomly chosen for treatment with cryotherapy and the other eye observed. Primary endpoint: Structural (retinal assessment) and functional (BCVA) outcomes. Follow-up: Three months, one, five and ten years.

CRYOROP Results Functional outcome: An unfavourable functional outcome was defined as BCVA worse than 20/200. Of treated eyes, 32.7% had an unfavourable functional outcome compared to 49.8% in the control group (P < 0.001). Anatomical outcome: Throughout follow-up, fundus photographs were graded by masked observers as having a favourable retinal outcome if they had: • An essentially normal posterior pole; • Abnormal angle of major temporal vascular arcade; • Macular ectopia; • stage 4A partial retinal detachment, schisis or retinal fold (fovea spared). An unfavourable anatomical outcome was defined as: • Stage 4B or 5 ROP; • Significant media opacity blocking adequate view of fundus. Of control eyes, 47.9% had an unfavourable anatomical outcome compared to 27.2% in the cryotherapy group (P < 0.001).

Risk factors: Risk factors for development of threshold disease were identified by as: low birthweight, younger gestational age, rate of development of ROP, presence of plus disease, multiple birth, and > six hours of stage-3 disease.

Weaknesses The interpretation of the results are limited to the benefit of treatment at the defined threshold. There was possible overrepresentation of black infants, multiple births, and male infants. In the advent of an objective grading method such as fundus photography in infants, grading was subjective. This may have affected reproducibility. Cryotherapy is now rarely used in modern practice.

Key message

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1. Treatment with cryotherapy is beneficial to the structural and functional outcome of those with a threshold level of ROP. 2. Even with cryotherapy treatment, the prognosis is guarded. 3. Many eyes with favourable anatomical outcome still had unfavourable visual outcomes. 4. Cryotherapy had no significant benefit over observation in patients with zone-1 disease at start of therapy.

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Early Treatment for Retinopathy of Prematurity (ETROP) Study design: RCT

Evidence level: 1b

Arch Ophthalmol 2003;121:1684 | Trans Am Ophthalmol Soc 2004;102:233 | Arch Ophthalmol 2006;124:24 | Br J Ophthalmol 2006;128:663 | Arch Ophthalmol 2010;128:663.

Key questions 1. Can early treatment of retinopathy of prematurity (ROP) in high-risk eyes improve visual and anatomical outcomes? 2. Which grades of retinopathy are most likely to benefit from early treatment?

Aims In the CRYOROP study, infants treated with cryotherapy had better outcomes than controls. However the prevalence of unfavourable outcomes was still significant. By lowering the threshold for treatment, could outcomes be improved? The threshold had previously been defined as the stage when there was a 50% risk of retinal detachment.

Methods

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Participants: Infants with a birthweight less than 1251 grams from 26 study centres prospectively screened between October 2000 to September 2002. Inclusion criteria: • These infants were examined every fortnight beginning at four to six weeks of age; • Pre-threshold ROP was defined as: »» Zone 1, any stage (when less than threshold); »» Zone 2, stage 2 with plus disease; »» Zone 2, stage 3 (when less than threshold). Exclusion criteria: • Progression to threshold level ROP prior to randomisation. Groups: Eight hundred twenty-eight infants were identified with pre-threshold ROP. These were classified as high 150

risk or low risk by the ‘RM-ROP2 risk model’ based on whether there was > 15% risk of progression to an unfavourable outcome. Sixty percent of the pre-threshold infants were classified as high risk by this model and were randomised to receive peripheral retinal ablation within 48 hours or observation. Where high-risk pre-threshold ROP was bilateral, one eye was randomly chosen for treatment and the other eye observed. Primary endpoint: Structural (retinal assessment) and functional (BCVA) outcomes. Follow-up: Six and nine months, two and six years.

ETROP Results Functional outcome: Visual acuity (VA) results were characterised as normal (20/40 or better), below normal (less than 20/40 to better than 20/200), poor (20/200 or worse) or blind (able to see only the test card at any distance or worse). There was no significant difference between early treatment vs. control (24.6% vs. 29.0% P=0.15) with regards to unfavourable visual outcome at six years. Anatomical outcome: Throughout follow-up, fundus photographs were graded by masked observers. An unfavourable anatomical outcome was defined as: • Retinal fold or detachment involving the macula; • Retrolental mass or tissue blocking adequate view of fundus; • Previous vitrectomy or buckling procedure. At two years, 9.1% of treated eyes had unfavourable outcomes compared with 15.4% of conventionally managed eyes (P = 0.002)

Revised indications for treatment: Based on the findings that early treatment did not significantly improve visual outcomes compared to conventional treatment the indications were revised to the following: Type 1 ROP: • Zone 1, any stage with plus disease; • Zone 1, stage 3 without plus disease; • Zone 2, stage 2 or 3, with plus disease. Type 2 ROP: • Zone 1, stage 1 or 2 without plus disease; • Zone 2, stage 3 without plus disease. At six years, Type 1 eyes had unfavourable outcome in 25.1% when treated early compared to 32.8% in conventionally treated eyes (P < 0.001). Type 2 eyes had unfavourable outcome in 23.6% when treated early compared to 19.4% in conventionally treated eyes (P = 0.18).

Weaknesses The majority of patients in this study were treated with transpupillary argon laser, however cryotherapy was also permitted, leading to heterogeneous treatments. The new criteria have been criticised as not taking into account the number of ‘clock hours’ of disease.

Key message

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1. The definition of pre-threshold ROP was refined to include Types 1 and 2, where Type 1 disease will benefit from therapy. 2. A ‘watch and wait’ approach is recommended for Type 2 ROP as 52% will undergo spontaneous regression without treatment..

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Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEATROP) Study design: RCT

Evidence level: 1b

Arch Ophthalmol 2008;126:1161 | N Engl J Med 2011;364:603.

Key questions 1. Should vascular endothelial growth factor (VEGF) inhibitors be used in the treatment of retinopathy of prematurity? 2. Which grades of retinopathy are most likely to benefit from treatment?

Aims Conventional therapies for retinopathy of prematurity (ROP) involve ablating peripheral ischaemic retina using either laser treatment or cryotherapy. Drawbacks of peripheral retinal ablation for ROP include loss of peripheral visual field and an association with increasing myopia. A randomised clinical trial was therefore performed to compare intravitreal anti-VEGF (aVEGF) injection to conventional laser therapy for ROP.

Methods

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Participants: Infants with a birthweight less than 1500 grams or a gestational age of less than 30 weeks from 15 study centres were recruited prospectively between March 2008 to August 2010. These infants were examined based on a standardised schedule, beginning at four weeks of chronological age or 31 weeks of post-menstrual age (whichever was later). Inclusion criteria: • Stage 3+ disease in zone 1 or posterior zone 2; • Bilateral involvement. Exclusion criteria: • Stage 4 or 5 disease. Groups: One hundred fifty infants were randomised to receive bilateral bevacizumab monotherapy (0.625 mg in 0.025 152

ml) vs. conventional laser therapy. Bilateral treatment with the same therapy aimed to avoid bias from any aVEGF which crossed into the systemic circulation. Bevacizumab injection could be repeated based on the ophthalmologist’s discretion. Primary endpoint: Failure of treatment, defined as recurrence of neovascularisation in one or both eyes arising from the retinal vessels requiring re-treatment by 54 weeks post menstrual age. Follow-up: RetCam photographs were taken of all infants at one week and one month after the initial, and any subsequent treatments, followed by another photograph at 54 weeks post-menstrual age.

BEATROP Results

Weaknesses

Rates of re-treatment: Rate of recurrence for Zone 1 disease was 42% for conventional laser vs. 6% for bevacizumab (95% CI 0.02 to 0.43, p = 0.003) at 54 weeks post menstrual age. Rate of recurrence did not differ significantly for posterior Zone 2 disease which was 12% for conventional laser vs. 5% for bevacizumab (95% CI 0.07 to 2.11, p = 0.002).

Population bias is a potential weakness with two thirds of the centres located in South & West Texas and more than 50% of the infants were of Hispanic race. The failure rate of laser treatment in this study was higher than in the ETROP study. If similar success rate with laser had been achieved, it is less likely that the results for Zone 1 disease would have been significant. The study was not powered to assess safety outcomes, but 71% of the infant deaths in this study (five out of seven) occurred in the bevacizumab group which has led some to question the safety of its use in infants. Animal models have suggested that bevacizumab enters the systemic circulation. The effects on the development of the brain and other organs are not yet known. In the absence of data on safety, several authors have suggested that bevacizumab should not replace laser ablation, but could have a role as a rescue therapy. This study did not aim to determine a protocol for bevacizumab treatment.

Revascularisation: It was observed that while laser therapy resulted in permanent reduction in new blood vessel growth in the peripheral retina, bevacizumab allowed for continued vessel growth. The authors suggested that avoiding ablation of peripheral retina might improve the prognosis for the visual field in the bevacizumab group, but this remains to be determined.

Key messages

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1. Bevacizumab is effective in the treatment of stage 3+ ROP in Zone 1 and posterior Zone 2. 2. Bevacizumab is no better than laser for reducing the rate of recurrence of posterior Zone 2 disease, but was shown to be superior for Zone 1 disease.

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Pediatric Eye Disease Investigators Group Study (PEDIG) –or– Amblyopia Treatment Study (ATS) Study design: RCT

Evidence level: 1b

Arch Ophthalmol 2002;120:268 | Arch Ophthalmol 2003;121:603 | Ophthalmol 2003;110:2075 | J AAPOS 2004;8:420 | Arch Ophthalmol 2005;123:437 | Ophthalmol 2006;113:895 | Ophthalmol 2006;113:904.

Key questions 1. 2. 3. 4. 5.

Can correcting the refractive error alone treat amblyopia? How much patching is required? What are the risks of recurrence after cessation of treatment? Until what age can amblyopia be treated? What is the role of atropine in managing amblyopia?

Aims Amblyopia is the most common cause of monocular visual loss in children. Occlusion or penalisation therapy have commonly performed with no evidence-based standardization. This trial aimed to facilitate an evidence-based approach to the treatment of amblyopia.

Methods

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Participants: Over 60 centres participated across the USA and Canada. Inclusion criteria (unless stated otherwise): • Age < seven years; • Best corrected visual acuity (BCVA) in the better eye > 20/40; • BCVA in the amblyopic eye < 20/40; • Previous refractive error corrected for at least four weeks prior to study enrolment until plateau of VA reached. Exclusion criteria: • Presence of an ocular cause for reduced VA; • Myopia greater than -6 D; • Previous intraocular surgery.

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Groups: Moderate amblyopia was defined as 20/40 to 20/80. Severe amblyopia was defined as 20/100 to 20/400. Successful treatment was defined as improvement of VA to within one line of the non-amblyopic eye. Recurrence of amblyopia was defined as a reduction in at least two lines after cessation of amblyopia therapy or when treatment was restarted at an investigator’s discretion. Primary endpoint: BCVA.

PEDIG - ATS Results Refractive correction alone in treating amblyopia: Eighty-four children were recruited and issued with glasses. At five-week follow-up, the BCVA improved by two lines on average. Overall 77% and 60% improved their BCVA by at least two and three lines respectively. VA was improved to within one line of the fellow eye in 27% of patients. Patching in treating amblyopia: Two hours of patching for five weeks resulted in a mean improvement of logMAR 0.07 (95%CI 0.02-0.12) in the patched group vs. controls. There was no significant difference in number of Snellen lines gained when 175 severe amblyopes were randomised to receive full time patching vs. six hours/day patching for four months (4.8 lines vs. 4.7 lines). Likewise, there was no significant difference when 189 moderate amblyopes were randomised to receive either two or six hours a day of patching for four months (average improvement = 2.4 Snellen lines). Recurrence of amblyopia: One hundred fifty-six children who had been treated with patching or atropine for at least three months with at least three lines of improvement were brought off therapy at the investigators discretion and followed up for one year. Average age was 5.9 years and no child was older than eight. Twenty-one percent of children experienced a recurrence of the amblyopia, with 40% occurring within the first five weeks.

Patching in older children: Five hundred and seven children with amblyopia aged 7 to 18 were recruited and randomised to receive optical correction ± patching for near activities. There was a significant improvement in BCVA in those treated with patching in the 7-12 age group. In the 13 -17 age group there was no statistical significance between the two groups. When only the 13-17-year olds with no previous treatment for amblyopia were considered, there was an improvement in the patched group. Atropine vs. patching: Four hundred nineteen children with moderate amblyopia were randomised to six hours of patching vs. daily atropine. After six months average increase in BCVA was 3.16 lines in the patching group vs. 2.84 lines in the atropine group. Overall, the two methods were found to be clinically equivalent.

Weaknesses Children younger than three were not included in the study as they were unable to comply with the standardised VA testing protocol. Twenty-eight percent of patients in the studies investigating atropine were switched to a plano lens in the sound eye to provide an optical penalisation as well as pharmacologically.

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Key messages 1. Refractive correction alone may be effective in the treatment of amblyopia in some cases. 2. There is no benefit in patching moderate amblyopes for longer than two hours and severe amblyopes for more than six hours per day. 3. Children need close follow-up after discontinuation of occlusion therapy. 4. There may be a benefit in treating amblyopia until 12 years of age. Teenagers with amblyopia who have never before received treatment may benefit from a trial of patching. 5. There is no clinical difference in using atropine vs. patching in moderate amblyopes. 155

Infant Aphakia Treatment Study (IATS) Study design: RCT

Evidence level: 1b

Arch Ophthalmol 2010;128:810 | Ophthalmol 2011;118:2330 | Arch Ophthalmol 2012;130:293 | JAMA Ophthalmol 2014;132:676.

Key questions 1. 2.

What are the visual outcomes of using contact lenses (CL) or intraocular lenses (IOL) to correct monocular aphakia during infancy? What are the adverse events associated with using CL or IOL to correct monocular aphakia during infancy?

Aims Correction of infantile aphakia has traditionally required the use of CL. Challenges with CL use include difficulty with lens insertion and removal which may impact on parental compliance. Primary intraocular lens (IOL) implantation may avoid many disadvantages of CL uses, but until this study there was limited evidence on whether pseudophakia was associated with additional risks, and whether the IOL would have an impact on the growing eye.

Methods

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Participants: One hundred 14 eyes of 114 patients were randomised to receive primary IOL implantation or refractive correction with CL. There were 12 participating centres in the USA. Inclusion criteria: • Infants with a unilateral congenital cataract undergoing surgery at between 28 days to six months of age. Exclusion criteria: • Persistent fetal vasculature (PFV) associated with involvement of ciliary processes, retina or optic nerve; • Acquired cataract; • Corneal diameter < 9 mm; • Medical comorbidity which may affect visual acuity (VA) testing or prematurity < 36 weeks. 156

Groups: The group with primary IOL insertion also underwent posterior capsulectomy during surgery. Refractive aim was 6D under-correction in those older than six weeks. Additional refractive correction was achieved with spectacles. The CL group were prescribed soft or gas permeable CLs to overcorrect refractive error by 2 D. Both groups underwent the same patching regime. Primary endpoint: Grating VA at one year; computerised optoTypes at five years. Secondary endpoints: Intraocular complications, adverse events, further operations required, ocular alignment. Follow-up: One to five years.

IATS Results VA at one year: The median logMAR VA was not significantly different between the treated eyes in the two groups (CL = 0.80, IOL = 0.97, p = 0.19). Intra-operative complications: There was a statistically significant greater incidence of intraoperative complications in the IOL group (28% vs. 11%, p = 0.31). The difference was primarily due to a higher incidence of iris prolapse in the IOL group. Post-operative adverse events: Seventy-seven percent of those in the IOL group had one or more adverse events compared with 25% in the CL group. Most commonly, these were lens re-proliferation (42%), pupillary membrane (30%), corectopia (11%) in the IOL group. There was no significant difference in glaucoma between the two groups. There was one case of microbial keratitis and one case of endophthalmitis in the CL group. Additional surgeries: There was a statistically significant greater incidence of additional intraocular surgery in the IOL group (63% vs. 12%, p < 0.001). The most common procedure was to clear the visual axis (60% vs. 11%). Ocular alignment: There was a trend for increased strabismus in the CL group at one year (62% vs. 42%, p = 0.051).

Five-year follow-up: There was still no difference in VA which was 0.90 logMAR in both groups. However, there was a significant difference in those achieving VA better than 20/40 (23% CL group vs 11% IOL group). There was no statistically significant difference in development of glaucoma (CL 35% vs. IOL 28%). Incidence of further surgeries by age five was 72% in IOL group compared with 28% in CL group.

Weaknesses The CL group received a subconjunctival injection of steroids whereas the IOL group did not. On presenting the incidence of glaucoma, the study did not take into account whether the IOL was placed in the capsular bag or the sulcus. Contact lenses, spectacles and patching were provided free of charge in this study. In other healthcare settings, associated costs to the parents may influence compliance. Additionally, compliance with CL use, spectacles and patching may have been superior to standard clinical practice due to the effects of participating in a study. Application of this study to healthcare systems in developing countries may be limited. At this current time, the study has not yet concluded follow-up past the amblyogenic period. The study provides no data on a suitable time to implant secondary IOL in the CL group.

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Key messages 1. There is no significant difference in visual acuity at one year or five years in congenital cataract patients undergoing primary IOL implantation as compared with CL use. 2. Primary IOL implantation is associated with an increased incidence of intraoperative complications, post-operative adverse events and the requirement for further surgery. 3. IOL insertion may have advantages in cases where there is doubt over compliance with CL use.

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Atropine for the Treatment of Myopia I (ATOM I) Study design: RCT

Evidence level: 1b

Ophthalmol 2006;113:2285 | Ophthalmol 2009;116:572 | Ophthalmol 2012;119:347.

Key questions 1. 2. 3.

Can atropine affect the progression of myopia in myopic Asian children? Is atropine safe to give to children on a regular basis? What happens after the cessation of atropine treatment?

Aims In some populations, the prevalence of myopia approaches 80%. As well as the refractive error, myopia is associated with macular degeneration, retinal detachment and glaucoma. Until this study, there was no treatment proven to reduce the progression of myopia in children.

Methods

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Participants: This double-masked, randomised, placebo-controlled trial took place at Singapore National Eye Centre. Patients were recruited over 17 months and followed up for three years. During the first two years, 13.5% of subjects were lost to follow-up. Inclusion criteria (unless stated otherwise): • Age 6-12 years; • Refractive error of spherical equivalent between -1 D and -6 D; • Best corrected visual acuity (BCVA) in both eyes of logMAR 0.2 or better; • Astigmatism of less than 1.50 D; • Anisometropia of less than 1.50 D. Exclusion criteria: • Allergy to any of the drops; • Previous use of contact lenses, bifocals, progressive addition lenses or atropine; • Absence of binocularity, amblyopia or strabismus.

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Groups: Four hundred children were randomised to receive either 1% atropine or placebo drop to one of their eyes every night for two years. Both groups were then followed-up for a further 12 months. Primary endpoint: Spherical equivalent (by cycloplegic autorefraction) and axial length (by A-scan ultrasonography).

ATOM I Results Progression of myopia: After two years, the mean progression of myopia was -1.20D ± 0.69 in the placebo group and -0.28D ± 0.92 in the atropine-treated eyes. The change in axial length was 0.38 mm ± 0.38 in the placebo group and -0.02 mm ± 0.35 in the treatment arm. Both primary endpoints were statistically significant (p < 0.001). The fellow eye of the atropine treated eye progressed in its myopia in a manner that was not statistically different from either of the placebo eyes. Safety: No serious adverse events related to atropine treatment were reported. Reasons for patients withdrawing from the study included allergic or hypersensitivity reactions or discomfort (4.5%), glare (1.5%), blurred near vision (1%), and logistical difficulties (3.5%). After cessation of atropine: Despite the success of atropine in reducing the progression of myopia in the treated eye when given for two years, there was a rebound phenomenon observed over the following 12 months once atropine therapy was stopped. The spherical equivalent of the atropine treated eye progressed by -1.14D ± 0.80 over the third

year of the study compared to -0.38D ± 0.39 in the placebo group (p < 0.0001). However, overall, after the third year, the eyes treated with atropine were significantly less myopic than the eyes in the placebo group: Mean total spherical equivalent was -4.29 D ± 1.67 compared with -5.22 D ± 1.38 (p < 0.001), respectively.

Weaknesses This study was conducted at a single centre in Singapore, which has a very high prevalence of myopia. The mechanism for atropine is incompletely understood. Animal models have suggested a mechanism of action with atropine directly affecting the retina or sclera. The implications for clinical treatment are challenging. If one eye were to be treated, the untreated eye may continue to progress, increasing the risk of anisometropia/aniseikonia. If both eyes were treated with atropine, the child would not be able to accommodate which may have implications on near-vision tasks including reading and writing. A child with bilateral atropinised eyes would require bifocal correction of their refractive error, which may confound the effects of the treatment.

Key messages

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1. Atropine may limit the progression of low/moderate myopia in children. 2. There is a rebound effect to the eye after cessation of myopia treatment. 3. Overall despite the rebound effect, total spherical equivalent may be less in eyes treated with atropine..

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Atropine for the Treatment of Myopia II (ATOM II) Study design: RCT

Evidence level: 1b

Ophthalmol 2012;119:347 | Am J Ophthalmol 2014;157:451 | Ophthalmol 2016;123:391.

Key questions 1. 2. 3.

Can atropine slow the progression of myopia without causing side effects from cycloplegia and mydriasis? What are the effects of different concentrations of atropine? What happens after the cessation of atropine treatment?

Aims The ATOM study showed that atropine 1% reduced the progression of myopia in children. However the mydriasis and cycloplegia are significant side effects, loss of accommodation occurs if both eyes are treated and anisometropia is a risk if one eye is treated. This study aimed to examine the effect of lower concentrations of atropine.

Methods

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Participants: This double-masked, randomised trial took place at Singapore National Eye Centre. A two-year treatment phase was followed by a one-year washout phase. Inclusion criteria (unless stated otherwise) • Age 6-12 years; • Refractive error of spherical equivalent of at least -2 D in both eyes; • Astigmatism of less than 1.50 D; • Documented progression of at least 0.5 D over the last 12 months. Exclusion criteria: • Allergy to any of the drops or cardiac/respiratory disease; • Previous use of atropine; • Absence of binocularity, amblyopia or strabismus.

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Groups: Four hundred children were randomised to receive either 0.5%, 0.1% or 0.01% atropine every night for two years at an allocation ratio of 2:2:1. Both groups were then followed up for a further 12 months. Primary endpoint: Near visual acuity (VA) while wearing best corrected distance spectacle correction, the near point of accommodation (by RAF rule), spherical equivalent (by cycloplegic auto-refraction) and axial length (by coherence interferometry).

ATOM II Results Progression of myopia: Myopia progression over two years was -0.49 ± 0.60 D, -0.38 ± 0.60 and -0.30 ± 0.63 D in the 0.01%, 0.1% and 0.5% groups, respectively. There was no significant difference between 0.01% and 0.1% or between 0.1% and 0.5%, but there was a significant difference between 0.01% and 0.5% (p = 0.01). Change in axial length was 0.41 ± 0.32 mm, 0.28 ± 0.27 mm and 0.27 ± 0.25 mm in the 0.01%, 0.1% and 0.5% groups respectively. The 0.01% had significantly greater increase in axial length compared to the other two groups (p < 0.001). Cycloplegic effects: The 0.01% atropine treated group had significantly less side effects from cycloplegia compared with the other two groups. Accommodation amplitudes were 11.8 D, 6.8 D and 4.0 D in the 0.01%, 0.1% and 0.5% groups respectively. Pupil size in both photopic and mesopic conditions increased above baseline measurements by 1 mm in the 0.01% group compared with 3 mm in the 0.1% and 0.5% groups. Near VA was logMAR 0.01, 0.10 and 0.29 in the 0.01%, 0.1% and 0.5% groups, respectively.

After cessation of atropine: The rebound effect after stopping atropine demonstrated in the ATOM study was greater in those receiving higher concentrations of atropine (-0.87 ± 0.52 D, -0.68 ± 0.45 D, -0.28 ± 0.33 D in 0.5%, 0.1% and 0.01%). Final change in spherical equivalent at the end of the three years was -1.15 ± 0.81 D, -1.04 ± 0.83 and -0.72 ± 0.72 D, respectively.

Weaknesses The mechanism for reducing the progression of myopia with atropine is incompletely understood, but animal models suggest that it is independent of its anti-accommodation effects. The authors suggest an effect via muscarinic receptors located within the sclera whereby 0.01% atropine reduces the progression of myopia without causing mydriasis. Without further research, it is difficult to understand the physiological mechanism by which the above results were achieved. The axial lengths of all groups were approximately the same at 36 months which suggests that the mechanism of action is not directly associated with axial length. The authors draw comparisons between ATOM I and II but significantly the method of axial length measurements had changed from the ATOM I trial and validity of direct comparison is uncertain.

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Key messages 1. Progression of myopia and cycloplegic effects show a dose-related response to atropine. 2. The authors suggest that atropine at a dose of 0.01% may slow the progression of myopia but cause minimal side effects from cycloplegia. 3. The rebound change in spherical equivalent at three years after stopping atropine was greater in those who had received higher concentrations of atropine.

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Index of Codes ABC&AVB, 38 AGIS, 24 ANCHOR, 78 AREDS I , 74 AREDS-2, 76 ATOM I, 160 ATOM II, 160 ATS, 154 BEATROP, 152 BENEFIT, 132 BOLT, 70 BRAVO, 110 BVOS, 100 CATT, 94 CHAMPS, 128 CIGTS, 26 CLEK, 10 CNTGS, 28 COPERNICUS & GALILEO, 112 CRASH, 136 CRUISE, 108 CRYOROP, 148 CVOS , 98 DA VINCI, 66 DCCT, 44 DRCR.NET, 52 DRCR.NET, 54 DRCR.NET, 56 DRS, 48 DRVS , 60 EAGLE, 40 EDIC, 44 EGPS, 18 EMGT, 20 ESCRS Study, 8 ETDRS, 50 ETOMS, 130 ETROP, 150

EVEREST, 120 EVS, 6 EXCITE, 88 FAME A & B, 72 FFSS, 34 FIELD, 58 GENEVA, 106 GLT, 32 HEDS – 1, 2 HEDS – 2, 4 IATS, 156 IIHTT, 138 IONTS, 134 IVAN, 92 LoGTS, 30 MARINA, 80 MIVI-TRUST, 122 MYRROR, 118 NASCET, 144 OHTS, 16 ONTT, 126 PIER, 82 PrONTO, 86 RADIANCE, 116 RESTORE, 64 RHODOS, 140 RISE & RIDE, 62 SAILOR Study, 90 SCORE - BRVO, 104 SCORE - CRVO, 102 SUSTAIN, 84 TVT, 36 UKGTS, 22 UKPDS, 46 VEGF Trap-Eye, 96 VIBRANT, 114 VIEW 1&2, 96 VIVID & VISTA, 68

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ISBN 978-90-6299-251-5

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