Intravitreal Ranibizumab vs Aflibercept vs Bevacizumab for Macular Edema From Retinal Vein Occlusion | Macular Diseases | JN Learning | AMA Ed Hub [Skip to Content]
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Clinical Effectiveness of Intravitreal Therapy With Ranibizumab vs Aflibercept vs Bevacizumab for Macular Edema Secondary to Central Retinal Vein OcclusionA Randomized Clinical Trial

Educational Objective
To determine whether intravitreal aflibercept or bevacizumab compared with ranibizumab results in a noninferior mean change in vision at 100 weeks for eyes with central retinal vein occlusion–related macular edema.
1 Credit CME
Key Points

Question  Does intravitreal aflibercept or bevacizumab result in a noninferior mean change in vision at 100 weeks compared with ranibizumab for eyes with central retinal vein occlusion–related macular edema?

Findings  In this randomized clinical trial of 463 individuals with central retinal vein occlusion–related macular edema from 44 UK National Health Service ophthalmology departments, aflibercept treatment was noninferior (no worse than) ranibizumab treatment at 100 weeks and the results for bevacizumab vs ranibizumab were not noninferior (ie, inconclusive compared with the ranibizumab group).

Meaning  This is important information for ophthalmologists to consider before treating such cases.

Abstract

Importance  The comparative clinical effectiveness of ranibizumab, aflibercept, and bevacizumab for the management of macular edema due to central retinal vein occlusion (CRVO) is unclear.

Objective  To determine whether intravitreal aflibercept or bevacizumab compared with ranibizumab results in a noninferior mean change in vision at 100 weeks for eyes with CRVO-related macular edema.

Design, Setting, and Participants  This prospective, 3-arm, double-masked, randomized noninferiority trial (Lucentis, Eylea, Avastin in Vein Occlusion [LEAVO] Study) took place from December 12, 2014, through December 16, 2016, at 44 UK National Health Service ophthalmology departments. Inclusion criteria included age 18 years or older, visual impairment due to CRVO-related macular edema of less than 12 months with best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score (approximate Snellen equivalent) in the study eye between 19 (20/400) and 78 (20/32), and spectral domain optical coherence tomography imaging central subfield thickness of 320 μm or greater. Data were analyzed from March 4, 2019, to April 26, 2019.

Interventions  Participants were randomized (1:1:1) to receive repeated intravitreal injections of ranibizumab (0.5 mg/0.05 mL) (n = 155), aflibercept (2.0 mg/0.05 mL) (n = 154), or bevacizumab (1.25 mg/0.05 mL) (n = 154) for 100 weeks.

Main Outcomes and Measures  Adjusted mean change in BCVA in the study eye at 100 weeks wherein noninferiority was concluded if the lower bounds of the 95% CI of both the intention-to-treat and the per protocol analyses were above –5 letters.

Results  Of 463 participants, 265 (57.2%) were male, with a mean (SD) age of 69.1 (13.0) years. The mean (SD) gain in BCVA letter score was 12.5 (21.1) for ranibizumab, 15.1 (18.7) for aflibercept, and 9.8 (21.4) for bevacizumab at 100 weeks. Aflibercept was noninferior to ranibizumab (intention-to-treat–adjusted mean BCVA difference, 2.23 letters; 95% CI, –2.17 to 6.63 letters; P < .001). Bevacizumab was not noninferior to ranibizumab (intention-to-treat–adjusted mean BCVA difference, –1.73 letters; 95% CI, –6.12 to 2.67 letters; P = .07). The per protocol analysis conclusions were similar. Fewer mean injections were given in the aflibercept group (10.0) than in the ranibizumab (11.8) group (mean difference at 100 weeks, –1.9; 95% CI, –2.9 to –0.8).

Conclusions and Relevance  Mean changes in vision after treatment of macular edema due to CRVO were no worse using aflibercept compared with ranibizumab. Mean changes in vision using bevacizumab compared with ranibizumab were inconclusive regarding vision outcomes (ie, the change in visual acuity from baseline, on average, may be worse or may not be worse when using bevacizumab compared with ranibizumab).

Trial Registration  ISRCTN13623634

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Article Information

Accepted for Publication: July 8, 2019.

Published Online: August 29, 2019. doi:10.1001/jamaophthalmol.2019.3305

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Hykin P et al. JAMA Ophthalmology.

Corresponding Author: Philip Hykin, FRCOphth, National Institute for Health Research, Moorfields Biomedical Research Centre, 162 City Rd, London EC1V 2PD, United Kingdom (philhykin@gmail.com).

Author Contributions: Mr Hykin and Dr Sivaprasad had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Hykin, Prevost, Murphy, Kelly, Yang, Harding, Lotery, Chakravarthy, Sivaprasad.

Acquisition, analysis, or interpretation of data: Hykin, Prevost, Vasconcelos, Murphy, Kelly, Ramu, Hounsome, Lotery, Chakravarthy, Sivaprasad.

Drafting of the manuscript: Hykin, Prevost, Vasconcelos, Murphy, Kelly, Ramu, Lotery, Sivaprasad.

Critical revision of the manuscript for important intellectual content: Hykin, Prevost, Vasconcelos, Murphy, Kelly, Ramu, Hounsome, Yang, Harding, Lotery, Chakravarthy, Sivaprasad.

Statistical analysis: Prevost, Vasconcelos.

Obtained funding: Hykin, Prevost, Murphy, Kelly, Harding, Lotery, Chakravarthy, Sivaprasad.

Administrative, technical, or material support: Hykin, Prevost, Murphy, Kelly, Ramu, Hounsome, Lotery, Chakravathy, Sivaprasad.

Supervision: Hykin, Prevost, Murphy, Kelly, Hounsome, Lotery, Sivaprasad.

Conflict of Interest Disclosures: Mr Hykin reported receiving research grants from Novartis Allergan and Bayer, travel grants from Novartis Allergan and Bayer, speaker fees from Novartis Allergan and Bayer, and attending advisory board meetings for Novartis, Bayer, and Allergan. Dr Sivaprasad reported receiving research grants from Novartis, Bayer, Allergan, Roche, Boehringer Ingelheim, and Optos Plc, travel grants from Novartis and Bayer, speaker fees from Novartis, Bayer, and Optos Plc, and attending advisory board meetings for Novartis, Bayer, Allergan, Roche, Boehringer Ingelheim, Optos Plc, and Heidelberg Engineering. Dr Hounsome reported receiving a grant from the National Institute for Health Research (NIHR) and was paid by the Kings Clinical Trials Unit with a portion of the LEAVO study NIHR grant. Dr Yang reported receiving research grants from Novartis, Bayer, Allergan, and Roche, travel grants from Novartis, Bayer, Allergan and Roche, speaker fees from Novartis, Bayer, Allergan, and Roche, and attending advisory board meetings for Novartis, Bayer, Allergan, and Roche. Dr Chakravathy reported receiving research grants from the NIHR, Allergan, and Novartis. Dr Harding reported receiving research grants from NIHR and Roche. Dr Lotery reported receiving travel grants from Novartis, Bayer, and Allergan, speaker fees from Novartis, Bayer, and Allergan, and attending advisory board meetings for Novartis, Bayer and Allergan. No other disclosures were reported.

Funding/Support: This study was funded by the United Kingdom Health Technology Assessment Grant from NIHR. The research was supported by the NIHR Biomedical Research Centre at Moorfields Eye Hospital National Health Service (NHS) Foundation Trust, the University College London Institute of Ophthalmology, and the United Kingdom Clinical Research Collaboration–registered King’s Clinical Trials Unit at King’s Health Partners, London, United Kingdom, which is partly funded by the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley, the NHS Foundation Trust and King’s College London, and the NIHR Clinical Research Network.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The LEAVO Study Group included the following: Investigator group members: Haralabos Eleftheriadis, FRCOphth (Department of Ophthalmology, King’s College Hospital NHS Foundation Trust, London, United Kingdom); Michael Briggs, FRCOphth (St Paul’s Eye Unit, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, United Kingdom); Michael Williams, FRCOphth (Department of Ophthalmology, Royal Victoria, Queen's University Belfast, Northern Ireland, United Kingdom); Salwa Abugreen, FRCOphth (Department of Ophthalmology, Royal Blackburn Hospital, Blackburn, United Kingdom); Faruque Ghanchi, FRCOphth (Bradford Ophthalmology Research Network, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, United Kingdom); Nirodhini Narendran, FRCOphth (New Cross Hospital, Wolverhampton & Midland Counties Eye Infirmary, Wolverhampton, United Kingdom); Edward Hughes, FRCOphth (Sussex Eye Hospital, Brighton, United Kingdom); Adam Ross, FRCOphth (Bristol Eye Hospital, Bristol, United Kingdom); Nitin Gupta, FRCOphth (Department of Ophthalmology, West Suffolk NHS Foundation Trust, Suffolk, United Kingdom); Stephen Turner, FRCOphth (Ophthalmology Department, Torbay Hospital, Devon, United Kingdom); Yinka Osoba, FRCOphth (Ophthalmology Department, Torbay Hospital, Devon, United Kingdom); Jignesh Patel, FRCOphth (Ophthalmology Department, Essex County Hospital, Colchester, United Kingdom); Sergio Pagliarini, FRCOphth (Macular Unit, Hospital of St Cross, Rugby, United Kingdom); Peck-Lin Lip, FRCOphth (Birmingham & Midlands Eye Clinic, Birmingham, United Kingdom); Nishal Patel, FRCOphth (Kent and Canterbury Hospital, Canterbury, United Kingdom); Afsar Jafree, FRCOphth (Kent and Canterbury Hospital, Canterbury, United Kingdom); Geeta Menon, FRCOphth (Ophthalmology Department, Frimley Park Hospital NHS Foundation Trust, Surrey, United Kingdom); Sudeshna Patra, FRCOphth (Whipps Cross Hospital, Barts Health NHS Trust, London, United Kingdom); Ben Burton, FRCOphth (James Paget University Hospital, Norfolk, United Kingdom); Simon Taylor, FRCOphth (Department of Ophthalmology, Royal Surrey County Hospital, Guildford, United Kingdom); Sarah Mackenzie, FRCOphth (Harrogate and District NHS Foundation Trust, Harrogate, North Yorkshire, United Kingdom); Richard Gale, FRCOphth (York Teaching Hospital NHS Foundation Trust, York, United Kingdom); Komala Vadivelu, FRCOphth (Darlington Memorial Hospital, County Durham and Darlington NHS Foundation Trust, County Durham, United Kingdom); Martin McKibbin, FRCOphth (Ophthalmology Department, St James’s University Hospital, Leeds Teaching Hospital NHS Trust, Leeds, United Kingdom); Sheena George, FRCOphth (Ophthalmology Department, Hillingdon Hospitals NHS Foundation Trust, London, United Kingdom); Goncalo Almeida, FRCOphth (Department of Ophthalmology, Maidstone Hospital, Maidstone & Tunbridge Wells NHS Trust, Kent, United Kingdom); Piyali Sen, MBBS (Moorfields Eye Hospital, London, United Kingdom); Namritha Patrao, MS (Moorfields Eye Hospital, London, United Kingdom); Deepthy Menon, MS (Moorfields Eye Hospital, London, United Kingdom); Luke Nicholson, FRCOphth (Moorfields Eye Hospital, London, United Kingdom); Yvonne D'Souza, FRCOphth (Central Manchester Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom); James Talks, FRCOphth (Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom); Venki Sundaram, FRCOphth (Luton and Dunstable NHS University Hospital, Hertfordshire, United Kingdom); Sanjiv Banerjee, FRCOphth (University Hospital of Wales, Cardiff, United Kingdom); Maged Habib, FRCOphth (Sunderland Eye Infirmary, Sunderland, United Kingdom); Raghu Ram, FRCOphth (Royal Glamorgan Hospital, North Glamorgan NHS Trust, Llantrisant, United Kingdom); Christopher Brand, FRCOphth (Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, United Kingdom); Douglas Newman, FRCOphth (Addenbrooke’s Hospital, Cambridge, United Kingdom); David Gilmour, FRCOphth (Department of Ophthalmology, Gartnavel General Hospital, Glasgow, United Kingdom); Simon Kelly, FRCOphth (Ophthalmology Department, Bolton NHS Foundation Trust, Bolton, United Kingdom); Rehna Khan, FRCOphth (Calderdale Royal Hospital, Halifax, United Kingdom); Theo Empeslidis, FRCOphth (University Hospitals of Leicester NHS Trust, Leicester, United Kingdom); Colin Jones, FRCOphth (Department of Ophthalmology, Norfolk & Norwich University Hospital, Norwich, United Kingdom); Emily Fletcher, FRCOphth (Cheltenham General Hospital, Gloucestershire, United Kingdom); Louise Downey, FRCOphth (Department of Ophthalmology, Hull and East Yorkshire Hospitals NHS Trust, Hull, United Kingdom); Saad Younis, FRCOphth (Western Eye Hospital, London, United Kingdom); Philip Severn, FRCOphth (James Cook University Hospital, South Tees NHS Foundation Trust, South Tees, United Kingdom); Priya Prakash, FRCOphth (Princess Alexandra Hospital, Harlow, United Kingdom); Ellen Lever, PhD (King’s Clinical Trials Unit, London, United Kingdom). Trial steering committee members: Susan Downes (Oxford Eye Hospital, Oxford, United Kingdom); Irene Stratton (Gloucestershire Hospitals NHS Foundation Trust, Gloucestershire, United Kingdom); Hiten Dodhia (Lambeth & Southwark Councils, Public Health, London, United Kingdom); Greg Fell (Sheffield Council, Public Health, Sheffield, United Kingdom); Riaz Asaria (Royal Free London NHS Foundation Trust, London, United Kingdom); Jonathan Byrne (King’s College NHS Foundaton Trust, London, United Kingdom); Vanessa Burgess (NHS Lambeth Clinical Commisssiong Group, London, United Kingdom); Alison Powling (Community Diabetes, Bartshealth NHS Trust, London, United Kingdom); and Melba Ryde (patient representative). Data monitoring committee members: Sarah Walker (Oxford University, Oxford, United Kingdom); Consuela Moorman (Stoke Mandiville NHS Trust, Aylesbury, United Kingdom); and Baljean Dhillon (Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland).

Disclaimer: The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the UK Department of Health.

Data Sharing Statement: See Supplement 3.

Meeting Presentations: This paper was presented at the Association for Research in Vision and Ophthalmology Annual Meeting; April 29, 2019; Vancouver, Canada; and the Royal College of Ophthalmologists Meeting; May 20, 2019; Glasgow, United Kingdom.

Additional Contributions: Blair McLennan, BSc, Aleksandra Kata, PhD, Janice Jimenez, and Beverley White-Alao, BSc (King’s College Clinical Trials Unit, London, United Kingdom), helped with trial management; Evangelos Georgiou, PhD (King’s College Clinical Trials Unit, London, United Kingdom), assisted with randomization; Shakeel Herwitzer (Liverpool and Broadgreen Pharmacy Aseptic Unit, Liverpool, United Kingdom), MSc, helped with pharmacy manufacture; Tunde Peto, PhD, Clare Newell, BA, Vittorio Silvestri, BTec HND, and Michelle McGaughey, BSc (NetwORC UK Reading Centre, Belfast, Ireland), helped with imaging data collection, processing, grading, and storage; Catherine Grigg, BSc (Moorfields Eye Hospital, London, United Kingdom), helped with trial management; Andi Skilton, PhD (Moorfields Eye Hospital, London, United Kingdom), helped with patient involvement; and Gillian Hood, PhD (the Diabetes Research Lay Panel Group, Queen Mary, University of London/Barts Health, London, United Kingdom), helped with patient involvement. The were not compensated outside their employment wages.

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