Nicedsu.org.uk

BEVACIZUMAB IN EYE CONDITIONS:
ISSUES RELATED TO QUALITY, USE, EFFICACY AND SAFETY
REPORT BY THE DECISION SUPPORT UNIT Edith Poku, John Rathbone, Emma Everson-Hock, Munira Essat, Ruth Wong, Abdullah Pandor, Allan Wailoo School of Health and Related Research, University of Sheffield Decision Support Unit, ScHARR, University of Sheffield, Regent Court, 30 Regent Street Sheffield, S1 4DA Tel (+44) (0)114 222 0734 ABOUT THE DECISION SUPPORT UNIT
The Decision Support Unit (DSU) is collaboration between the Universities of Sheffield, York and Leicester. We also have members at the University of Bristol, London School of Hygiene and Tropical Medicine and Brunel University. The DSU is commissioned by The National Institute for Health and Clinical Excellence (NICE) to provide a research and training resource to support the Institute's Technology Appraisal Programme. Please see our website for further information The production of this document was funded by the National Institute for Health and Clinical Excellence (NICE) through its Decision Support Unit. The authors are grateful to Jenny Dunn and Andrea Shippam for administrative support. The following also provided support and assistance at various stages of the project: Sonia Rizzo, Tony Mead, Anthea Sutton, Rachel Archer, Tim Gomersall, Joanna Leaviss, Sue Harnan and Lesley We received invaluable expert assistance from a number of sources including Greg Fell, Daphne Austin, Bernard Chang and others at the Royal College of Ophthalmologists, Shakeel Herwitker, Nick Precious and Frank Ahfat. We are also grateful for constructive feedback from Christian Griffiths, Elisabeth George, Frances Sutcliffe, Meindert Boysen and Joanne Holden at NICE. We would also like to thank all survey respondents. Referencing
This report should be referenced as follows: Bevacizumab in eye conditions: Issues related to quality, use, efficacy and safety. Poku E, Rathbone J, Everson-Hock E, Essat M, Wong R, Pandor A, Wailoo AJ. NICE DSU Report; 2012. Disclaimer
This report was prepared by the DSU, School of Health and Related Research (ScHARR), based at the University of Sheffield. This report includes a review of the current evidence – studies, literature and information– that was available to the DSU at the time the project was undertaken. The accuracy of the contents of accessed documentation used in this report is not guaranteed or supported by the DSU. The authors do not take responsibility for the propriety, errors, mis-representations or quality of any information, statements or conclusions in the accessed documentation. The DSU takes sole responsibility for the content of this final report. The views, and any errors or omissions, expressed in this document are of the authors only. NICE may take account of part or all of this document if it considers it appropriate, but it is not bound to do so. ABBREVIATIONS AND DEFINITIONS
age-related macular degeneration Area Prescribing Committee best-corrected visual acuity branch retinal vein occlusion provider of private health insurance Comparison of Age-related macular degeneration Treatment Trials cystoid macular oedema choroidal neovascularisation central retinal vein occlusion clinically significant macular oedema diabetic macular oedema Diabetic Retinopathy Clinical Research Network Early Treatment Diabetic Retinopathy Study glycated haemoglobin intraocular pressure intravitreal bevacizumab intravitreal pegaptanib intravitreal ranibizumab intravitreal triamcinolone logarithm of the minimum angle of resolution Milton Keynes, Oxfordshire, Berkshire East, Berkshire West and Buckinghamshire National Institute for Health and Clinical Excellence National Health Service North Derbyshire County PCTs, South Yorkshire and Bassetlaw Commissioning Consortium North East Specialised Commissioning Team Primary Care Trust proliferative diabetic retinopathy photodynamic therapy pigment epithelium detachment punctuate inner choroidopathy provider of private health insurance randomised controlled trial retinal vein occlusion Strategic Health Authority Southampton City PCT, Hampshire PCT, Isle of Wight PCT, Portsmouth City PCT. vascular endothelial growth factor CONTENTS
1 INTRODUCTION
1.1 BACKGROUND
Bevacizumab (Avastin, Roche Products Ltd) is licensed as a treatment for cancer. It is a monoclonal antibody which works by inhibiting vascular endothelial growth factor A (VEGF). VEGF is a mediator in the pathogenesis of certain eye conditions, including wet age-related macular degeneration (AMD), diabetic retinopathy and macular oedema secondary to retinal vein occlusions. There is evidence that VEGF inhibitors can improve vision, whereas the main outcome of traditional treatments such as photodynamic therapy for AMD or laser photocoagulation for macular oedema, is to delay deterioration in vision. There are licensed VEGF inhibitors available in the UK. Ranibizumab (Lucentis, Novartis) is licensed for the treatment of wet AMD, diabetic macular oedema (DMO) and retinal vein occlusion (RVO). Pegaptanib (Macugen) is licensed for the treatment of wet AMD. However these therapies are much more costly than bevacizumab for use in the eye. Ranibizumab costs £742.17 per injection according to the latest edition of the British National Formulary (ref BNF no 63). Pegaptanib costs £514 per injection. Whilst bevacizumab does not have a license for ocular use, it is a much less costly alternative. A 4ml vial for its licensed intravenous use costs £242.66. Intravitreal use requires much smaller doses which are produced by breaking open a vial and drawing them up into a fine syringe to deliver small volumes. Many doses for the eye can be produced from a single bevacizumab vial and therefore can be supplied for a much lower cost of approximately £50 to £100. This is one of the reasons that bevacizumab has been used in this manner since The process of manipulating bevacizumab supplied for use in oncology is not undertaken by the sponsor (Roche) and there have been concerns raised about the risks to patients introduced via this process. The Medicines and Healthcare products Regulatory Agency (MHRA) considers that this manipulation creates an unlicensed medicine. In this report we provide evidence on four issues relating to the use of bevacizumab in eye conditions. These issues are those considered by NICE to be of value in helping to inform committee considerations relating to the considerations of bevacizumab as a comparator in Technology Appraisals for RVO. The DSU will answer four questions: 1) What evidence is there relating to the pharmaceutical quality of reformulated bevacizumab as used in eye conditions in general? (section 2) 2) How widespread is Intravitreal Bevacizumab (IVB) used in the UK? (section 3) 3) What is the evidence for efficacy of IVB in adults with RVO and DMO specifically? (section 4). The evidence base around AMD is not included in this review. 4) What evidence is there regarding adverse events for IVB in eye conditions in general? (section 5). Here the evidence from ALL eye conditions is drawn upon. 2 THE PRODUCTION OF BEVACIZUMAB FOR INTRAVITREAL
INJECTION
Bevacizumab is supplied in 100mg and 400mg vials for its licensed use as an anti-cancer drug where medication is given intravenously. Intravitreal injections require much smaller doses, typically 1.25mg. Therefore the product must be diluted and aliquoted into individual doses. An individual vial of bevacizumab is opened and drawn up into a fine syringe designed to deliver small volumes. There is some dead space within the syringe and so some of the drug will be wasted. Even so it can be seen that one vial of bevacizumab can provide many doses for use in the eye, and this contributes to the much lower cost. This process can either be performed by the hospital pharmacist for same day use or it can be manufactured on a larger scale by specialist units. The former approach was typical historically. There is potentially a greater risk of contamination despite the fact that this is performed under strict sterile conditions because doses will be drawn from a vial over several days, requiring repeated puncturing of the rubber seal and greater operator error as one or more pharmacists in each hospital may be involved. The larger scale manufacturing units are more recent and carry out repackaging in bulk under tightly controlled conditions. It is the view of the MHRA that ocular use of bevacizumab constitutes an "unlicensed" as opposed to "off-label" use because of the manipulation of the licensed product.4 In order to supply reformulated bevacizumab, or any other unlicensed medicinal product, sites must hold a "specials" licence issued by the MHRA.5 Medicines legislation permits the manufacture and supply of unlicensed medicinal products (commonly known as 'specials') subject to certain conditions. The conditions are that there is a bona fide unsolicited order, the product is formulated in accordance with the requirement of a doctor or dentist registered in the UK, and the product is for use by their individual patients on their direct personal responsibility. A 'special' may not be advertised and may not be supplied if an equivalent licensed product is available which could meet the patient's needs. Essential records must be kept and serious adverse drug reactions reported to the MHRA. There are two major suppliers of IVB in the UK, though there are other smaller suppliers: Moorfields Pharmaceuticals, which is the manufacturing arm of the Moorfields Eye Hospital NHS Foundation Trust, and Liverpool and Broadgreen University Hospitals pharmacy. Both hold specials licences and began producing these preparations originally to service clinical trials within the NHS. We undertook a survey of consultant ophthalmologist members of the Royal College of Ophthalmologists (RCO). Whilst the primary aim of this survey was to estimate the extent to which IVB is used in various eye conditions in the UK (and therefore full details of the survey are provided in section 3), we also asked those that prescribe IVB to indicate where the supply comes from. Responses are displayed in Figure 1 below. One hundred and forty three respondents gave a response to this question (excluding 44 N/As). Some respondents indicated multiple sources. 56% indicated that supplies of IVB came from Moorfields Pharmaceuticals. 32% indicated that Liverpool provided their supplies. Figure 1: Source of supplies for IVB
QC18: If you prescribe bevacizumab (Avastin) for any eye condition, do you know where the supply comes from? As part of the IVAN trial, which compares IVB with ranibizumab, Liverpool undertook additional stability testing to provide supplies to the trial. This process can be complex and costly, but is undertaken to establish the safety of extending the shelf-life of the product given the specific circumstances in which it is being manufactured. The stated shelf life of the product supplied by Liverpool is 3 months. The greatest risk from reformulation of bevacizumab is infection. Infectious endophthalmitis is a medical emergency which can lead to loss of vision or even the eye itself. Despite the requirement for strict aseptic conditions when repackaging bevacizumab, cluster outbreaks of endophthalmitis have arisen with IVB. The US Food and Drug Administration (FDA) issued a warning concerning repackaged bevacizumab following 12 reported cases of endopthalmitis arising in three clinics using a single source (a compounding pharmacy) where the Avastin was repackaged in August 2011 following a cluster of infections in Miami.6 The warning stated that "Health care professionals should be aware that repackaging sterile drugs without proper aseptic technique can compromise product sterility, potentially putting the patient at risk for microbial infections. Health care professionals should ensure that drug products are obtained from appropriate, reliable sources and properly administered." The details of the repackaging are not reported. Eleven patients went blind in the affected eye. The most likely cause of this outbreak was contamination during syringe preparation by the compounding pharmacy.7 The New York Times reported two additional clusters;8 one at the Veterans Affairs Hospital in Nashville (4 cases of infection) and another at the Veteran Affairs Hospital in Los Angeles (5 cases). These incidences led to the temporary withdrawal of use of Avastin for AMD in the There were 25 reports of signs and symptoms consistent with sterile endophthalmitis or uveitis suspected to be due to bevacizumab supplied by Moorfields in February 2012 which prompted a recall of several batches and a suspension of production as a precaution.9 Production was restarted at Moorfields on 23 April 2012. No root cause was found. Indeed, one patient received a product not manufactured by Moorfields. 3 THE EXTENT OF USE OF BEVACIZUMAB IN EYE CONDITIONS
The primary aim of this section was to estimate the use of IVB in patients with any eye condition in the UK. Three alternative approaches were employed to make such estimates: A systematic search and review of all publicly available documents from NHS commissioners on the use of bevacizumab in eye conditions Evidence from the two main manufacturers of bevacizumab on the quantity supplied to both NHS and private practitioners A survey of hospital based consultant ophthalmologists The first of these approaches provides indirect evidence relating to use only, since policies on commissioning do not necessarily translate directly into usage at the individual patient level. 3.1 REVIEW OF COMMISSIONING DOCUMENTS
3.1.1 Methods
The aim of the searches was to identify documents relating to bevacizumab use in eye conditions in health establishments in the UK. A mapping process was adopted to identify and retrieve documents that suggested, recommended or supported the use of bevacizumab in the non-private health sectors in England, Scotland and Wales. Searches within specific databases and web-pages of Primary Care Trusts (PCTs) and National Health Service (NHS) sites in England; local health boards in Wales; Health and Social Care Trusts in Northern Ireland and NHS health boards in Scotland were undertaken. In addition, NHS eye hospital websites via NHS Choices were identified and searched. Searching using the Google search engine was also undertaken. Keyword searching was undertaken in web-pages of healthcare establishments. Searching within these websites was possible by the presence of a search box within the site homepage. Search terms ‘bevacizumab' or ‘avastin' were used. Articles and papers were considered to contribute data to this evidence base if IVB use was suggested, recommended or supported for the management or treatment of an ophthalmic condition. Retrieved documents were then examined. Relevant data were abstracted. For records related to NHS and PCT web-pages, data extracted included a description of the document (title, type of document, issue date and review date), related condition(s) of interest according to identifiable PCT or clusters of Search results of the web-pages of PCTs and NHS sites in England were searched on 10th – 11th May, 2012; Local health boards in Wales; Health and Social Care Trusts in Northern Ireland and the NHS health boards in Scotland were searched on 28th May 2012. The lists of websites searched are summarised in Appendix 1. 3.1.2 Results
3.1.2.1 Manufacturing and use of bevacizumab in the UK No relevant results were obtained following searches of the identified web-sites of health board in Wales (n=7); Health and Social Care Trusts in Northern Ireland (n=6) and NHS web-sites (n=14) in Scotland. Seven of the 145 identified NHS and PCT web-sites in England could not be searched due to the absence of a search facility. Of the searchable web-pages, there were 28 distinct links to information that suggested, recommended or supported the use of bevacizumab in eye conditions. Table 1 summarises information on bevacizumab use in the NHS in England. Three of six eye hospital sites suggest the use of bevacizumab. This information is summarised in Table 2.
Table 1: Information indicating bevacizumab use in the UK (NHS)

Condition
Document/ summary of information
Choroidal neovascular membrane NORCOM recommended policy: General policy
secondary to myopia, inflammatory retinal disease, inherited retinal The document was reviewed and supported by NHS Bassetlaw, NHS Barnsley, NHS Doncaster, and NHS Sheffield. The document indicated a commissioning position to routinely fund intra-vitreal Avastin injection for use in choroidal neovascular membrane secondary to myopia, inflammatory retinal disease, inherited retinal disease and trauma up to a maximum of 4 injections. This policy was effective from 1st April 2010. Date (undefined): 12th March 2010 Review date: January 2012 Choroidal neovascular membrane NORCOM recommended policy: General policy
secondary to myopia, inflammatory retinal disease, inherited retinal disease and trauma The document was reviewed and supported by NHS Bassetlaw, NHS Barnsley, NHS Doncaster, and NHS Sheffield. The document indicated a commissioning position to routinely fund intra-vitreal Avastin injection for use in choroidal neovascular membrane secondary to myopia, inflammatory retinal disease, inherited retinal disease and trauma up to a maximum of 4 injections. This policy was effective from 1st April 2010. Date of approval : Risk Management July 2010 Review date: January 2012 ◊ Condition
Document/ summary of information
Minutes of sub-committee meetings Pre-operative treatment in patients requiring plana vitrectomy due to It was noted that the CEC had ‘ratified' a number of policies from the proliferative diabetic retinopathy Milton Keynes, Oxfordshire, Berkshire East, Berkshire West and Buckinghamshire (MOBB) Priorities Committee.(Minutes of CEC meeting, 14th December 2011, page 51) Two of the policies were related to bevacizumab and are listed below. Policies approved by the the CEC from the Milton Keynes, Oxfordshire, Berkshire East, Berkshire West and Buckinghamshire (MOBB) Priorities Committee included: Policy 56: Ranibizumab (Lucentis®), bevacizumab (Avastin®), pegaptanib (Macugen®) and fluocinolone acetonide (Iluvien®) for diabetic macular oedema (An update); Policy 57: Dexamethosone implant (Ozurdex®), ranibizumab (Lucentis®) and bevacizumab (Avastin®) for macular oedema caused by retinal vein occlusion (An update) Date of paper - 12th January 2012; Date of meeting 24th January 2012 Neovascular glaucoma Bevacizumab as a treatment for neovascular glaucoma [Policy
Summary and recommendations Intravitreal bevacizumab (IVB) is considered as an option for patients with neovascular glaucoma (rubeotic glaucoma) which may be associated with CRVO or PDR. Issue date February 2011 Review date: February 2014 Non –AMD choroidal neovascular Bevacizumab for the treatment of non –AMD choroidal neovascular http://www.brightonhovecitypct.nhs.uk/HealthProfessio
disease [Policy document]
Summary and recommendations IVB can be used for the treatment of non- AMD choroidal neovascularisation, a condition associated with uveitis, myopia and previous trauma. However, unlike AMD-related choroidal neovascularisation, remission of the condition can be achieved following one or two injections of IVB. Issue date February 2011 Review date: February 2014 Condition
Document/ summary of information
Pre-operative treatment for Use of bevacizumab for pre-operative treatment for vitrectomy surgery http://www.brightonhovecitypct.nhs.uk/HealthProfessio
vitrectomy surgery in patients with [Policy document] non-remitting DR following conventional laser therapy Summary and recommendations: Bevacizumab can be used to reduce the incidence of intra-operative and post-operative complications such as bleeding. Issue date February 2011 Review date: February 2014 Choroidal neovascularisation Bevacizumab for treatment of choroidal neovascularisation associated
with angioid streaks and retinal dystrophies
angioid streaks and retinal [Policy document]
Summary and recommendations
-IVB use is guided by pre-specified eligibility criteria. Ranibizumab is
considered for ‘IVB-treatment' eligible patients who are allergic to IVB.
-Prescribing physician must meet requirements for off-label prescribing.
-Departmental audit of expected benefits (reduction in laser treatment) and
adverse events in treated patients.
Issue date: 15th April 2010
Review date: Earliest of either SHA guidance, NICE publication or one
year from issue
Neovascular glaucoma due to Bevacizumab in the treatment of neovascular glaucoma due to
ischaemic central retinal vein occlusion
[Policy document]

Summary and recommendations
- Adjunctive use of IVB in this setting
- Usual regime is a single dose of IVB to support pan-retinal
photocoagulation therapy.
- Prescribing physician must meet requirements for off-label prescribing.
- Departmental audit of expected benefits (reduction in laser treatment) and
adverse events in treated patients.
Issue date: 15th April 2010
Review date: Earliest of SHA guidance, NICE publication or one year from
issue.
Condition
Document/ summary of information
Non-ischaemic CRVO Bevacizumab in the treatment of non-ischaemic central retinal vein http://www.bristol.nhs.uk/idoc.ashx?docid=528bd80a-
occlusion is provided on a restricted basis for patients meeting agreed c4fb-4389-931a-2dc85e5a54cc&version=-1
criteria.
[Policy document]

Summary and recommendations:
- IVB use is guided by pre-specified eligibility criteria.
- Usual treatment regime will consist of up to 3 doses of IVB.
Issue date: 15th April 2010
Review date: Earliest of SHA guidance, NICE publication or one year from
issue.
Diabetic macular oedema Unspecified document: South Central Priorities Committee (Milton
Keynes, Oxfordshire, Berkshire East, Berkshire West and
Buckinghamshire PCTs)
Policy recommendation 56: Ranibizumab (Lucentis®), bevacizumab (Avastin®),pegaptanib (Macugen®) and fluocinolone acetonide (Iluvien®) for diabetic macular oedema (An update) Summary Evidence supporting the policy of interest was noted to be limited. Therefore, the committee proposed that the policy needed to be considered ‘LOW PRIORITY' Date of issue: November 2011 Diabetic retinopathy with Minutes of meeting (Milton Keynes, Oxfordshire, Berkshire East,
Berkshire West and Buckinghamshire (MOBB) Priorities Committee):
Date 25th August 2010
Summary Funding for the use of bevacizumab pre-operatively in patients that require plana vitrectomy arising as a complication of proliferative diabetic retinopathy Minutes: NHS Bury Board meeting – 5th August 2010
The Board recommended the use of bevacizumab for the standard treatment of AMD (p. 3). It was also proposed that private providers who were keen to use bevacizumab in the AMD patients should be involved.(p. 1) Date of issue: 25th August 2010 Condition
Document/ summary of information
Peninsula Health Technology Commissioning Group - Commissioning
decision: bevacizumab for the treatment of neovascular (wet) age
related macular degeneration. [unspecified document type]

Summary
The commissioning group agreed on the use of bevacizumab in the
treatment of AMD, as a ‘justifiable alternative' to ranibizumab in patients
eligible to treatment according to the criteria specified in the NICE
technology appraisal guidance 155.
Issue date (date of decision): 22nd June 2011
Review date: Unspecified. However, it was noted that the decision will be
reviewed following available data from ‘further' comparative randomised
studies.
Response to request for information on the Trust's current policy on the
treatment of wet AMD, under the provisions of the Freedom of Information Act 2000, received on 6th December 2011[unspecified document type]
Summary Responses of NHSCD&D were as follows: ‘Treatment for wet AMD and use of either Lucentis or Avastin for wet AMD is commissioned by NORSCORE the North East Specialised Commissioning Group on our behalf.' Document template (v0.6) by Derbyshire County PCT Commissioning
Improvement Team: Service specification
Summary Within the document, it is noted that ‘If and when the dose ranging trial of bevacizumab ('TANDEM) is established this must be actively offered to patients as an option. Patients agreeing to participate will be free to leave the trial and receive ranibizumab if they so wish, at any time.'(p. 3) In another section, it is reported that patients with wet AMD eligible for treatment as per NICE TA 155 recommendations will be offered ranibizumab or bevacizumab as options (p.4). It is not clear whether such patients were participants of the TANDEM trial at the time the document was prepared. Period: 26th November 2008 onwards i The TANDEM Trial: A randomised controlled Trial of high and low dose Avastin® for Neovascular macular Degeneration in the East Midlands. Condition
Document/ summary of information
Policy Recommendation PR007/03: Anti-vascular Endothelial Growth
Factors (Anti-VEGFs) for Age-Related Macular Degeneration (AMD)
Summary and recommendations Photo-dynamic therapy is the recommended first-line treatment for patients with ‘classic or predominantly classic sub-types of AMD' in accordance to NICE guidance. Access to pegatanib treatment based on pre-specified criteria. In the section, entitled – key finding and conclusions – it is stated that, ‘Lucentis® [ranibizumab] and Macugen® [pegaptanib] are licensed for the treatment of AMD, Avastin® [bevacizumab] is not licensed for use in the treatment of wet AMD, but is used off-label.' Issue date: April 2007 Review date : October 2007 NHS Great Yarmouth and Waveney - Annual Operating Plan 2011-12
[Delivery Plans 2011/12 (Operating Plan 11/12)] Summary In relation to Ophthalmology, documented planned action indicated the commencement of Avastin use ‘to improve side effects and reduce the use of Lucentis'. Reported milestones were April 2011 to July 2011. It was unclear what these dates referred to. Date of version: 5th May 2011 Date of review: not stated Untitled Statement
The SHIP PCT Cluster Board approved a policy for clinicians to offer patients the choice of either Avastin or Lucentis in the treatment of Age- Related Macular Degeneration (AMD). Date: unspecified. ii It is unclear whether bevacizumab use is recommended from the information provided. iii A news release on 26th July 2012 stated that the SHIP PCT had cancelled the related policy. Condition
Document/ summary of information
Policy recommendation 100: Bevacizumab for wet age-related macular http://www.southamptonhealth.nhs.uk/EasysiteWeb/get
degeneration
Summary and recommendations The Priorities Committee recommends bevacizumab for all patients with wet AMD, who are eligible to be treated with an anti-VEGF agent. Enhanced audit of clinical outcomes, procedures for IVB procurement and data collection for a local registry were also recommended. Issue date March 2011 Review date: Not stated Non-ischaemic CRVO Bevacizumab in the treatment of non-ischaemic central retinal vein http://www.northsomerset.nhs.uk/Services/funding/Poli
occlusion
[Policy Statement ] Bevacizumab use in patients is based on specified criteria and policy restrictions. Date of Issue/ approval: 15 April 2010 Review date: Earliest of SHA guidance, NICE publication or one year from issue. Minutes of the meeting of the Somerset Primary Care Trust held on
Wednesday, 15 December 2010 at Lyngford House, Taunton, Somerset.
Summary Minutes of meeting held on 15th December 2010 detailing minutes of previous meetings (on 30th September 2010 and 25th November 2010). This document records the discussion of recommendations of the Prescribing Forum in the off-license use of drugs, including Avastin. It is noted that the Professional Executive committee had supported its use in Age-related macular degeneration. Stockport PCT board, Avastin/Lucentis for AMD [unspecified document] Recommendations for the future commissioning of Avastin/ lucentis for Lucentis%20-%20March%2009%20item%2013a.doc AMD Issue date: March 2009 Condition
Document/ summary of information
T27 Bevacizumab for Retinal Vein Occlusion, Diabetic Maculopathy, Diabetic Maculopathy Diabetic Retinopathy, Neovasucular Glaucoma or Choroidal Neovascularisation Neovasucular Glaucoma Choroidal [Form to be completed by attending consultant and endorsed by a designated Neovascularisation commissioner of services] Summary This document details the criteria for commissioning IVB use within the NHS Suffolk Treatments for Age Related Macular Degeneration [Board meeting
Appendix 1: Patients information sheet: New treatments for age-related macular degeneration It was reported under ‘Summary: Treatment for age-related macular ternal-uds-cse&usg=AFQjCNEMV8w6CeFCiLOE-degeneration: Policy position of West Sussex Primary Care Trust' that Avastin, was, at the time, being used in the private sector in the UK and outside of the UK for the treatment of wet AMD. It was also noted that major insurance companies (PPPa and BUPA) had accepted IVB usage. The patient information sheet lists Avastin as one of the treatment options, and also provides information about its unlicensed use in this setting. Issue date: 27th March 2008 Minutes of meeting held on 7th May 2008: Strategic Commissioning Boards
Minutes were reported as an accurate version. An accepted proposal regarding the use of Avastin in AMD patients was noted. (p. 2) Date: 9th May 2008 Summary of Wirral Medicines Guide, 6th Edition: Compiled 2007/08
This is a joint formulary for primary and secondary care. The retrieved version related to Primary Care management. ‘Bevacizumab – hospital only' was recorded under the list of treatment options for various eye conditions. This option was specified for acute macular degeneration. Condition
Document/ summary of information
Neovascular glaucoma Position Statement: Worcestershire NHS: Worcestershire Area
Proliferative diabetic retinopathy Prescribing Committee
Summary The document lists choroidal neovascularisation (CNV) in conditions other than wet age-related macular degeneration (AMD) for which anti-vascular endothelial factor treatment is indicated. In relation to the commissioning of treatment, the report states that restricted use of IVB had been approved for the following: • To facilitate laser coagulation in patients with PDR who had received previous panretinal laser coagulation associated with vitreous haemorrhage • To support surgical delamination of the fibrovascular membranes in PDR patients requiring surgery • Adjunct treatment in patients with neovascular glaucoma. Issue date: 10th May 2011 Review date: May 2013 or May 2013 or sooner if national guidance is made available or a new drugs application for an unapproved indication is submitted to the Worcestershire Area Prescribing Committee (APC) Abbreviations: AMD-age- related macular degeneration; CNV-choroidal neovascularisation; DMO-diabetic macular oedema; DR-Diabetic retinopathy; RVO-retinal vein occlusion; PDR-proliferative diabetic retinopathy; NICE- National Institute for Health and Clinical Excellence; NHS- National Health Service; PCT- Primary Care Trust aPPP – provider of private health insurancebBUPA- provider of private health insurance iv Individual conditions listed in this category include neovascular glaucoma; proliferative diabetic retinopathy; diabetic macular oedema*; macular oedema secondary to retinal vein occlusion; retinopathy of prematurity; multifocal choroidopathy [including punctuate inner choroidopathy (PIC) and multiple evanescent white dot;syndrome]; atypical choroiditides (including histoplasmosis, tuberculous; syphilitic, etc); myopic CNV; CNV in angioid streaks; CNV in choroidal sarcoma; CNV in Gronblad-Strandberg syndrome; CNV in psuedoxanthoma elasticum; CNV in serpiginous choroiditis; CNV in Stargardt's Disease; CNV in vitelliform macular dystrophy. ◊A more recent document could not be accessed. Table 2: Summary of information related to bevacizumab use in eye hospitals

Hospital
Condition
Source(s)
Moorfields Eye Hospital New treatments for wet age-related macular Listed treatment options included Avastin, Macugen and Lucentis Manchester Royal Eye Hospital Subfoveal CNV or A representative group of patients included in juxtafoveal CNV caused the Greater Manchester Avastin trial for choroidal neovascularisation (GMAN) trial. The study evaluates two different dosing regimens of Avastin over a period of two years. Funding for the trial is by the Primary Care Trusts of Greater Manchester. Proposed date of completion: December 2012 Birmingham Eye Hospitals Various conditions Avastin is included in list of available including AMD, RVO treatments at the centre. Available evidence is based on 15 policy-related documents, 5 minutes of board meetings or similar discussions and a number of unspecified documents. The most common disease condition considered was AMD. From the existing evidence, it was unclear whether bevacizumab was the first-line of treatment in selected eye conditions in most situations. Typically, PCTs permit the use of IVB as a treatment option alongside other licensed alternatives. However, its role as an adjunctive treatment in pre-operative treatment for vitrectomy surgery in patients with non-remitting diabetic retinopathy (DR) following conventional laser therapy,10 neovascular glaucoma due to ischaemic central retinal vein occlusion (CRVO)11 and proliferative diabetic retinopathy (PDR)12 were reported. Bevacizumab was also recommended ‘to improve side effects and reduce the use of Lucentis' in unspecified Information on the exact dose of IVB was not stated in any document. Dosing regimens varied between a single dose, one to two doses and up to three doses for neovascular glaucoma due to ischaemic CRVO; non-AMD choroidal neovascular disease and non-ischaemic CRVO respectively.11 In the related policy documents, patient eligibility criteria were described. The responsibilities of prescribers were also stated. In some cases, information provided in the retrieved documents was unclear. For instance, one PCT noted that it would consider bevacizumab use in AMD patients following the results of the TANDEM trial, a randomised controlled Trial of high and low dose Avastin for Neovascular macular Degeneration in the East Midlands.14 On the other hand, it mentioned, under another section ‘that patients with wet AMD eligible for treatment as per NICE TA 155 recommendations will be offered ranibizumab or bevacizumab as options'. In two cases the extensive use of IVB in private practice and internationally was referred to as one of the considerations of funders considering their NHS based policies PCT reports.15,16 3.1.2.2 International use of bevacizumab A study based on 2008 US Medicare claims data found that use of bevacizumab was substantially higher than ranibizumab for patients with AMD. They found that from more than 200,000 beneficiaries, 64.4% received bevacizumab and 35.6% ranibizumab. In 39 out of 50 states the rate of injection was higher with bevacizumab than ranibizumab.17 Medicare is the national social insurance programme that provides coverage for those aged 65 years and over, as well as some young people with certain disabilities. It is worth noting here that patients typically pay 20% of the drug cost under Medicare coverage. Other US health insurance companies sanction the use of bevacizumab for eye conditions such as A survey of Israeli Retinal Specialists obtained an 80% response rate (n=50 respondents) and found that most (56%) offered both bevacizumab and ranibizumab to their patients with AMD.20 40% offered bevacizumab as the treatment of choice and just 4% offered ranibizumab as the treatment of choice. These choices were often influenced by the socioeconomic status of the patient, which is relevant because ranibizumab is substantially more expensive than bevacizumab and is not fully covered by Israeli health funds. An internet survey conducted between November 2005 and April 2006, is reported by Fung et al.21 The International Intravitreal Bevacizumab Survey primarily reported adverse events following the use of bevacizumab for ocular conditions in 70 centres across 12 countries and 4 continents. The survey utilised a web-based questionnaire to collect data on individual centres; data included details of the centre and contributing physicians, number of patients treated and number of administered injections during the course of treatment. The survey reported that 5,228 patients received 7,113 injections during the study period (Nov 2005 to April 2006), with participating centres reporting a mean of 75 patients (median: 40; range: 1-506) and a mean of 102 injections (median: 50; range: 1- 691). This translates to an estimated 1.36 injections per patient over a 6 month period. Ranibizumab is usually given once monthly. Further details needed to identify centres or participating countries were not available from the publication. However, it is of note that the authors conclude that "Intravitreal bevacizumab is being used globally for ocular diseases". 3.1.3 Summary
The review of publicly available documentation related to commissioning of services provides some indications of policy directions on the use of bevacizumab in certain regions of the UK. The commonest condition where bevacizumab is used, based on NHS and PCT-related information, is Not all PCTs provide publicly available or web-based statements of policy on this matter. Those that do may be out of date and therefore not fully representative of current policy. For example, the Central and East Cheshire PCT site yielded no records related to bevacizumab use, whereas recent news reports make it clear that this PCT cluster does have a policy associated with the unlicensed use Identified reports indicate general policy stances in relation to bevacizumab and, in general, consider it as an option alongside the licensed alternatives. However, some commissioners have gone further and state that bevacizumab should be the standard commissioned treatment for some conditions, including AMD despite existing positive NICE guidance relating to ranibizumab. None of these documents directly indicate the number of patients treated with IVB in specific health settings. 3.2 QUANTITY SUPPLIED BY MAIN UK MANUFACTURERS
As reported above, there are two main suppliers of IVB in the UK: Moorfields Pharmaceuticals and Liverpool and Broadgreen Hospitals trust, though supplies may also come from local hospital dispensing units and from other manufacturing units. We made requests to Moorfields and Liverpool for their sales data in order to provide estimates of the extent of UK use. Results are provided in Table 3: Sales of bevacizumab for use in the eye (individual doses)
**************** **************** **************** **************** **************** A very crude approximation of the total supply of IVB can be made based on the response to the survey of use reported in section 2. Here we found that 56% and 32% respectively of clinicians reported that the IVB they prescribe is supplied by Moorfield and Liverpool respectively. Because respondents can receive supplies from more than one source, responses sum to 118% of the total sample. Therefore, one might estimate that 75% (47% + 27%) of supplies overall are provided by these two manufacturers. It is impossible to estimate the number of patients treated from these figures since we are unaware of the dosing regimen typically used by clinicians in practice. Two main options considered in the IVAN and CATT trials are for monthly doses or retreatment as required. The CATT study reports that in the first year, the mean number of injections received by those in the "on demand" treatment Estimates of the populations eligible for treatment using VEGF are difficult to make. There are uncertainties surrounding the precise conditions for which VEGFs are suitable, the prevalence of those populations, the size of those populations eligible for VEGF treatment, the numbers that have previously been treated and stopped therapy, etc. Nevertheless some estimates are required for The manufacturer submission for TA 237 (Ranibizumab for diabetic macular oedema) suggests prevalence figures of between 25,000 and 75,000 in England and Wales. The ERG suggest that prevalence is unknown, that non UK based estimates may be higher, but that their generalisability to the UK may be limited. The manufacturer submission for TA 229 (Dexamethasone for macular oedema caused by RVO) estimates the annual incident number of patients eligible for treatment at 23,430. Both the manufacturer submission for technology appraisal of ranibizumab for macular oedema caused by RVO (currently ongoing) and the ERG report highlight the fact that data to estimate the population of patients that may be eligible for treatment with ranibizumab is extremely limited. In TA 155, Ranibizumab and pegaptanib for age-related macular degeneration, the assessment group cite a study that suggests 4,655 new cases per year eligible for Photodynamic Therapy (PDT) in the UK. Novartis presented estimates of 6,425 eligible patients progressing to treatment per year. Estimates of the eligible population receiving pegaptanib from the manufacturer submission varied by year and according to the assumptions made but were a maximum of ***********. 3.3 SURVEY OF HOSPITAL BASED CONSULTANTS
We devised a survey which asked clinicians to indicate the extent to which they prescribe IVB, distinguishing AMD, RVO, DMO and other eye conditions and private from NHS practice. The survey was conducted exclusively online during a two week period in the summer of 2012. Participants were invited to complete the survey via an email which was sent to all hospital consultants registered as members of the Royal College of Ophthalmologists (RCO). A single reminder was sent after one week. 1163 invites were sent out and 199 (17%) responses were received. Responses to the following questions are reported in Table 4: "Thinking about the last 6 months, in NHS/private patients for whom you consider an anti VEGF drug to be appropriate, do you prescribe bevacizumab (Avastin) in patients diagnosed with AMD/RVO/DMO/other eye conditions: Always or nearly always / Sometimes/ Hardly ever / Never / NA" This was asked separately by eye condition and for NHS and private work i.e. 8 different questions. For NHS work only, the following supplementary question was asked, with available options dependent on the answer to the previous question: "In approximately what proportion of patients with AMD/RVO/DMO/other eye conditions do you prescribe bevacizumab (Avastin)? under 10% / 10% to 29% / 30% to 49% / 50% to 70% / Over 70%" We asked respondents to indicate the reasons why they did or did not tend to prescribe IVB, if their practice had changed for AMD patients following the production of positive NICE guidance for ranibizumab in 2008 and where the IVB they prescribe is supplied from. There was also the option for respondents to leave open ended comments at various stages of the survey. Table 4: Responses to questions on use of IVB by eye condition and by NHS/private practice
Always or
nearly always
Sometimes
Hardly ever
Other eye conditions Other eye conditions We found that for all questions on use there were a large number of respondents that indicated "NA" for all questions. In open ended responses, many indicated that they do not prescribe VEGFs at all but refer patients to retinal specialists. This left 150 responses to these questions when referring to NHS practice. For private practice the proportion of NAs increased as many of the same do not undertake private work. 10 responses were obtained for these questions. For AMD patients in the NHS, most respondents (80%) never prescribe bevacizumab. Only 3% said that they prescribe IVB "always or nearly always". 5% indicated that they prescribe IVB 50% of the time or more. Responses to this question indicated much lower use than for other eye conditions of for private practice AMD patients. When asked why they do not prescribe IVB for this patient group, the most common reason cited was "NICE guidance" (73% of the 26 that responded). Other common reasons cited were "PCT / funding policy", "guidance from other bodies", "fear of litigation" and "concerns around safety". When asked how their current practice compared to that prior to NICE guidance only 31 responses were obtained. Of those, 55% said they use IVB less now, 10% more now and 26% said they use IVB about the same amount now. For RVO and DMO, responses were broadly similar regarding NHS practice. Slightly over 40% of respondents never prescribe IVB. Almost 30% of respondents "sometimes" prescribe IVB and 20% "always or nearly always". Prescribing rates are slighly higher in RVO compared to DMO. 22% of respondents prescribe IVB 50% of the time or more for patients with RVO compared to 19% for For other eye conditions respondents were less likely to choose either extreme of "never use" or "always or nearly always". 46% of respondents indicated that they "sometimes" prescribe IVB. In all situations, a greater proportion of respondents indicated they were more likely to prescribe IVB in private practice than in NHS practice. 41% of respondents indicated that they prescribe IVB either "always or nearly always" or "sometimes" for patients with AMD in private practice. The figures for RVO, DMO and other eye conditions were 63%, 58% and 54% respectively. There are clearly some limitations to the survey. The response rate is relatively low given the size of the population that the emailed invitation was mailed to. The RCO used their own membership email records. We have no knowledge of how accurate those might be, nor how many of those clinicians check their emails regularly. The survey was live during late July when many take their holidays. We do not know if the comparisons of private and NHS practice are robust because these are not the same samples. It may be the case that those that engage in private practice are more likely to also prescribe IVB in NHS practice as well. 3.4 SUMMARY
Three approaches have been described in order to estimate the extent of use of IVB in eye conditions in the UK: a review of commissioning policies, supply data from the two major manufacturers of IVB and a survey of consultant ophthalmologists. In general terms it appears that there is substantial use of IVB across the UK NHS but there is also substantial variation. Few PCTs advocate the use of IVB exclusively in the documents we identified from publicly available sources, particularly in AMD. The majority of the documents we identified permit the use of IVB but alongside other licensed alternatives. There are two major manufacturers of IVB in the UK. The quantity of IVB supplied from these centres was almost ******** in 2011. How many patients this equates to is unclear as the dosing for different disease areas is unknown and potentially variable. For example, some studies have considered monthly doses of IVB in AMD patients compared to other studies in DMO where a single baseline injection may be used. Estimates of the size of the patient populations treated with these or other therapies is also extremely uncertain. A survey of hospital based consultants reveals that there is little use of IVB in NHS patients with AMD, mainly as a result of NICE guidance in favour of an alternative therapy. In other disease areas a substantial use of IVB is reported. Use of IVB is even more widespread in private practice, including in patients with AMD. 4 THE EFFICACY OF INTRAVITREAL BEVACIZUMAB FOR THE
TREATMENT OF DMO AND RVO
4.1 METHODS
A systematic review of the literature and meta-analysis (where appropriate) was undertaken to evaluate the efficacy of bevacizumab monotherapy in the treatment of diabetic macular oedema (DMO) and retinal vein occlusion (RVO). A review of the evidence was undertaken in accordance with the general principles recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 4.1.1 Literature searching
a) Electronic databases Studies were identified by searching the following electronic databases and research registers: • MEDLINE(R) In-Process & Other Non-Indexed Citations and MEDLINE(R) (Ovid) 1948 to • EMBASE (Ovid) 1974 to May 2012 • Cochrane Database of Systematic Reviews (Wiley Interscience) 1996 to May 2012 • Cochrane Central Register of Controlled Trials (Wiley Interscience) 1898 to May 2012 • Health Technology Assessment Database (Wiley Interscience) 1995 to May 2012 • Database of Abstracts of Review of Effects (Wiley Interscience) 1995 to May 2012 • Clinicaltrials.gov • EU Clinical Trials Register • metaRegister of Controlled Trials Sensitive keyword strategies using free text and, where available, thesaurus terms using Boolean operators and database-specific syntax were developed to search the electronic databases. Synonyms relating to the condition (e.g. RVO or DMO) were combined with synonyms relating to the intervention (e.g. bevacizumab, avastin). A methodological search filter aimed at restricting search results to RCTs was used in the searches of MEDLINE and EMBASE only. No language restrictions were used on any database. Although no date restrictions were applied for the review of IVB in patients with RVO, the clinical effectiveness searches were restricted by date for the review of IVB in patients with DMO. For this review, the current review updated an existing systematic review on IVB for the treatment of DMO22 (within the scope of the current review). In the review by Fortin et al.,22 the searches examined the period from 1948 to November 2011 (with no language restrictions). The search strategies from the existing systematic review were of good quality and clearly reported. To minimise the risk of missing potentially relevant papers, the clinical effectiveness searches were limited by date from January 2010 to May 2012 in an attempt to cover the period in the last two years which would overlap with the search period of the existing review. An example of the MEDLINE RVO and DMO search strategy is provided in Appendix 2. b) Other resources To identify additional published, unpublished and on-going studies, the reference lists of all relevant studies (including existing systematic reviews) were checked and a citation search of relevant articles (using the Web of Science Citation Index Expanded and Conference Proceedings Citation Index - Science) was undertaken to identify articles that cite the relevant articles. In addition, key experts in the field were contacted. All identified citations from the electronic searches and other resources were imported into and managed using the Reference Manager bibliographic software, (version 12.0; Thomson Reuters, Philadelphia, PA). 4.1.2 Selection criteria
The inclusion of potentially relevant articles was undertaken using a two-step process. First all titles were examined for inclusion by one reviewer. Any citations that did not meet the inclusion criteria i.e. non-human, unrelated to bevacizumab and or RVO / DMO were excluded. Second, remaining abstracts and full text articles were examined independently. Any disagreements in the selection process were resolved through discussion with a second reviewer and if agreement could not be reached, a third reviewer was consulted. The relevance of each article for the systematic review was assessed according to the following criteria: All RCTs that were published or unpublished were included. Reviews of primary studies were not included in the analysis, but were retained for discussion and identification of additional studies. Moreover, the following publication types were excluded from the review: animal models; preclinical and biological studies; narrative reviews, editorials, opinions; and non-English language The population comprised adults (defined as ≥ 18 years of age) with DMO or RVO. c) Interventions The intervention was the administration of IVB (any dose) monotherapy. d) Relevant comparators The relevant comparators for the DMO and RVO reviews were as follows: • Laser photo-coagulation • Sham treatment or placebo • Dexamethasone (RVO review only). The outcomes of interest for the DMO and RVO review were as follows: visual acuity, contrast sensitivity and central macular thickness (DMO review only). 4.1.3 Data abstraction and quality assessment
Data abstraction was performed by one reviewer into a standardised data extraction form. Any uncertainties or queries were resolved by discussion with a second reviewer and if agreement could not be reached, a third reviewer was consulted. Where multiple publications of the same study were identified, data were extracted and reported as a single study. Moreover, for the DMO review all relevant data was extracted from the Fortin et al. review22 in the first instance, and cross checked for accuracy with the original papers. Where necessary, additional data was extracted from the original papers or in cases where information was missing from the articles, authors of the respective studies were contacted to provide further details. The following information was extracted for all studies when reported: study characteristics (e.g. author, year of publication, country, follow-up, funding), participant details (e.g. inclusion and exclusion criteria), intervention and comparator details (e.g. description and dose) and outcomes. The methodological quality of each included study was assessed by one reviewer. Any uncertainties or queries were resolved by discussion with a second reviewer and if agreement could not be reached, a third reviewer was consulted. The study quality characteristics were assessed according to the Cochrane Collaboration Risk of Bias Tool (namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and ‘other issues').23 4.1.4 Data analysis
Data were tabulated and discussed in a narrative review. Where appropriate, meta-analyses were employed to estimate a summary measure of effect on relevant outcomes using the Cochrane Review Manager software RevMan 5.0 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). The relative risk and/ or risk difference were calculated for dichotomous outcomes. Where continuous scales of measurement were used, the mean difference was used. A standard I-squared statistic for heterogeneity was used to test for heterogeneity of treatment effect between trials and a threshold of 50% was considered significant. The fixed effects model was applied to obtain summary statistics of pooled trials unless significant between study heterogeneity was present, in which case a random effects method was used. 4.2 RESULTS
4.2.1 Quantity and quality of research available
4.2.1.1 Number of studies identified/included The literature searches identified 408 citations. For the DMO review, one RCT24 met the inclusion criteria and was added to the six trials25-30 from the previous systematic review.22 For the RVO review, five RCTs31-35 met the inclusion criteria. A flow chart describing the process of identifying relevant literature can be found in Figure 2. A summary of excluded full text papers with reasons is presented in Appendix 3. Figure 2: Study flow chart (adapted): Efficacy review36

Records identified through database Additional records identified through other sources Records screened by title Excluded by title Record screened by Excluded by abstract Full-text articles (references) assessed for Full-text articles excluded Full text articles included Studies from existing systematic review meeting the review inclusion criteria Studies included Studies included 4.2.1.2 Number and type of studies excluded A total of 62 full text articles were excluded as they did not meet all the pre-specified inclusion criteria. The majority of the articles were excluded primarily on the basis of inappropriate study design (not RCTs), incorrect intervention (not IVB for the treatment of DMO or RVO), incorrect comparator or unsuitable publication type (reviews, commentaries or editorials). A full list of excluded studies with reasons for exclusion is presented in Appendix 3. 4.2.2 Assessment of effectiveness
4.2.2.1 Description of included studies (design and patient characteristics) • DMO review
Seven RCTs contributed data to the review of efficacy in DMO patients. One study25 compared bevacizumab with sham injection. Six studies compared bevacizumab to laser photocoagulation.24,26- 30 Studies were conducted in Iran, USA, UK and Egypt, and included patients diagnosed with DMO. Two studies25,26 enrolled patients with DMO refractory to laser treatment. Two studies29,30 enrolled treatment-naive patients. Solaiman22 randomised the smallest number of eyes (n=62), whilst Soheilian21 was the largest study with (n=150) eyes. Michaelides18 randomised (n=80) eyes, Mansourian16 (n=103) eyes, DRCRN27 (n=109) eyes, Ahmadieh25 (n=115) eyes and Faghihi28 randomised (n=130) eyes. The frequency of injections (where reported) varied between the studies. In the Ahmadieh25 study 1.25 mg of bevacizumab was given at baseline and weeks 6, 12 in comparison to sham injection. In the studies using laser therapy as the control group, Faghihi28 reported using 1.25 mg of bevacizumab but repeat injections were not stated. Mansourian24 reported using 1.25 mg of bevacizumab but did not report if repeat injections were used. Michaelides26 gave 1.25mg of bevacizumab at baseline, and at 6 and 12 weeks, and subsequent injections were administered until a stable central macular thickness was attained, but the number of patients requiring further injections was not reported. Solaiman30 gave 1.25mg of bevacizumab once at baseline. Soheilian29 gave 1.25 mg at baseline and retreatment given based on persistence of clinically significant macular oedema, although the number of patients given additional IVB was not reported. In the DRCRN27 study participants in group 1 were given 1.25 mg of bevacizumab at baseline and week 6; group 2 received 2.5 mg at baseline and week 6 and in group 3, 1.25 mg of bevacizumab was given at baseline. Further details of the design and patients characteristics are presented in Appendix 4. • RVO review
Five RCTs were identified that examined the effectiveness of IVB on BCVA in patients with RVO. Two were reported in journal articles,31,34 whereas the remaining three were only available as conference abstracts32,33,35 so limited information is available for these three studies. Three RCTs examined the impact of IVB among patients with central retinal vein occlusion (CRVO)31-33 and two others examined patient populations with branch retinal vein occlusion (BRVO)34,35 (Appendix 5, table A8). Three studies compared 1.25 mg doses of IVB with sham injections that were six weeks apart, however two studies examined the effectiveness of two IVB/sham injections (at baseline and week 6), measuring outcomes at 6 and 12 weeks,34,35 whereas in the other study four IVB/sham injections were administered (at baseline and weeks 6, 12 and 18), with outcomes measured at 6, 12, 18 and 24 weeks.31 In two studies reported in abstracts the IVB was compared with IVB/triamcinolone combined therapy (not examined in this review) and sham injections, however concentrations of IVB administered were not reported.32,33 One of these abstracts also did not report the number of injections administered,32 however in the other IVB was administered three times, six weeks apart. Studies sizes were similar with Epstein31 randomising 60 eyes, Habibabadi32 randomised 63 patients, and Moradian27 randomised 70 patients. The method used to assess BCVA differed across trials. One trial assessed change in BCVA by the number of ETDRS letters,31 whereas another measured change in BCVA using a Snellen chart transformed to logMAR.34 The three trials reported in abstracts did not provide any details on the measurement of BCVA.32,33,35 One trial34 had slightly older participants and a lower proportion of females than another trial,31 with no information on participants being specified in the three trials reported in abstracts only (Appendix 5, table A9). Baseline BCVA could not easily be compared between trials as the only two trials reporting this variable used different measures of BVCA. Both trials for which baseline participant characteristics were given reported no difference in baseline study characteristics;31,34 it was not possible to ascertain similarity of groups at baseline in the studies reported in abstracts only.32,33,35 4.2.2.2 Quality assessment of RCTs • DMO review
Only four studies reported how randomisation was performed.25,26,28,29 Three studies25,26,29 reported methods used to conceal allocation to treatment. Blinding of participants and personnel was attempted by two studies24,29 whilst three studies25,28,30 did not report if blinding was attempted, and in two studies blinding was not undertaken.26,27 Blinding of outcome assessors was reported in six studies.24-29 Study attrition was only reported in four studies.25-27,29 It was unclear in six studies if outcomes were selectively reported, one study27 stated outcomes measures a priori. A summary of the methodological quality of each included study is presented in Figure 3. Figure 3: Methodological quality summary: Review authors judgments about each
methodological quality item for each included study in the DMO review
• RVO review
The overall methodological quality of the five included studies is summarised in Figure 4. One of the included RCTs was considered to be of good quality 34 and another was of moderate quality.31 The quality of three RCTs was largely unclear,32,33,35 due to only an abstract being available. Figure 4: Methodological quality summary: Review authors judgments about each
methodological quality item for each included study in the RVO review
4.2.2.3 Effects of interventions • DMO review
Results were synthesised by meta-analyses for the DMO efficacy data. Comparators were laser therapy and sham injections. The following outcomes were considered: improvement in BCVA (ETRDS of 15 letters or 3 lines) at 6 weeks, 12 weeks to 16 weeks and 36-52 weeks; BCVA (ETRDS 15 letters) at 12 weeks and 12 months; mean difference in BCVA logMAR by 4 to 6 weeks, 12 to 16 weeks, at 24 weeks, at 48 weeks and up to 2 years; mean change in BCVA (ETDRS logMAR) score; deterioration of BCVA (ETRDS of 15 letters or 3 lines) at 6 weeks, at 12 weeks to 16 weeks and at 36-54 weeks and mean change in central macular thickness (CMT) scores at 6, 12, 18 and 24 weeks. a) Bevacizumab versus laser therapy
i) Outcome: BCVA ETDRS 15-Letter (3 lines) Figure 5 summarises the BCVA ETDRS 15-Letter (3 lines) data of IVB compared with laser therapy. By six weeks (using fixed effects model) improvement on BCVA 15-letters significantly favoured the IVB group (Graph not shown, 2 RCTs, n=187, RR 4.42 CI 1.45 to 13.46) compared with laser therapy, but data were heterogeneous (I2 =50%). Due to significant heterogeneity, converting to a random effects meta-analysis rendered the data non-significant (2 RCTs, n=187, RR 3.33 CI 0.56 to 19.74). Significant improvement at 12-16 weeks occurred in the IVB group (2 RCTs, n=187, RR 3.73 CI 1.51 to 9.25) compared with laser therapy. Longer term BCVA data from 36 to 52 weeks significantly favoured IVB (2 RCTs, n=180, RR 2.57 CI 1.21 to 5.44) compared with laser therapy.
Figure 5: Improvement in BCVA ETDRS 15- letter (3 lines)
ii) Outcome: BCVA ETDRS ≥10 Letters Figure 6 summarises the BCVA ETDRS data of IVB compared with laser therapy. At 12 weeks, no significant difference (1 RCT, n=87, RR 1.40 CI 0.45 to 4.33) was found. Results at 12 months revealed significantly greater improvement in BCVA in IVB group (1 RCT, n=80, RR 3.92 CI 1.21 to 12.71) compared with laser therapy. Figure 6: Improvement in BCVA ETDRS ≥10 letters
Risk Ratio
Risk Ratio
Study or Subgroup
Total Events Total Weight
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
1.2.1 by 12 weeks
1.40 [0.45, 4.33] Subtotal (95% CI)
19 100.0%
1.40 [0.45, 4.33]
Heterogeneity: Not applicableTest for overall effect: Z = 0.58 (P = 0.56) 1.2.2 by 12 months
3.92 [1.21, 12.71] Subtotal (95% CI)
38 100.0%
3.92 [1.21, 12.71]
Heterogeneity: Not applicableTest for overall effect: Z = 2.28 (P = 0.02)
iii) Outcome: Mean difference in BCVA logMAR for Bevacizumab versus Laser (high score=worse)
Figure 7 summarises the BCVA ETDRS logMAR data of IVB compared with laser therapy. At 4 to 6 weeks, the IVB group had significantly lower mean BCVA scores compared with laser therapy (Graph not shown, 3 RCTs, n=194, RR -0.07 CI -0.14 to -0.01), although data were heterogeneous (I2=93%) and therefore a random effects model was adopted which rendered 4-6 week data non- significant (RR -0.11 CI-0.37 to 0.14). Soheilian29 also reported results at six weeks but data are skewed (not normally distributed) and were not added to the meta-analysis. At 12 to16 weeks data were equivocal between IVB and laser therapy (1 RCT, n=89, RR -0.01 CI -0.14 to 0.12). Three studies24,29,30 reported BCVA logMAR scores but the data were skewed and were not added to the meta-analysis. At 24 weeks data were equivocal between IVB and laser therapy (1 RCT, n=40, RR - 0.03 CI -0.39 to 0.33). One study24 reported results at 24 weeks but the data were skewed and not added to the meta-analysis. At 48 weeks, significantly greater improvement in BVCA occurred in the laser group (1 RCT, n=65, RR 0.21, CI 0.10 to 0.32) compared with the IVB group (Figure 7). One study29 reported one and two year outcome data for BCVA but data are skewed and not added to the meta-analysis.
Figure 7: Mean difference in BCVA ETDRS LogMAR score
Study or Subgroup
SD Total Mean
SD Total Weight
IV, Random, 95% CI
IV, Random, 95% CI
1.2.1 BCVA ETDRS LogMAR, mean final point data (by 4-6 weeks, high score = worse)
-0.16 [-0.28, -0.04] 0.12 [0.02, 0.22] -0.31 [-0.44, -0.18] Subtotal (95% CI)
99 100.0%
-0.11 [-0.37, 0.14]
Heterogeneity: Tau² = 0.05; Chi² = 29.81, df = 2 (P < 0.00001); I² = 93%Test for overall effect: Z = 0.87 (P = 0.38) 1.2.2 BCVA ETDRS LogMAR (12-16 weeks)
-0.01 [-0.14, 0.12] Subtotal (95% CI)
47 100.0%
-0.01 [-0.14, 0.12]
Heterogeneity: Not applicableTest for overall effect: Z = 0.15 (P = 0.88) 1.2.3 BCVA ETDRS LogMAR (24 week)
-0.03 [-0.39, 0.33] Subtotal (95% CI)
19 100.0%
-0.03 [-0.39, 0.33]
Heterogeneity: Not applicableTest for overall effect: Z = 0.16 (P = 0.87) 1.2.4 BCVA ETDRS LogMAR (48 weeks)
0.21 [0.10, 0.32] Subtotal (95% CI)
33 100.0%
0.21 [0.10, 0.32]
Heterogeneity: Not applicableTest for overall effect: Z = 3.60 (P = 0.0003) Favours IVB Favours Laser iv) Deterioration or any deterioration (BCVA ETDRS 15 letter - 3 lines) Figure 8 summarises the deterioration in BCVA of patients treated with IVB compared with laser therapy. Two studies reported data at 6 weeks and no significant difference in deterioration of BCVA 15-letters was found between IVB and laser therapy (n=187, RR 0.37 CI 0.08, 1.60). By 12- 16 weeks, significantly fewer participants in the IVB group had visual acuity deterioration compared with laser therapy (2 RCTs, n=187, RR 0.15 CI 0.03 to 0.70). However, data were heterogeneous (I2=66%). Random effects analysis rendered this outcome non-significant (Graph not shown, RR 0.22 CI 0.01 to 4.84). Longer term follow up data (36 to 54 weeks) significantly favoured IVB (2 RCTs, n=180, RR 0.17 CI 0.05 to 0.56) compared with laser therapy. Figure 8: Deterioration or any deterioration (BCVA ETDRS 15 -letter - 3 lines) (High score =
worse)
Risk Ratio
Risk Ratio
Study or Subgroup
Events Total Weight
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
1.3.1 by 6 weeks
0.28 [0.04, 1.85] 0.50 [0.05, 5.34] Subtotal (95% CI)
0.37 [0.08, 1.60]
Heterogeneity: Chi² = 0.14, df = 1 (P = 0.70); I² = 0%Test for overall effect: Z = 1.33 (P = 0.18) 1.3.2 by 12-16 weeks
0.84 [0.09, 7.61] 0.05 [0.00, 0.79] Subtotal (95% CI)
0.15 [0.03, 0.70]
Heterogeneity: Chi² = 2.98, df = 1 (P = 0.08); I² = 66%Test for overall effect: Z = 2.42 (P = 0.02) 1.3.3 by 36 to 54 weeks
0.11 [0.01, 0.86] 0.22 [0.05, 0.98] Subtotal (95% CI)
0.17 [0.05, 0.56]
Heterogeneity: Chi² = 0.28, df = 1 (P = 0.60); I² = 0%Test for overall effect: Z = 2.93 (P = 0.003) Favours IVB Favours laser
v) Mean difference in Central Macular Thickness score
Figure 9 summarises the CMT mean scores of IVB compared with laser therapy. Fixed effects analysis of CMT mean scores at 4 to 6 weeks significantly favoured IVB (Graph not shown, 4 RCTs, n=294, RR -63.79 CI -80.05 to -47.54) compared with laser therapy but data were heterogeneous (I2 =84%). Using a random effects model, the data remained significant (p=0.05) however, the confidence intervals were wider (RR -44.83 CI -90.01 to 0.35). At 12 to 16 weeks the CMT mean scores were equivocal between IVB and the laser therapy groups (4 RCTs, n=294, RR -0.60 CI - 23.44 to 22.24). At 24 weeks, no significant differences were found in CMT mean scores (3 RCTs, n=194, RR 8.78 CI -38.97 to 56.53) between IVB and laser therapy. Longer term data at 36 to 52 weeks found no significant difference in CMT mean scores between IVB and laser therapy (3 RCTs, n=230, RR -27.64 CI -58.48, 3.19). No significant differences were found in CMT mean scores at two year follow up between IVB and laser therapy (1 RCT, n=77, RR 10.00 CI -39.16 to 59.16). Figure 9: Mean difference in CMT scores (High score = worse)
Study or Subgroup
SD Total Mean
SD Total Weight
IV, Random, 95% CI
IV, Random, 95% CI
1.10.1 at 4-6 weeks
28.6% -96.00 [-118.33, -73.67] -43.00 [-76.32, -9.68] -22.00 [-79.17, 35.17] -6.00 [-47.78, 35.78] Subtotal (95% CI)
149 100.0%
-44.83 [-90.01, 0.35]
Heterogeneity: Tau² = 1726.09; Chi² = 18.89, df = 3 (P = 0.0003); I² = 84%Test for overall effect: Z = 1.94 (P = 0.05) 1.10.2 at 12-16 weeks
-43.00 [-101.10, 15.10] -4.00 [-24.18, 16.18] -3.00 [-53.77, 47.77] 28.00 [-8.15, 64.15] Subtotal (95% CI)
149 100.0%
-0.60 [-23.44, 22.24]
Heterogeneity: Tau² = 189.80; Chi² = 4.57, df = 3 (P = 0.21); I² = 34%Test for overall effect: Z = 0.05 (P = 0.96) 1.10.3 at 24 weeks
-45.00 [-104.00, 14.00] 12.00 [-36.94, 60.94] 41.00 [19.29, 62.71] Subtotal (95% CI)
96 100.0%
8.78 [-38.97, 56.53]
Heterogeneity: Tau² = 1291.19; Chi² = 7.67, df = 2 (P = 0.02); I² = 74%Test for overall effect: Z = 0.36 (P = 0.72) 1.10.4 at 36-52 weeks
-46.00 [-101.19, 9.19] -35.00 [-94.03, 24.03] -9.00 [-56.87, 38.87] Subtotal (95% CI)
113 100.0%
-27.64 [-58.48, 3.19]
Heterogeneity: Tau² = 0.00; Chi² = 1.07, df = 2 (P = 0.59); I² = 0%Test for overall effect: Z = 1.76 (P = 0.08) 1.10.5 at 2 years
10.00 [-39.16, 59.16] Subtotal (95% CI)
38 100.0%
10.00 [-39.16, 59.16]
Heterogeneity: Not applicableTest for overall effect: Z = 0.40 (P = 0.69) Favours IVB Favours Laser b) Bevacizumab versus sham injection
i) Outcome: Mean change in BCVA LogMAR One study25 (n=78) reported data for IVB versus sham injection. At 6 weeks significantly greater improvement occurred in the IVB group (RR -0.07 CI -0.13 to 0.01) compared with sham injection for BCVA. Results at 12 weeks (RR -0.12 CI -0.22 to -0.02), 18 weeks (RR -0.18 CI -0.27 to 0.09) and 24 weeks follow up also significantly favoured IVB (RR -0.15 CI -0.26 to 0.04) compared with sham injection (Figure 10). Figure 10: Mean change in BCVA LogMAR (High score = worse)
Study or Subgroup
SD Total Weight
IV, Fixed, 95% CI
IV, Fixed, 95% CI
2.1.1 at 6 weeks
-0.07 [-0.13, -0.01] Subtotal (95% CI)
100.0% -0.07 [-0.13, -0.01]
Heterogeneity: Not applicableTest for overall effect: Z = 2.38 (P = 0.02) 2.1.2 12 weeks
-0.12 [-0.22, -0.02] Subtotal (95% CI)
100.0% -0.12 [-0.22, -0.02]
Heterogeneity: Not applicableTest for overall effect: Z = 2.46 (P = 0.01) 2.1.3 at 18 weeks
-0.18 [-0.27, -0.09] Subtotal (95% CI)
100.0% -0.18 [-0.27, -0.09]
Heterogeneity: Not applicableTest for overall effect: Z = 3.77 (P = 0.0002) 2.1.4 at 24 weeks
-0.15 [-0.26, -0.04] Subtotal (95% CI)
100.0% -0.15 [-0.26, -0.04]
Heterogeneity: Not applicableTest for overall effect: Z = 2.65 (P = 0.008) Favours IVB Favours sham injecti o
ii) Mean change in CMT scores
One study25 (n=78) reported data for IVB versus sham injection (Figure 11). At 6 weeks, significantly greater improvement occurred in the IVB group (RR -90.50 CI-129.19 to -51.81) compared with the sham injection group. Follow up data at 12 weeks (RR-65.90 CI -111.38 to - 20.42), 18 weeks (RR -48.70 CI -90.66, -6.74) and 24 weeks (RR -130.60 CI -187.27, -73.93) also significantly favoured the IVB group. Figure 11: Mean change in CMT scores (High score = worse)
Study or Subgroup
SD Total Mean
SD Total Weight
IV, Fixed, 95% CI
IV, Fixed, 95% CI
2.2.1 at 6 weeks
-90.50 [-129.19, -51.81] Subtotal (95% CI)
-90.50 [-129.19, -51.81]
Heterogeneity: Not applicableTest for overall effect: Z = 4.58 (P < 0.00001) 2.2.2 at 12 weeks
-65.90 [-111.38, -20.42] Subtotal (95% CI)
-65.90 [-111.38, -20.42]
Heterogeneity: Not applicableTest for overall effect: Z = 2.84 (P = 0.005) 2.2.3 at 18 weeks
-48.70 [-90.66, -6.74] Subtotal (95% CI)
-48.70 [-90.66, -6.74]
Heterogeneity: Not applicableTest for overall effect: Z = 2.27 (P = 0.02) 2.2.4 at 24 weeks
-130.60 [-187.27, -73.93] Subtotal (95% CI)
100.0% -130.60 [-187.27, -73.93]
Heterogeneity: Not applicableTest for overall effect: Z = 4.52 (P < 0.00001) Favours IVB Favours sham injecti o • RVO review
Due to heterogeneity in the type of RVO (central and branch) and method of assessing BCVA, a meta-analysis was considered inappropriate. All trials31-35 reported significant mean improvements in BCVA in the IVB group over time (p values ranged from 0.047 to p<0.0001). Of the two trials that presented results for the sham group, one reported a mean improvement in BCVA over the 12- week study duration,34 whereas the other reported a mean worsening in BCVA over the 24-week study duration.31 Further details are provided in Appendix 6. Only two of the five trials31,34 reported differences between groups at the follow-up measurement points. In one trial of patients with BRVO,34 where interventions were administered twice, 6 weeks apart, the two groups were statistically different at 6 weeks (p=0.05), however by 12 weeks the difference was no longer significant (p=0.064). In another trial of patients with CRVO,31 where interventions were administered four times, 6 weeks apart, there was a significant difference between groups in weeks 12, 18 and 24 (p<0.01), but not at week 6. Taken together, these findings suggest that administering four 1.25 mg IVB injections at 6-weekly intervals can be more effective for longer-term improvement in BCVA than administering two 1.25 mg IVB injections at 6-weekly intervals, although this must be interpreted with caution given the small number of studies and the differences in participant age, gender distribution and type of RVO. 4.2.3 Discussion
• DMO review
Efficacy measures for visual acuity (BCVA ETDRS 15-letter -3 lines) favoured bevacizumab (6 week and 12-16 week outcomes) compared with laser therapy, although the effect size diminished as follow up times increased. Visual acuity (BCVA ETDRS 10-letters) indicated no benefit for IVB at 12 weeks; however longer term data at 12 months from a single study favoured IVB. The effect of bevacizumab on BCVA LogMAR scores was significantly different compared with laser therapy at 6 weeks although data were heterogeneous, but 12 and 24 week data were equivocal. Longer term follow up data at 48 weeks significantly favoured laser therapy, but this was based on one small study (n=65). Deterioration in BCVA (15-letter – 3 lines) for short term data at 6 weeks was not significantly different; data reported up to 16 weeks favoured bevacizumab but was heterogeneous; longer term data up to 54 weeks favoured bevacizumab, which suggests that benefits are only achieved during longer term treatment. The number of injection that patients received varied between the studies or was not clearly reported and it is not clear what impact this has on efficacy. No consistent treatment direction emerged for mean scores in central macular thickness; initially CMT scores favoured bevacizumab (4-6 week data) but data were heterogeneous, and at 12-16 weeks data were equivocal. Data reported at 24 weeks was also heterogeneous and was not significantly different. Longer term data at one year indicated a trend favouring IVB but data were non-significant, whilst two year data from a single study indicated no significant difference between IVB and laser therapy. Only one study compared bevacizumab with sham injection. Outcome measures of change scores in visual acuity up to 24 weeks favoured bevacizumab, although the data are limited by the small sample size used (n=78). Mean change scores in central macular thickness across 6, 12, 18 and 24 weeks favoured bevacizumab compared with sham injection. • RVO review
Overall, IVB appeared to confer some improvement in BCVA among patients with branch and central RVO, although three of the five trials32,33,35 were only reported in abstract form and detailed data were not available. From the two trials31,34 that reported differences between BCVA and control (sham injection) groups, it seems that administering four 1.25 mg IVB injections at 6-weekly intervals31 can be more effective for longer-term improvement in BCVA than administering two 1.25 mg IVB injections at 6-weekly intervals.34 Caution is warranted in interpreting this finding however, due to the small number of studies, relatively small sample sizes and the differences in participant age, gender distribution and type of RVO. The relatively short-term follow-up durations of the studies reviewed should also be borne in mind; the maximum follow-up duration was 24 weeks. 4.2.4 Comparison of findings with existing literature
In the DMO studies, improvement at 12-16 weeks was seen in BCVA ETDRS 15-letter scores, although the treatment effect of bevacizumab was reduced in longer term follow-up data at 3-52 weeks. This is consistent with reports indicating that bevacizumab is most effective from 6-12 weeks after the initial injection.30
Compared with sham injection, the treatment effects of bevacizumab were more consistent and
indicated significantly greater improvement in BCVA and CMT scores, although this is based on a single study (n=78) with a follow up time of 24 weeks. In the RVO studies, detailed data were not available for three of the studies, which were only reported in abstract form and also did not report group differences at follow-up. It seems that on-going IVB injections may be more effective at increasing BCVA than only two injections; however, this conclusion is based on the findings of two trials with relatively small sample sizes and relatively short-term follow-up (the longest was 24 weeks) that differed in terms of participants' age, gender distribution and type of RVO. 4.2.5 Conclusions
From the available evidence, results for visual acuity from dichotomous data generally favoured bevacizumab compared with laser therapy, but data were often heterogeneous and between group differences were often related to longer follow up times. However, BCVA LogMAR scores indicate that only longer term treatment is advantageous over laser therapy, whilst changes in CMT did not indicate that IVB confers a sustained advantage over laser therapy. Compared with sham injection bevacizumab was superior for the outcomes of BCVA logMAR, and mean change in CMT but these findings are based on a single small study. For patients with RVO, bevacizumab appears to provide some improvement in BCVA but more studies are needed before valid conclusions are reached. 5 EVIDENCE REGARDING THE SAFETY OF IVB FOR THE
TREATMENT OF EYE CONDITIONS IN GENERAL
5.1 METHODS
A systematic review of the literature and meta-analysis (where appropriate) was undertaken to evaluate the safety of IVB monotherapy for the treatment of all eye conditions. A review of the evidence was undertaken in accordance with the general principles recommended in the PRISMA statemen 5.1.1 Literature searching
a) Electronic databases Studies were identified by searching the following electronic databases. • MEDLINE(R) In-Process & Other Non-Indexed Citations and MEDLINE(R) (Ovid) 1948 to • EMBASE (Ovid) 1974 to May 2012 • Cochrane Database of Systematic Reviews (Wiley Interscience) 1996 to May 2012 • Cochrane Central Register of Controlled Trials (Wiley Interscience) 1898 to May 2012 • Health Technology Assessment Database (Wiley Interscience) 1995 to May 2012 • Database of Abstracts of Review of Effects (Wiley Interscience) 1995 to May 2012 • TOXLINE (US NIH) 1965 to May 2012 Sensitive search strategies using free text and thesaurus terms were developed to search the electronic databases. Synonyms relating to the intervention (e.g. bevacizumab, avastin) were combined with adverse events floating subheadings or specific adverse events terms (e.g. a list of adverse events such as endophthalmitis, retinal detachment and stroke listed in an International IVB safety survey published by Fung et al.21) Adverse events statements were combined with the Boolean operator ‘NOT' with chemotherapy terms so that records retrieved would be related bevacizumab for eye conditions rather than chemotherapy treatment. The current review updated (and adapted) the search strategy reported in an existing systematic review on adverse events of intravitreal anti- VEGF37 (within the scope of the current review). In the review by van der Reis et al.,37 the searches examined the period from 1948 to 2009. The adverse event searches were limited by date from January 2009 to May 2012. The search methodology used by van der Reis et al.38 was considered by the review team to be of good quality however fewer adverse event terms were used and some terms were considered too broad such as "cause" and "response" and a study design filter for experimental and functional study design for electrophysiology or in vitro or cytology studies was applied. The review team adapted van der Reis et al's search strategy by including more adverse events terms and removing the broader terms. In addition, it was not considered necessary to apply an experimental and functional study design filter. No language restrictions were used on any database. An example of the MEDLINE search strategy is provided in Appendix 7. b) Other resources To identify additional published, unpublished and on-going studies, the reference lists of all relevant studies (including existing systematic reviews) were checked and a citation search of relevant articles (using the Web of Science Citation Index Expanded and Conference Proceedings Citation Index - Science) was undertaken to identify articles that cite the relevant articles. In addition, key experts in the field were contacted. All identified citations from the electronic searches and other resources were imported into and managed using the Reference Manager bibliographic software, (version 12.0; Thomson Reuters, Philadelphia, PA). 5.1.2 Selection criteria
The inclusion of potentially relevant articles was undertaken using a two-step process. First all titles were examined for inclusion by one reviewer. Any citations that clearly did not meet the inclusion criteria i.e. non-human, unrelated to bevacizumab were excluded. Second, all abstracts and full text articles were examined independently by a minimum of two reviewers. Any disagreements in the selection process were resolved through discussion. The relevance of each article for the systematic review was assessed according to the following criteria: All published or unpublished RCTs, controlled trials or observational studies including ≥10 participants reporting adverse events data following IVB administration were included. Reviews of primary studies were not included in the analysis, but were retained for discussion and identification of additional studies. Moreover, the following publication types were excluded from the review: animal models; preclinical and biological studies; narrative reviews, editorials, opinions; non-English language papers, case reports, and case series with less than 10 participants. The population comprised adults (defined as ≥ 18 years of age) with any eye condition. However, patients with eye conditions who had received prior surgery (vitrectomy) or other non-surgical treatments/ procedures (e.g. photodynamic therapy, corticosteroids, other anti-VEGF therapies, laser photocoagulation and radiation delivered to the eye) were excluded. c) Interventions The intervention was the administration of IVB (any dose) monotherapy as the primary treatment of an eye condition. The following were excluded: administration of bevacizumab other than via the intravitreal route (e.g. intracameral, subconjunctival, systemic, nasal etc.), IVB as a combination therapy and IVB used as an adjunctive treatment or peri-operative/pre-operative/post-operative d) Relevant comparators Comparators were limited to monotherapies for RCTs. The outcomes of interest for the safety review divided into ocular (eye) and systemic adverse effects as presented in Figure 12. Data on safety was limited to important and serious adverse events. A serious adverse event is defined by the Food and Drugs Agency as ‘any undesirable experience associated with the use of a medical product in a patient' with an outcome results in death, hospitalisation (initial or prolonged), congenital birth defects, disability or permanent damage, life- threatening medical events that require medical or surgical intervention to prevent impairment or damage. Studies that evaluated but reported that no adverse events (specified and unspecified as per review) were observed were considered eligible for inclusion. Estimates of the incidence of adverse events were calculated by dividing the number of events by the number of patients that received IVB (event rate per patient) or the number of eyes treated (event rate per treated eye). Figure 12: Safety review outcomes

Systemic adverse events Ocular adverse events Infectious endophthalmitis (infection of the eye) Retinal detachment Non ocular haemorrhage (gastrointestinal, Retinal (pigment epithelium) tear pulmonary, other non-ocular bleeds) Anterior chamber reaction (includes acute intraocular Arterial thromboembolism inflammation; uveitis (inflammation of the anterior chamber) Myocardial infarction Ocular haemorrhage Cerebrovascular accident (stroke) Lens damage/injury (including cataract, clouding of the lens) Transient ischaemic attack Ocular hypertension (raised intraocular pressure >21 mmHg) 5.1.3 Data abstraction and quality assessment
Data abstraction was performed by one reviewer into a standardised data extraction form. Any uncertainties or queries were resolved by discussion with a second reviewer and if agreement could not be reached, a third reviewer was consulted. Where multiple publications of the same study were identified, data were extracted and reported as a single study. Moreover, all relevant studies from the van der Reis et al.39 review were examined and data extracted. The following information was extracted for all studies when reported: study characteristics (e.g. author, year of publication, follow-up, funding), participant details (e.g. number of patients, eye condition, mean age, and baseline comparability), intervention and comparator details (e.g. description including method of preparation, dose including frequency, number of injections) and The methodological quality of each included RCT study was assessed by one reviewer (no quality assessment was undertaken for observational studies). Any uncertainties or queries were resolved by discussion with a second reviewer and if agreement could not be reached, a third reviewer was consulted. The study quality characteristics were assessed according to a Cochrane Collaboration Risk of Bias Tool for RCTs (namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and ‘other issues').23 This was modified to include additional items to assess the quality of adverse effects data (namely follow-up time sufficient to assess safety [to assess long-term harm such as fatal or non-fatal systemic complications, follow-up time less than 6 months were considered insufficient to assess these complications], definition of reported adverse event, definition of method used to collect adverse event data, transparency of patient flow and validity of safety data.) 5.1.4 Data analysis
Data were entered and where appropriate, meta-analysed to estimate a summary measure of effect on relevant outcomes using the Cochrane Review Manager software RevMan 5.1 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). The relative risk was calculated for dichotomous outcomes. The fixed effects model (Mantel-Haenszel method) was applied to obtain summary statistics of pooled trials of rare events as it has been shown to be the more appropriate and less biased approach compared to a random effects model (inverse variance method).40 5.2 RESULTS
5.2.1 Quantity and quality of research available
5.2.1.1 Number of studies identified/included The literature searches identified 1,831 citations. Of these, 69 full text articles met the inclusion criteria (n= 21 RCTs, n= 48 non-randomised studies) and were added to the 20 studies from the previous systematic review (n= 1 RCT, n= 19 non-randomised studies).41 A flow chart describing the process of identifying relevant literature can be found in Figure 13. Figure 13: Study flow chart (adapted): Safety review36
Records identified through database Additional records identified through other sources Records screened by title Excluded by title Record screened by Excluded by abstract Full-text articles (references) assessed for Full-text articles excluded, Full text articles included Studies from existing systematic review meeting the review inclusion criteria (n =20, including Studies included in the safety review (n = 89) 5.2.1.2 Number and type of studies excluded A total of 284 full text articles were excluded as they did not meet all the pre-specified inclusion criteria. The majority of the articles were excluded primarily on the basis of inappropriate study design, unsuitable publication type (reviews, commentaries or editorials) or due to lack of usable data. A full list of excluded studies with reasons for exclusion is presented in Appendix 11. 5.2.1.3 Description of included studies A total of 22 RCTs were included25,26,42 27-29,31,34,43-56 evaluating the safety of bevacizumab compared with laser therapy (n=9), sham injection (n=5), IVT (n=5), IVR (n=4), pegaptanib (n=2) and observational control (n=1). Seven studies included participants with AMD, eight studies with DMO, four studies with RVO, one study with patients with pathologic myopia, one study with vitreous haemorrhage secondary to Eale's disease, and one study included patients with neovascular glaucoma. For details on participants, intervention and outcomes see Appendix 8. • Observational studies
Sixty-seven non-RCT studies were included in the safety review of IVB. Sample sizes ranged from 11 patients57 to 27,962 patients.58 Reported ages ranged from 33 years (median)59 to 82 years (mean).60,61 A majority of studies provided adverse events data for a single condition (e.g. age- related macular degeneration), while fewer studies evaluated clusters of patients with more than 3 eye conditions. A summary of study characteristics of observational studies is provided in Appendix Administration of 1.25 mg/0.05ml was the most commonly reported dosage of IVB. Other dosages were 1mg,57,62-65 1.5 mg66,67 and 2.5mg.68-72 Frequency of dosing and follow-up schedules varied across studies. The mean number of injections per patient or eye ranged from 159,63,73-77 to 7.78 One study reported a total of 10,958 injection.79 Information on the source of IVB preparation was reported in less than a fifth (19%; n=13/67) of included studies.60,63,64,66,69,80-87 IVB injections were mainly provided by a local dispensing service such as the hospital's pharmacy. In one study study,75 bevacizumab was provided by Alcaine; Alcon-Couvreur, Puurs, Belgium, a manufacturer of ophthalmic surgical products. Funding from a non-pharmaceutical institution (e.g. academic source) was declared in 18 reports.71,88 58,69,89,90 62,65,91-100 However, one study86 was partly funded by a pharmaceutical organisation. 5.2.1.4 Quality characteristics Twelve studies reported how randomisation was performed.25,26,28,29,31,34,45,48-50,52,56 It is unclear if randomisation was adequately performed in the remaining 10 studies, although no imbalances were identified in baseline measures. Ten studies reported methods used to conceal allocation to treatment.25,26,29,31,34,45,48,50,53,56 It is unclear if allocation concealment was performed in the remaining 12 studies. Blinding of participants and personnel was attempted by five studies.29,31,45,48,53 Blinding of outcome assessors was reported in twelve studies.25,26,28,29,31,34,45,48,50,53,55,56 Study attrition was reported in fourteen studies.25-27,29,31,42-45,47-49,53,55 It was unclear in 17 studies if outcomes were selectively reported, five studies reported outcomes measures a priori. 27,31,45,48,50 The validity of the safety data was assessed according to sufficient length of follow up to detect adverse events, definitions of expected adverse events and methods used to collect data. Only two studies45,48 met the criteria for valid safety data. A summary of the methodological quality of each included study is presented in Figure 14. e http://www.alcon.com/en/alcon-locations/belgium.aspx Figure 14: Methodological quality summary: Review authors judgments about each
methodological quality item for each RCT included study in adverse events review
• Observational studies
A formal quality assessment was not undertaken for included observational studies. It was anticipated that a variety of study designs would be identified. While checklists exist for evaluating the methodological quality of a range of non-randomised studies, there is no agreement on how to incorporate a single tool to appraise different study types in a review.101,102 For this review, criteria assessed included study design (e.g. prospective or retrospective), length of follow-up and baseline comparability when appropriate. Where data was available, information on the IVB administration and preparation was also considered. Of the identified observational studies, approximately 65% (n=44/67) were retrospective in design. Baseline characteristics of study populations were comparable in 2 non-randomised studies69,75 and 3 case-control studies.74,78,103 Comparability at baseline was generally absent or not relevant in the remaining studies which were predominantly reports of case series. The length of follow-up periods was at least up to 6 months in 18 studies. 5.2.2 Assessment of adverse events
• Randomised controlled trials
i) IVB versus laser therapy for DMO Reports of adverse events were low and were not significantly different between IVB and laser therapy. Other ocular and systemic safety measures had zero events in both treatment groups. Figure 15: IVB versus laser for DMO
Risk Ratio
Risk Ratio
Study or Subgroup
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
1.10.1 Death
0.87 [0.04, 20.53] 0.75 [0.18, 3.18] Subtotal (95% CI)
0.77 [0.21, 2.86]
Heterogeneity: Chi² = 0.01, df = 1 (P = 0.93); I² = 0%Test for overall effect: Z = 0.39 (P = 0.70) Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable 1.10.3 Retinal detachment
Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable 1.10.4 Severe lens opacity requiring cataract surgery
1.00 [0.06, 15.55] Subtotal (95% CI)
1.00 [0.06, 15.55]
Heterogeneity: Not applicableTest for overall effect: Z = 0.00 (P = 1.00) 1.10.5 Ocular hypertension (≥23 mmHG)
Faghihi 2008
2.72 [0.11, 64.85] Subtotal (95% CI)
2.72 [0.11, 64.85]
Heterogeneity: Not applicableTest for overall effect: Z = 0.62 (P = 0.54) 1.10.6 High risk proliferative diabetic retinopathy
1.17 [0.42, 3.23] Subtotal (95% CI)
1.17 [0.42, 3.23]
Heterogeneity: Not applicableTest for overall effect: Z = 0.30 (P = 0.77) 1.10.7 Vitreous haemorrhage
0.30 [0.01, 7.21] Subtotal (95% CI)
0.30 [0.01, 7.21]
Heterogeneity: Not applicableTest for overall effect: Z = 0.74 (P = 0.46) 1.10.8 Loss of 30 ETDRS letters
0.18 [0.01, 3.66] Subtotal (95% CI)
0.18 [0.01, 3.66]
Heterogeneity: Not applicableTest for overall effect: Z = 1.11 (P = 0.27) 1.10.9 Cerebrovascular accident
0.18 [0.01, 3.66] Subtotal (95% CI)
0.18 [0.01, 3.66]
Heterogeneity: Not applicableTest for overall effect: Z = 1.11 (P = 0.27) 1.10.10 Thromboembolic adverse event
Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable ii) IVB versus sham injection for DMO Similarly, adverse events were low in the IVB and sham injection groups with no significant differences found between groups. Other ocular safety measures had zero events in both treatment groups (Figure 16). Figure 16: IVB versus sham injection for DMO
Risk Ratio
Risk Ratio
Study or Subgroup
Total Weight
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
2.3.1 Death
0.30 [0.01, 7.18] Subtotal (95% CI)
37 100.0%
0.30 [0.01, 7.18]
Heterogeneity: Not applicableTest for overall effect: Z = 0.74 (P = 0.46) 2.3.2 Marked anterior chamber reaction
2.71 [0.11, 64.65] Subtotal (95% CI)
37 100.0%
2.71 [0.11, 64.65]
Heterogeneity: Not applicableTest for overall effect: Z = 0.62 (P = 0.54) 2.3.3 Progression of fibrous proliferation
2.71 [0.11, 64.65] Subtotal (95% CI)
37 100.0%
2.71 [0.11, 64.65]
Heterogeneity: Not applicableTest for overall effect: Z = 0.62 (P = 0.54) 2.3.4 vitreous haemorrhage
Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable 2.3.5 Intraocular pressure rise
Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable 2.3.6 Iris neovascularization
Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable Favours IVB Favours sham injecti iii) IVB versus IVT in DMO Rates of raised IOP>21mmHg were significantly higher in the IVT group (3 RCTs, n=183, RR 0.13 CI 0.02 to 0.69) compared with IVB. Other ocular and systemic safety measures had zero events in both treatment groups (Figure 17). Figure 17: IVB versus IVT in DMO
iv) IVB versus IVR for AMD (one year data) Death at one year was not significantly different (2 RCT, n=1795 RR 1.38 CI 0.71 to 2.68) between IVB and IVR. Any serious systemic adverse event was significantly lower in the IVR group (2 RCT n=322, RR 1.27 CI 1.05 to 1.55) compared with IVB. Arteriothrombotic events were not significantly different between IVB and IVR (2 RCT, n=1795, RR 0.81 CI 0.42 to 1.59) at one year. In the IVAN study, cardiac disorders, transient ischaemic attack, and hospitalisation for angina were not significantly different between IVB and IVR. One study by Biswas (2011)44 reported no events for significant adverse events (Figure 18). Figure 18: IVB versus IVR for AMD
iv) IVB versus IVR for AMD The CATT45 (2 year data) and IVAN48 (1 year preliminary data) were pooled to provide long term data analyses. There was no significant difference in death between IVB and IVR. Any serious systemic adverse event remained significantly lower in the IVR group (n=1795, RR 1.27 CI 1.09 to 1.47) compared with IVB. Other adverse events including arteriothrombotic events, cardiac disorders endophthalmitis, and hypertension, were not significantly different between IVB and IVR treatment groups (Figure 19). Figure 19: IVB versus IVR for AMD
v) IVB versus laser therapy for AMD Three studies reported adverse event data for IVB and laser therapy in patients with AMD. One short term study at 3 months49 found that posterior vitreous detachment was significantly higher in the IVB group compared with laser therapy, although confidence intervals are wide (n=110, RR 17.00 CI 1.01 to 287.50). Death, myocardial infarction, uveitis, vitreous haemorrhage, pigment epithelial tears and cataract progression were low and indicated no significant differences between IVB and IVR. Other ocular and systemic safety measures had zero events in both treatment groups Figure 20: IVB versus laser therapy for AMD
vi) IVB versus sham injection for AMD No significant differences were found for death, myocardial infarction or vitreous haemorrhage. Uveitis was significantly lower in the IVB group (1 RCT, n=77, RR 0.07 CI 0.02 to 0.22). Other ocular and systemic adverse events were unremarkable with no event rates in either treatment group. Figure 21: IVB versus sham injection for AMD
vii) IVB versus pegaptanib for AMD No significant differences were found for death, myocardial infarction, uveitis, retinal detachment, or vitreous haemorrhage. Other ocular and systemic adverse events were unremarkable with no event rates in either treatment group (Figure 22). Figure 22: IVB versus pegaptanib for AMD
Risk Ratio
Risk Ratio
Study or Subgroup
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
4.1.1 Death
2.95 [0.15, 59.97] Subtotal (95% CI)
2.95 [0.15, 59.97]
Heterogeneity: Not applicableTest for overall effect: Z = 0.71 (P = 0.48) 4.1.2 Myocardial infarction
2.95 [0.15, 59.97] Subtotal (95% CI)
2.95 [0.15, 59.97]
Heterogeneity: Not applicableTest for overall effect: Z = 0.71 (P = 0.48) 4.1.3 Stroke
Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable 4.1.4 Cerebral infraction
Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable 4.1.6 Significant change in IOP
Schimid-Kubista 2011 Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable 4.1.7 Significant change in blood pressure
Schimid-Kubista 2011 Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable 4.14 [0.22, 77.98] Subtotal (95% CI)
4.14 [0.22, 77.98]
Heterogeneity: Not applicableTest for overall effect: Z = 0.95 (P = 0.34) 4.1.9 Retinal detachment
0.08 [0.00, 1.59] Subtotal (95% CI)
0.08 [0.00, 1.59]
Heterogeneity: Not applicableTest for overall effect: Z = 1.65 (P = 0.10) 4.1.10 Retinal tear
Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable 4.1.11 Vitreous haemorrhage
2.95 [0.15, 59.97] Subtotal (95% CI)
2.95 [0.15, 59.97]
Heterogeneity: Not applicableTest for overall effect: Z = 0.71 (P = 0.48) 4.1.12 Lens damage
Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable Favours bevacizumab Favours pagaptanib viii) IVB versus sham injection for neovascular glaucoma No significant differences were found between IVB and sham injection for the outcome of hyphema. No serious injection related adverse events occurred (Figure 23).
Figure 23: IVB versus sham injection for neovascular glaucoma
iv) IVB versus IVT for RVO In a single study (n=32), rates of IOP>21mmHg were not significantly different between IVB and IVT although the data suggest a trend towards higher rates of raised IOP in the IVT group. Other ocular and systemic adverse events were unremarkable with no event rates in either treatment group Figure 24: Adverse event IVB versus IVT for RVO
Risk Ratio
Risk Ratio
Study or Subgroup
Total Weight
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
6.1.1 IOP >21 mmHg
0.08 [0.00, 1.26] Subtotal (95% CI)
16 100.0%
0.08 [0.00, 1.26]
Heterogeneity: Not applicableTest for overall effect: Z = 1.80 (P = 0.07) Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable 6.1.4 thromboembolic events
Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable 6.1.5 Injection complications
Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable Favours bevacizumab Favours triamcinolone x) IVB versus sham injection for RVO No significant differences in rates of foveal haemorrhage, or ischemia were found between IVB and sham injection. Other ocular and serious non-ocular adverse events were unremarkable with no event rates in either treatment group (Figure 25). Figure 25: IVB versus sham injection for RVO
Risk Ratio
Risk Ratio
Study or Subgroup
Total Events Total Weight
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
7.1.1 Foveal haemorrhage
0.62 [0.28, 1.35] Subtotal (95% CI)
0.62 [0.28, 1.35]
Heterogeneity: Not applicableTest for overall effect: Z = 1.20 (P = 0.23) 7.1.2 Foveal ischemia
1.11 [0.37, 3.36] Subtotal (95% CI)
1.11 [0.37, 3.36]
Heterogeneity: Not applicableTest for overall effect: Z = 0.19 (P = 0.85) 7.1.3 Retinal detachment
Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable 7.1.5 Retinal tear
Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable 7.1.6 Serious non-ocular adverse events
Subtotal (95% CI)
Heterogeneity: Not applicableTest for overall effect: Not applicable Favours IVB Favours sham xi) IVB versus IVR in choroidal neovascularization in pathological myopia A single study47 (n=32) reported no incidences of systemic or ocular adverse events between IVB and IVR during 6 months follow up. xii) IVB versus observational control in Eale's disease In a single study (n=20) no significant differences were found in rates of tractional retinal detachment (Figure 26) between IVB and observational control group. Figure 26: IVB versus observational control in Eales disease
Risk Ratio
Risk Ratio
Study or Subgroup
Events Total Weight
M-H, Fixed, 95% CI
M-H, Fixed, 95% CI
9.1.1 Tractional retinal detachment
7.00 [0.41, 120.16] Subtotal (95% CI)
7.00 [0.41, 120.16]
Heterogeneity: Not applicableTest for overall effect: Z = 1.34 (P = 0.18) Favours IVB Favours control 5.2.2.1 Observational studies A summary of adverse events is presented in Appendix 10. Available evidence suggests fewer systemic events compared to ocular adverse events. A number of studies did not provide detailed information on the type of adverse events assessed. Of the 67 included observational studies, 84% (n=56/67) of studies did not report or observe systemic adverse events following IVB treatment. Twenty-eight studies (41%) did not report or observe ocular adverse events of interest. Reported adverse events were generally low; however, in a few studies high incidence rates for hypertension,77 anterior chamber inflammation,104 retinal detachment,59 ocular haemorrhage,105,106 visual loss107,108 and increased intraocular pressure (ocular hypertension)109-111 were reported. • Systemic adverse events
Systemic adverse events reported included death (0.43%-1.83%)60,90,106,112 hospitalisation;86 arterial thromboembolism (1.35%);86 hypertension; (0.3% to 15%)62,77,92,106 myocardial infarction (0.09% to 1.27%);58,69,86,106 cerebrovascular accident (0.14% to 0.5%);58,62,89,106,112 and transient ischaemic attack (0.45% to 1.03%).86,90 Evidence on systemic events was not conclusive. One large study involving an analysis of 146, 942 Medicare payees between 2005 and 2006 reported a significantly lower risk of all-cause mortality and stroke in patients who received IVR compared to patients treated with IVB.58 However, a secondary analysis limited to only newly-treated patients on IVR or IVB showed no significant difference between treatment groups. Patients included this study were those who had received first- line treatment for AMD. Data were censored at the time that a patient's treatment was switched from initially assigned intervention to another. Between July and December of the study year (2006), study population was limited to treatment-naïve patients who received bevacizumab or ranibizumab. With the exception of the presence of diabetes mellitus, baseline characteristics between IVR and IVB patients were similar (28% versus 25%, p<0.001). The authors concluded that ‘the risks of mortality, myocardial infarction and stroke were not different between groups'. However, as the sample size of patients for the secondary analysis (IVB: IVR) was smaller compared to the primary analysis, it is important to interpret the results with caution. However, Sharma86 reported an increased risk of arterial thromboembolic events (odds ratio [IVB:IVR]=1.71;95%CI 0.44-41). In this study, arterial thromboembolic events included emergency room visits for patients with transient ischaemic attacks, myocardial infarction and pulmonary embolism. • Ocular adverse events
At least 1 ocular event was reported in all included studies. The least commonly reported adverse events were related to lens damage (0.4%)106 and retinal detachment (1.2%).72 Visual loss was the most commonly reported ocular event.69,73,74,108,111,113-115 However, the definition of visual loss was often unclear and occasionally associated with adverse events such as anterior chamber inflammation, severe intraocular inflammation or retinal detachment. As a result, the relationship between visual loss and IVB requires cautious interpretation. Infectious endophthalmitis was reported in 10 studies (range 0.02% to 0.9%). Three of the 13 studies60,63,64,66,69,80-87 in which locally prepared IVB was administered mentioned reports of infectious endophthalmitis. Reported rates were 0.02% (n=3/12,585 injections),83 0.16% (n=1/625),66and 0.8% (n=1/112).80 A rate of 0.9% (n=1/109) was reported in a study with IVB supplied by a compounding pharmacy.60 Positive cultures of micro-organisms were reported in two 5.3 DISCUSSION
5.3.1 Randomised controlled trials
Overall, adverse event rates were low in all bevacizumab and comparators groups, and most outcomes were not significantly different. Raised intraocular pressure (>21mmHg) was significantly higher in the triamcinolone group compared with bevacizumab. Uveitis in one study was significantly higher in the bevacizumab group compared with those receiving sham injection but other studies recording uveitis did not support this finding. Tufail et al.55 reported that there was no increased risk of adverse events in patients treated with IVR or IVB compared with those receiving sham treatment. However, a higher risk of adverse events was reported in head-to-head comparisons of IVR and IVB by investigators of the Comparison of Age-related Macular Degeneration Treatments Trials.45,116 However, there are concerns that adverse events assessed were not those that are usually related to the action of anti-VEGF therapy.117 It is also important to note that IVB patients in this study receiving more treatments had a better safety profile compared to participants with fewer injections. Serious systemic adverse events ≥1, from the IVAN48 and CATT45 studies (1-year data and 1 & 2- year data combined) indicated significantly higher rates in the bevacizumab treatment group, although the IVAN result was not significant, but when added into the meta-analysis with the CATT study, the overall finding was significant. Authors of CATT also examined the baseline characteristics and adjusted for any small group differences but this did not change the outcome. Further analyses were undertaken by authors of IVAN on the difference between different regimens (continuous/discontinuous) for death, arteriothrombotic events and any serious systemic adverse event using pooled estimates of IVAN and CATT data, but no significant differences were found. Event rates were proportionally higher in the CATT study which may have been due to differences in definitions used to report serious adverse events. The CATT study defined serious adverse events as arteriothrombotic events, systemic haemorrhage, congestive heart failure, venous thrombotic events, hypertension, and vascular death. The IVAN study defined serious systemic adverse events as including any non-ocular serious adverse event. Also, The CATT study included slightly older participants and reported data at two years follow up, whereas the IVAN study reported preliminary data at one year. It is possible that the CATT and IVAN study did not have had sufficient statistical power to detect differences in adverse events.58 However, future studies and the anticipated two year follow-up data from the IVAN study will help to clarify if there is a real difference in systemic adverse event rates, or whether this is a chance statistical finding. Many of the studies reported zero event rates for the safety outcomes. It is common practice to exclude all zero-total-event trials from meta-analyses because they provide no information about the magnitude of the odds or risk ratios and do not contribute to producing a combined treatment effect greater or less than nil.40,118,119 However, these trials may provide relevant information by showing that event rates for both the intervention and control groups are low and relatively equal.120-122 Including such trials can sometimes decrease the effect size estimate and narrow confidence intervals. Diamond et al.123 suggest that excluding trials with zero events in the index meta-analysis probably exaggerated risk estimates and that including these trials by applying continuity adjustments in this instance temper the exaggerated estimates. Moreover, seven studies reported outcomes at less than 6 month which limits the chance to detect adverse events, especially systemic adverse effects. Only two studies45,48 were adequately conducted to meet the quality assessment 5.3.2 Observational studies
The review of observational data showed that ocular adverse events were more common than systemic events. The reporting of safety, generally, could not be linked with source of funding as reported in the review conducted by Schmucker.124 Reported ocular rates were also comparatively higher than incidence rates for systemic adverse events. Rates differed from those reported in the van der Reis125 review which included case reports and calculated cumulative incidence rates across different study types. This can be explained further by the differences in review methods (e.g. eligibility, grouping of adverse events and synthesis of results). A number of population-based studies have been conducted to assess the safety of IVB with inconsistent findings. While a number of included studies did not report or observe serious adverse events, reported incidence rates were high in a few studies. These rates were commonly associated with anterior chamber reaction86,104,112 raised intraocular pressure109 and ocular haemorrhage.81,105 Despite the incidence of increased IVB-related adverse events in these studies, there are concerns associated with small sample sizes and potential confounding. Data from a few larger studies provided information on how likely confounding factors were handled in the assessment of adverse events. For example, Curtis et al58 undertook a primary analysis of their results and reported an increased risk of stroke in individuals treated with IVB compared to those receiving IVR. However, a further analysis, adjusting for the potential confounding of socioeconomic status resulted in no difference in adverse event risk between the two treatment groups. On the other hand, results of an unpublished study of Medicare patients112 found an increased risk of stroke and death in IVB patients. The available abstract, however, did not provide sufficient information to an in-depth analysis of the results of this study. A recently published population-based, nested case-control study reported by Campbell et al.117 (n=91,378) compared adverse events due to IVR and IVB. The authors reported that there was no relationship between the risk of systemic events such as myocardial infarction, venous thromboembolism, stroke or congestive heart failure and the administration of IVR or IVB. While, the risk of systemic adverse events was similar for the two treatment groups, there was an increased risk of acute myocardial infarction for a subgroup of diabetic patients that received IVB. For patients who were exclusive users of IVB or IVR, reported adjusted odds ratios (IVB versus IVR) were 1.23 (0.85 to 1.77) for acute myocardial infarction, 1.03 (0.67 to 1.60) for ischaemic stroke, 0.92 (0.51 to 1.69) for venous thromboembolism and 1.35 (0.93 to 1.95) for congestive heart failure. It must be noted that this finding was based on a single analysis of one outcome in a specific subgroup of the study population. Furthermore, exclusive users of IVB or IVR referred to patients who received treatment in a practice that administered a minimum of 20 injections, of which 95% or more were single drug treatments. 5.3.2.1 Relationship between adverse events and IVB preparation The relationship between IVB preparation and infectious endophthalmitis could not be established in this review. This was due to the varied quality and extent of reporting in the included papers which limited detailed analyses of the link between IVB preparation and rates of infectious endophthalmitis. Information on IVB preparation was reported in only 19% of included studies. A single study106 reported that seven cases of bacterial endophthalmitis were associated with positive cultures of coagulase negative staphylococci, Staphylococcus aureus and Streptococcus pneumoniae. Of these, 6 patients had received IVB injections stored in single-use syringes. No further information was provided on length or temperature of storage conditions. However, the study authors reported that bevacizumab was refrigerated in two ways; preparations were stored as a single vial of 100ml/4mg to be re-utilised as needed or as ‘aliquoted' sterile single-use syringes. It was not certain whether IVB injections were prepared locally or by a compounding pharmacy. However in another study, Fong 200860 (n=109), one case of Staphylococcus epidermidis endopthalmitis was reported following the third IVB injection in a treated patient. In this study, a compounding pharmacy supplied 1.25mg/0.05ml of bevacizumab prepared under aseptic conditions in 1.0ml single-use syringes. The lack of additional information made it difficult to assess factors that could have resulted in endopthalmitis in this patient. According to the Royal College of Ophthalmologists: Information from the Professional Standards Committee,126 ‘most cases of postoperative endophthalmitis are caused by patients' own bacterial flora. Standard procedures should therefore aim to limit the risk from this source e.g. by isolating the lid margins with a non-permeable drape, and by using preoperative 5% povidone iodine in the conjunctival sac. Alternatively, the source of infection may be exogenous: for example cases may result from contaminated instruments, intraocular solutions or implants either due to manufacturing problems, faulty sterilization, poor operating technique or theatre environment. Such cases may include fungal endophthalmitis.' Presently, case reports related to contaminated batches of IVB have been the primary source for data on the link between adverse events and intravitreal preparations. A published review of patient safety information held by the National Patient Safety Agency in England and Wales127 reported an increased risk of serious adverse events including endophthalmitis following IVB treatment. The authors acknowledged that identifying the source of infection (that is contaminated injection procedure or infected anti-VEGF) could be complex. On the contrary, Jonas67 reporting on adverse events rates in a study population which included patients who had received IVB and IVT, indicated that event rates were statistically independent of drug injected (P=0.45); operating surgeon (P=0.18) and patient's age (P=0.87). 5.3.3 Limitations of evidence
Considering RCTs, many of the studies randomised small numbers of participants and these may have been underpowered to detect differences in adverse events.124,128 Generalisability of findings may also be limited due to differences between study participants and patients seen in routine practice. Furthermore, there are concerns related to ascertainment of exposure particularly in observational studies.117 Current evidence from observational data appears to be limited with respect to definition, evaluation and reporting of safety outcomes as well as length of follow-up. The quality of reporting of studies made it impossible to evaluate the impact of both known and unknown confounding factors (e.g. the use of prophylactic anti-biotic eye drops) on the incidence of adverse events. Consequently, it is uncertain whether the high incidence of events such as visual loss occurred as a result of treatment or progression of the patient's condition. In general, there seems to be insufficient data to explore the relationship between the incidence of adverse events and other variables such as injection techniques, pre-existing risk factors (e.g. immunosuppression, cross- contamination) and quality of IVB. It is also important to highlight limitations related to undertaking the review. The influence of excluding non-English publications in this review is unclear. Additionally, adopting a narrow focus in the definition of adverse events implies that data on less serious or rare events were not presented 5.4 CONCLUSIONS
Overall, the review demonstrated that rates of adverse events following IVB were low when compared to other intravitreal treatments, sham injection and laser therapy. Most outcomes were not significantly different between groups. Higher risks of adverse events have been reported in head-to- head studies of IVB versus ranibizumab.45,116 However, this trend tends to disappear when possible confounders such as socio-economic status (related to cost and access to treatment) are controlled in the analysis of study results.58 The most robust data set for safety are from the IVAN48 and CATT45 trials which were large trials that reported longer term data. Serious systemic adverse events were significantly higher in the bevacizumab group. The available evidence related to IVB-related adverse events from observational data was limited as have been reported elsewhere.124,129 Included studies are often associated with methodological weaknesses that limited the validity of the reported findings. In this review, the relationship between locally produced IVB preparations and infectious endophthalmitis could not be established. In general, the likelihood of confounding is a threat to the validity of findings.130 6 CONCLUSIONS AND IMPLICATIONS FOR DECISION-MAKING
NICE requested the DSU to consider four questions of potential relevance to the consideration of IVB as a comparator in appraisals of licensed therapies for DMO and RVO. 1) What evidence is there relating to the pharmaceutical quality of reformulated bevacizumab as used in eye conditions in general? (section 2) 2) How widespread is Intravitreal Bevacizumab (IVB) use in the UK? (section 3) 3) What is the evidence for efficacy of IVB in adults with RVO and DMO specifically? (section 4) What evidence is there regarding adverse events for IVB in eye conditions in general? This report provides evidence on each of those questions in turn. 6.1 THE MANUFACTURING PROCESS
Licensed bevacizumab is supplied for intravenous use in cancer patients. For intravitreal injection, much smaller quantities are required. Reformulating bevacizumab for use in the eye is considered by the MHRA to result in an unlicensed product. As such, manufacturers must hold a "specials" license from the MHRA which requires the adherence to a range of conditions and associated inspections. Both of the major manufacturers in the UK, Liverpool and Moorfields hold such licenses. There have been cluster outbreaks of infection reported internationally, including a suspected case involving Moorfields. However, some argue that the risks of infection are greater when local pharmacists perform this compounding and this should therefore be avoided. According to our survey of consultant ophthalmologists, a small but significant proportion of supplies are currently produced by local pharmacies. 6.2 EXTENT OF USE IN THE NHS
We found evidence from publicly available documents that only a small number of commissioners are actively promoting the use of IVB over other licensed alternatives in patients with AMD. IVB is more typically reported as a treatment option in those situations where it is referred to at all in this patient group. Greater variation is evident in other eye conditions. Sales figures from the two main suppliers indicate that they together supplied nearly ********of IVB in 2011. It is difficult to estimate the proportion of all eligible patient populations that this represents but is clearly a non-trivial quantity. A survey of consultant ophthalmologist members of the RCO reinforced the view that, following NICE guidance in favour of the use of ranibizumab in patients with AMD, few clinicians use IVB in this patient group. In other conditions where no such guidance exists, such as DMO and RVO, there is significant use of IVB. IVB use is more widespread in private practice, mirroring the findings of international studies in settings where patient copayments are commonplace. The NICE 2008 Method Guide states that comparators should include "routine and best practice in the NHS" (Section 2.2.4). Further relevant guidance is given in the following two paragraphs: "There will often be more than one relevant comparator technology because routine practice may vary across the NHS and because best alternative care may differ from routine NHS practice. For example, this may occur when new technologies are used inconsistently across the NHS." "Relevant comparator technologies may also include those that do not have a marketing authorisation (or CE mark for medical devices) for the indication defined in the scope but that are used routinely for the indication in the NHS." It would seem that based on the evidence we have identified, the use of unlicensed IVB is variable across the NHS as a whole. However, IVB is widely used by a substantial number of clinicians and hospitals in the NHS for DMO, RVO and eye conditions other than AMD. AMD use has diminished as a result of NICE guidance in favour of a licensed alternative. 6.3 EVIDENCE OF EFFICACY IN DMO AND RVO
Seven RCTs were included in the review of efficacy in DMO patients. One study compared IVB with sham injection. Six studies compared IVB to laser photocoagulation. Compared to sham injection the results favour IVB in terms of change in visual acuity and change in central macular thickness. Meta analysis of studies comparing IVB to laser therapy provide broadly favourable results for IVB but some outcomes are only superior at longer term follow up of one year. For example, results favour IVB for deterioration or any deterioration (BCVA ETDRS 15-letter -3 lines) from 26 to 54 weeks (2 RCTs, n=180, RR 0.17 CI 0.05 to 0.56). The effect of IVB on BCVA LogMAR scores was significantly different compared with laser therapy at 6 weeks although data were heterogeneous, whilst 12 and 24 week data were equivocal. Longer term follow up data at 48 weeks significantly favoured laser therapy, though this was based on one small study (n=65). No significant differences for mean scores in central macular thickness were detected beyond 4-6 weeks. Data were limited for RVO. We included five trials comparing IVB with sham injection but three were available only in abstract form and only two provided data on the differences between the two treatment options. Analysis is also hampered by the relatively short follow up in these studies (the maximum was 24 weeks) and the different types of RVO patients (central and branch). In one trial of patients with BRVO where interventions were administered twice, 6 weeks apart, the two groups were statistically different at 6 weeks (p=0.05), however by 12 weeks the difference was no longer significant (p=0.064). In another trial of patients with CRVO,23 where interventions were administered four times, 6 weeks apart, there was a significant difference between groups in weeks 12, 18 and 24 (p<0.01), but not at week 6. 6.4 REVIEW OF EVIDENCE OF ADVERSE EVENTS
89 studies were included in a systematic review of adverse events, 22 of which were RCTs. Trials compared IVB with a number of different therapies and eye conditions, though most were in AMD, DMO and RVO. In these studies, adverse event rates were low overall in all bevacizumab and comparators groups, and most outcomes were not significantly different. Of particular note is the fact that in head to head comparisons of IVR and IVB (CATT and IVAN trials), when results are meta- analysed, there is a statistically significantly higher rate of 1 or more serious systematic adverse event (RR 1.27, 95% CI 1.09 to 1.47) in the IVB group. Some potential caveats to this finding are relevant. The IVAN study alone did not show a statistically significant difference. Event rates were higher in the CATT study overall which may be due to different definitions of serious adverse events. It is also important to note that these SAEs were more common in those patients randomized to receive discontinuous rather than continuous treatment, that is, those with lower exposure to the drug experienced higher adverse event rates. Also in the CATT study there were some imbalances between randomised patients that may be relevant. More patients randomized to IVB had had a previous transient ischaemic attack (TIA) compared to those in the IVR arms (44 vs 24). Similarly, more IVB patients had a history of myocardial infarction (MI) – 76 vs 64.116 These patients may be more likely to be on therapies such as anticoagulants that may contribute to the observed higher incidence of GI haemorrhage. Despite these caveats we consider these trial designs to offer the most robust assessment of adverse events. Further investigation and follow up from these and other trials will be of value. Overall, the evidence on safety of IVB from observational studies was inconclusive. The majority of studies were retrospective in design with small study samples or inadequate follow-up periods (less than 6 months). With respect to larger studies, observational data from Curtis et al58 suggest no difference in the risk of adverse events between IVB and IVR once socioeconomic confounders are accounted for. On the other hand, results of an unpublished study of Medicare patients funded by Genentech112 found an increased risk of stroke and death in IVB patients. The available abstract, however, did not provide sufficient information to an in-depth analysis of the results of this study. A recently published population-based, nested case-control study reported by Campbell et al.117 (n=91,378) compared adverse events due to IVR and IVB. The authors reported that there was no relationship between the risk of systemic events such as myocardial infarction, venous thromboembolism, stroke or congestive heart failure and the administration of IVR or IVB. While, the risk of systemic adverse events was similar for the two treatment groups, there was an increased risk of acute myocardial infarction for a subgroup of diabetic patients that received IVB. 7 REFERENCES
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Comparison of bevacizumab and triamcinolone for treatment of macular edema secondary to central retinal vein occlusion--a matched-pairs analysis. Ophthalmologica 2010; 224(2):126-132. 346. Hannan, S.R., Madhusudhana, K.C., Lotery, A.J., Newsom, R.S.B. Retinal pigment epithelial tear following intravitreal bevacizumab for choroidal neovascular membrane due to age-related macular degeneration. British Journal of Ophthalmology 2007; 91(7):977-978. 347. Jalil, A., Fenerty, C., Charles, S. Intravitreal bevacizumab (Avastin) causing acute glaucoma: an unreported complication. Eye 2007; 21(12):1541. 348. Jonas, J.B., Schmidbauer, M., Rensch, F. Progression of tractional retinal detachment following intravitreal bevacizumab. Acta Opthalmologica 2009; 87(5):571-572. 349. Kawashima, M., Mori, R., Mizutani, Y., Yuzawa, M. Choroidal folds and retinal pigment epithelium tear following intravitreal bevacizumab injection for exudative age-related macular degeneration. Japanese Journal of Ophthalmology 2008; 52(2):142-4. 350. Kim, K.S., Chang, H.R., Song, S. Ischaemic change after intravitreal bevacizumab (Avastin) injection for macular oedema secondary to non-ischaemic central retinal vein occlusion. Acta Ophthalmologica 2008; 86(8):925-7. 351. Kopel, A.C., Carvounis, P.E., Holz, E.R. Bacillus cereus endophthalmitis following intravitreous bevacizumab injection. Ophthalmic Surgery, Lasers & Imaging : the Official Journal of the International Society for Imaging in the Eye 2008; 39(2):153-4. 352. Maier, M., Feucht, N., Lanzl, I., Kook, P., Lohmann, C.P. [Retinochoroidopathy after intravitreal anti-VEGF treatment]. [German]. Ophthalmologe 2009; 106(8):729-734. 353. Mathews, J.P., Jalil, A., Lavin, M.J., Stanga, P.E. Retinal pigment epithelial tear following intravitreal injection of bevacizumab (avastin-«): optical coherence tomography and fluorescein angiographic findings. Eye 2007; 21(7):1004-1005. 354. Mennel, S., Callizo, J., Schmidt, J.C., Meyer, C.H. Acute retinal pigment epithelial tear in the untreated fellow eye following repeated bevacizumab (AvastinΓäó) injections. Acta Ophthalmologica Scandinavica 2007; 85(6):689-690. 355. Meyer, C.H., Mennel, S., Schmidt, J.C., Kroll, P. Acute retinal pigment epithelial tear following intravitreal bevacizumab (Avastin) injection for occult choroidal neovascularisation secondary to age related macular degeneration. British Journal of Ophthalmology 2006; 90(9):1207-1208. 356. Meyer, C.H., Mennel, S., H+Ârle, S., Schmidt, J.C. Visual hallucinations after intravitreal injection of bevacizumab in vascular age-related macular degeneration. American Journal of Ophthalmology 2007; 143(1):169-170. 357. Mitamura, Y., Ogata, K., Oshitari, T., Asaumi, N., Yamamoto, S. Retinal detachment with macular hole following intravitreal bevacizumab in patient with severe proliferative diabetic retinopathy. British Journal of Ophthalmology 2008; 92(5):717-8. 358. Montero, J.A., Ruiz-Moreno, J.M., De La Vega, C. Incomplete posterior hyaloid detachment after intravitreal pegaptanib injection in diabetic macular edema. European Journal of Ophthalmology 2008; 18(3):469. 359. Neri, P., Mariotti, C., Mercanti, L., Salvolini, S., Giovannini, A. Vitritis in the contralateral uninjected eye following intravitreal bevacizumab (Avastin). International Ophthalmology 2008; 28(6):425-7. 360. Nicolo, M., Ghiglione, D., Calabria, G. Retinal pigment epithelial tear following intravitreal injection of bevacizumab (Avastin). European Journal of Ophthalmology 2006; 16(5):770. 361. Peng, C.H., Cheng, C.K., Chiou, S.H., Peng, C.H., Cheng, C.K., Chiou, S.H. Retinal pigment epithelium tear after intravitreal bevacizumab injection for polypoidal choroidal vasculopathy. Eye 2009; 23(11):2126-2129. 362. Pieramici, D.J., Avery, R.L., Castellarin, A.A., NASIR, M.A.A.N., Rabena, M. Case of anterior uveitis after intravitreal injection of bevacizumab. Retina 2006; 26(7):841. 363. Rodrigues, E.B., Shiroma, H., Meyer, C.H., Maia, M., Farah, M.E. Metrorrhagia after intravitreal injection of bevacizumab. Acta Ophthalmologica Scandinavica 2007; 85(8):915-916. 364. Sayanagi, K., Ikuno, Y., Soga, K., Wakabayashi, T., Tano, Y., Sayanagi, K. et al. Marginal crack after intravitreal bevacizumab for myopic choroidal neovascularization. Acta Opthalmologica 2009; 87(4):460-463. 365. Shah, N.J., Shah, U.N. Long-term effect of early intervention with single intravitreal injection of bevacizumab followed by panretinal and macular grid photocoagulation in central retinal vein occlusion (CRVO) with macular edema: a pilot study. Eye 2011; 25(2):239-244. 366. Shah, P.K., Morris, R.J., Narendran, V., Kalpana, N., Shah, P.K., Morris, R.J. et al. Visual acuity and electroretinography findings 3 1/2 years after the first intravitreal injection of bevacizumab (Avastin) in aggressive posterior retinopathy of prematurity. Indian Journal of Ophthalmology 2011; 59(1):73-74. 367. Shaikh, S., Olson, J.C., Richmond, P.P. Retinal pigment epithelial tears after intravitreal bevacizumab injection for exudative age-related macular degeneration. Indian Journal of Ophthalmology 2007; 55(6):470. 368. Shah, C.P., Hsu, J., Garg, S.J., Fischer, D.H., Kaiser, R. Retinal pigment epithelial tear after intravitreal bevacizumab injection. American Journal of Ophthalmology 2006; 142(6):1070-1071. 369. Shimura, M., Yasuda, K., Shimura, M., Yasuda, K. Macular ischaemia after intravitreal bevacizumab injection in patients with central retinal vein occlusion and a history of diabetes and vascular disease. British Journal of Ophthalmology 2010; 94(3):381-383. 370. Shoeibi, N., Ahmadieh, H., Abrishami, M., Poorzand, H., Shoeibi, N., Ahmadieh, H. et al. Rapid and sustained resolution of serous retinal detachment in Sturge-Weber syndrome after single injection of intravitreal bevacizumab. Ocular Immunology & Inflammation 2011; 19(5):358-360. 371. Song, J.H., Bae, J.H., Rho, M.I., Lee, S.C., Song, J.H., Bae, J.H. et al. Intravitreal bevacizumab in the management of subretinal fluid associated with choroidal osteoma. Retina 2010; 30(6):945-951. 372. Subramanyam, A., Phatak, S., Chudgar, D. Large retinal pigment epithelium rip following serial intravitreal injection of avastin in a large fibrovascular pigment epithelial detachment. Indian Journal of Ophthalmology 2007; 55(6):483. 373. Tarantola, R.M., Folk, J.C., Boldt, H.C., Mahajan, V.B., Tarantola, R.M., Folk, J.C. et al. Intravitreal bevacizumab during pregnancy. Retina 2010; 30(9):1405-1411. 374. Teixeira, A., Mattos, T., Velletri, R., Teixeira, R., Freire, J., Moares, N. et al. Clinical course of choroidal neovascularization secondary to angioid streaks treated with intravitreal bevacizumab. Ophthalmic Surgery, Lasers & Imaging 2010; 41(5):546-549. 375. Tranos, P., Gemenetzi, M., Papandroudis, A., Chrisafis, C., Papadakos, D. Progression of diabetic tractional retinal detachment following single injection of intravitreal Avastin. Eye 2007; 22(6):862. 376. Wiegand, T.W., Rogers, A.H., McCabe, F., Reichel, E., Duker, J.S., Wiegand, T.W. et al. Intravitreal bevacizumab (Avastin) treatment of choroidal neovascularisation in patients with angioid streaks. British Journal of Ophthalmology 2009; 93(1):47-51. 377. Wu, P.C., Chen, Y.J., Wu, P.C., Chen, Y.J. Intravitreal injection of bevacizumab for myopic choroidal neovascularization: 1-year follow-up. Eye 2009; 23(11):2042-2045. 378. Yenerel, N.M., Dinc, U.A., Gorgun, E. A case of sterile endophthalmitis after repeated intravitreal bevacizumab injection. Journal of Ocular Pharmacology & Therapeutics 2008; 24(3):362-3. 379. Yoon, Y.H., Kim, J.G., Chung, H., Lee, S.Y., Yoon, Y.H., Kim, J.G. et al. Rapid progression of subclinical age-related macular degeneration in the untreated fellow eye after intravitreal bevacizumab. Acta Opthalmologica 2009; 87(6):685-687. 380. Angulo, B.M.C., Glacet-Bernard, A., Zourdani, A., Coscas, G., Soubrane, G. Intravitreous injection: retrospective study on 2028 injections and their side effects]. Journal Francais D'Ophtalmologie 2008; 31(7):693. 381. Baeteman, C., Hoffart, L., Galland, F., Ridings, B., Conrath, J., Baeteman, C. et al. [Subretinal hemorrhage after intravitreal injection of anti-VEGF for age-related macular degeneration: a retrospective study]. [French]. Journal Francais D'Ophtalmologie 2009; 32(5):309-313. 382. Bidot, M.L., Malvitte, L., Bidot, S., Bron, A., Creuzot-Garcher, C., Bidot, M.L. et al. [Efficacy of three intravitreal injections of bevacizumab in the treatment of exudative age-related macular degeneration]. [French]. Journal Francais D'Ophtalmologie 2011; 34(6):376-381. 383. Demircelik, G., Onen, M., Yazar, Z., Evren, O., Ucgun, N.I. Ocular and systemic complications associated with intravitreal bevacizumab injection. Retina-Vitreus 2009; 17(4):269-272. 384. Dithmar, S., Schaal, K.B., Hoh, A.E., Schmidt, S., Schutt, F. [Intravitreal bevacizumab for choroidal neovascularization due to pathological myopia]. [German]. Ophthalmologe 2009; 106(6):527-530. 385. Dolezalova, J., Karel, I., Hallova, H., Dolezalova, J., Karel, I., Hallova, H. [Our two-year experience with the bevacizumab (Avastin) treatment of the age related macular degeneration wet form]. Ceska a Slovenska Oftalmologie 2010; 66(1):10-14. 386. Guthoff, R., Schrader, W., Hennemann, K., Meigen, T., bel, W. [Prognostic factors for visual outcome after intravitreal drug therapy for chronic diabetic macular oedema]. Klin Monbl Augenheilkd 2011; 228(5):468-72. 387. Guthoff, R., Schrader, W., Hennemann, K., Meigen, T., Gobel, W. [Prognostic factors for visual outcome after intravitreal drug therapy for chronic diabetic macular oedema]. Klinische Monatsblatter Fur Augenheilkunde 2011; 228(5):468-472. 388. Hasler, S., Schmid, M.K., Becht, C.N. [Acute anterior non-granulomatous uveitis after intravitreal injection of bevacizumab]. Klinische Monatsblatter Fur Augenheilkunde 2008; 225(5):446-447. 389. Hoh, A.E., Schaal, K.B., Scheuerle, A., Sch, t., Dithmar, S. [OCT-guided reinjection of 2.5 mg bevacizumab for treating macular edema due to retinal vein occlusion]. Ophthalmologe 2008; 105(12):1121-6. 390. Hong, H., Liu, Q.H. Clinical observation of intravitreous injections of bevacizumab (Avastin) for exudative age-related macular degeneration. International Journal of Ophthalmology 2010; 10(11):2176-2178. 391. Horn, W., Hoerauf, H. [Intravitreal injections during anticoagulant treatment]. Klin Monbl Augenheilkd 2008; 225(3):217-9. 392. Jamrozy-Witkowska, A., Kowalska, K., Jankowska-Lech, I., Terelak-Borys, B., Nowosielska, A., Grabska-Liberek, I. et al. [Complications of intravitreal injections--own experience]. Klinika Oczna 2011; 113(4-6):127-131. 393. Malgorzata, F. [Effectivity and safety of bevacizumab intravitreal injections for exudative age-related macular degeneration treatment--6 months observations]. Klinika Oczna 2010; 112(7-9):213-6. 394. Meng, L., Chen, S. Advance in the study of complication of anti-vascular endothelial growth factor following intravitreal injection. Chinese Ophthalmic Research 2009; 27(11):1039-1043. 395. Meyer, C.H., Mennel, S., Eter, N. Incidence of endophthalmitis after intravitreal Avastin injection with and without postoperative topical antibiotic application]. Der Ophthalmologe: Zeitschrift Der Deutschen Ophthalmologischen Gesellschaft 2007; 104(11):952. 396. Meyer, C.H., Ziemssen, F., Heimann, H. [Intravitreal injection. Monitoring to avoid postoperative complications]. Ophthalmologe 2008; 105(2):143-55. 397. Meyer, C.H., Helb, H.M., Eter, N. [Monitoring of AMD patients on anti-vascular endothelial growth factor (VEGF) treatment. Practical notes on functional and anatomical examination parameters from drug approval studies, specialist information and case series]. [Review] [68 refs] Ophthalmologe 2008; 105(2):125-138. 398. Schaal, K.B., Hoh, A.E., Scheuerle, A., Schutt, F., Dithmar, S. [OCT-based re-injections for anti-VEGF-treatment for neovascular ARMD]. Ophthalmologe 2009; 106(4):334-339. 399. Schaal, K.B., Hoeh, A.E., Scheuerle, A., Schuett, F., Dithmar, S., Schaal, K.B. et al. Intravitreal bevacizumab for treatment of chronic central serous chorioretinopathy. European Journal of Ophthalmology 2009; 19(4):613-617. 400. Schaal, K.B., Hoh, A.E., Scheuerle, A., Dithmar, S. Endophthalmitis after repeated bevacizumab injections. Ophthalmologe 2009; 106(4):356-359. 401. Schiano, L.D., Parravano, M.C., Chiaravalloti, A., Varano, M., Schiano Lomoriello, D., Parravano, M.C. et al. Intravitreal bevacizumab for choroidal neovascularization in ocular histoplasmosis. European Journal of Ophthalmology 2009; 19(1):151-153. 402. Sekeryapan, B., Ozdek, S., Ozmen, M.C., Gurelik, G., Hasanreisoglu, B. Treatment of choroidal neovascularization secondary to age-related macular degeneration with intravitreal bevacizumab monotherapy or combination with photodynamic therapy: 12 month results. Retina-Vitreus 2011; 19(2):97-102. 403. Sun, W.T., Lei, C.L., Bi, C.C., Wang, R. Clinical study on intravitreous injection of avastin for macular edema induced by central retinal vein occlusion. International Journal of Ophthalmology 2010; 10(10):1906-1908. 404. The Lucentis/Avastin story: Cost-effectiveness should not endanger safety! Deutsche Apotheker Zeitung 2009; 149(15):72-73. 405. Vidinova, C., Vidinov, N. [The effect of bevacizumab on the ultrastructure of choroidal neovascular membranes in patients with age-related macular degeneration (AMD)]. Klin Monbl Augenheilkd 2009; 226(6):491-5. 406. Yu, X.R., Wang, X.Z. Clinical effect for intravitreal injection of avastin for 400 cases fundus disease. International Journal of Ophthalmology 2010; 10(10):1913-1915. 407. Zhou, Y.Y., Zhang, R.J. [Avastin combined with vitreous cavity injection of triamcinolone acetonide in treatment of diabetic retinopathy with macular edema] LA: Chi. International Journal of Ophthalmology 2010; 10:475-476. 408. Zwaan, T. Clarity needed about off-label use of Avastin: A thorn in the eye. Pharmaceutisch Weekblad 2009; 144(19):27. 8 APPENDICES

APPENDIX 1: SEARCH RESULTS OF NHS AND PCT WEB-PAGES

Table A 1: Search results of Primary Care Trust and NHS site searches in England
Source:
Results?*
32. see County Durham) 35. (See Cornwall) 63. see Hampshire) 98. (Also see Cornwall) 99. Also see Hampshire) 115. (See Gateshead) 117. (See also Hampshire) 123. See Gateshead) *Yes = results on search "bevacizumab" or "avastin" are available - recommendation/policy document
No = no relevant results/results on "bevacizumab" or "avastin" for eye conditions in PCT website searches
Unclear = results on "bevacizumab" or "avastin" is available. Document is a letter, provisional statement or discussion document on
use of bevacizumab.
Not available = No search box in PCT website to search for "bevacizumab" or "avastin"

Table A 2: Search results of Local Health Board sites in Wales
Source:
Health board
Results?*
*Yes = results on search "bevacizumab" or "avastin" are available - recommendation/policy document No = no relevant results/results on "bevacizumab" or "avastin" for eye conditions in health board website search No search = No search box in PCT website to search for "bevacizumab" or "avastin" †Concerns bevacizumab for the treatment of advanced renal cancer. Table A 3: Search results of Health and Social Care Trusts in Northern Ireland
Source:
Health and Social Care Trust *Yes = results on search "bevacizumab" or "avastin" are available, could be recommendation/policy document No = no relevant results/results on "bevacizumab" or "avastin" for eye conditions in PCT website searches Table A 4: Search results of NHS health board sites in Scotland
Source:
NHS Health board
Results?*
*Yes = results on search "bevacizumab" or "avastin" are available - recommendation/policy document No = no relevant results/results on "bevacizumab" or "avastin" for eye conditions in health board website search Not available = No search box in PCT website to search for "bevacizumab" or "avastin" †Concerns bevacizumab for the treatment of advanced ovarian cancer. ¤Concerns bevacizumab in health bulletins. §Relates to discussions around the use of Lucentis or Avastin Table A 5: Search results of Eye Hospital sites
Source:
Searched for ‘bevacizumab' or ‘avastin' in each hospital website
Eye hospital
Results?*
*Yes = results on search "bevacizumab" or "avastin" are available, could be recommendation/policy document No = no relevant results/results on "bevacizumab" or "avastin" for eye conditions in hospital website search †Yorkshire Eye Hospital is now called the Optegra Yorkshire Eye Hospital. APPENDIX 2: MEDLINE SEARCH STRATEGY – EFFICACY REVIEW
Search date: 21st May 2012 Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) <1946 to Present> 1. bevacizumab.mp. 5. diabetic retinopathy/ 6. (diabet$ adj2 retinopath$).mp. 7. macular edema/ 8. ((central or diabetes or diabetic or fovea or macula or macular or retina or retinal) adj2 (edema? or oedema?)).mp. 9. (dme or dmo).mp. 10. (irvine-gass adj2 syndrome).mp. 13. Randomized controlled trials as Topic/ 14. Randomized controlled trial/ 15. Random allocation/ 16. randomized controlled trial.pt. 17. Double blind method/ 18. Single blind method/ 19. Clinical trial/ 20. exp Clinical Trials as Topic/ 21. controlled clinical trial.pt. 23. (clinic$ adj25 trial$).ti,ab. 24. ((singl$ or doubl$ or treb$ or tripl$) adj (blind$ or mask$)).tw. 26. Placebo$.tw. 27. (allocated adj2 random).tw. 30. Case report.tw. 32. Historical article/ 34. exp Animals/ 36. 34 not (34 and 35) 40. limit 39 to yr="2010 -Current" Search date: 21st May 2012 Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) <1946 to Present> 1. bevacizumab.mp. 4. Retinal Vein Occlusion/ 6. ((retina or retinal or branch or central) adj3 vein occlusion).mp. 7. ((vein$ or occlu$ or obstruct$ or clos$ or stricture$ or steno$ or block$ or embolism$) adj3 retina$).mp. 8. (RVO or CRVO or CVO or BRVO).mp. 11. Randomized controlled trials as Topic/ 12. Randomized controlled trial/ 13. Random allocation/ 14. randomized controlled trial.pt. 15. Double blind method/ 16. Single blind method/ 17. Clinical trial/ 18. exp Clinical Trials as Topic/ 19. controlled clinical trial.pt. 21. (clinic$ adj25 trial$).ti,ab. 22. ((singl$ or doubl$ or treb$ or tripl$) adj (blind$ or mask$)).tw. 24. Placebo$.tw. 25. (allocated adj2 random).tw. 28. Case report.tw. 30. Historical article/ 32. exp Animals/ 34. 32 not (32 and 33) APPENDIX 3
Table A 6: Efficacy review - table of excluded studies with reasons

Author, year
Reason for exclusion
Not RCT, not DMO ( patients with diabetic retinopathy) Ah-Chan 2006132 Not RCT (review, not systematic) Algvere 2011134 No control group Algvere 2008135 Not RCT (review, not systematic) Full text report unobtainable Campochiaro 2010139 10. CATT Research Group 2011116 Not RVO (patients with AMD) 11. Cekic 201042 No relevant comparator 13. Ciulla 2009141 Not RCT (review, not systematic) 14. Di Lauro 2010142 Not DMO (patients with severe proliferative diabetic retinopathy) No relevant comparator 16. Farahvash 2011143 17. Fard 2011144 No relevant comparator 18. Feltgen 2010145 Not RCT, not English 19. Ferrara 2010146 Not RCT (review, not systematic) No control group 21. Forte 2012148 22. Fulda 2010149 Full text report unobtainable 23. Garber 2010150 24. Gulati 2011151 Not RCT (review, not systematic) 26. Hara 2010153 Not English language 27. Hernandez-Da-Mota 2010154 No relevant comparator 28. Isaac 2012155 No relevant comparator Not RCT (review, not systematic) 30. Jaissle 2006157 Not RCT, not English 31. Jeganathan 2009158 Not RCT (review, not systematic) 32. Kakkassery 2010159 Not English language 33. Karim 2010160 Not RCT (review, not systematic) 34. Kazazi-Hyseni 2010161 35. Lim (2012)50 No relevant comparator 36. Lynch 2007162 Not RCT (review, no additional studies to include) 37. Marey (2011)51 No relevant comparator 38. Mete 2010163 39. Micieli 2010164 Full text report unobtainable 41. Moradian 201134 42. Nghiem-Buffet 2009166 Not RCT, not English 43. Nicholson 2010167 Not RCT (review, not systematic) 44. Ockrim 2010168 45. Paccola (2008)169 No relevant comparator 46. Prager 2009170 47. Russo 2009 171 48. Shahin &El-Lakkany (2010)54 No relevant comparator 49. Sivkova 2010172 No control group 50. Soheilian 2010173 51. Stewart 2012174 Not RCT (review, not systematic) 52. Subramanian 2010175 Not DMO (patients with AMD) 53. Synek 2010176 No relevant comparator 54. Synek 2011177 No relevant comparator 55. Wang 2011178 No relevant comparator 56. Wolf-Schnurrb 2011179 57. Wykoff 2011180 Full text report unobtainable 58. Yilmaz 2011181 Not RCT systematic review 59. Zechmeister-Koss 2012182 Not RCT systematic review 60. Zhang 2011183 61. Zhao 2011184 Not RCT (systematic review of diabetic retinopathy) APPENDIX 4
Table A 7: Design and patient characteristics of included studies: DMO review of efficacy
Author, year, country, No. of
Inclusion criteria /exclusion
Baseline data, Sponsor
Comparators
Outcomes
eyes (patients), IVB
criteria
Preparation
Ahmadieh 200825
Patients with significant macular Total mean age = 59 Bevacizumab 1.25 mg at
Sham injection (n=37 eyes)
oedema, refractory to previous baseline and weeks 6, 12 Change in BCVA logMAR; laser treatment were included. Safety assessments (IVB prepared by F Hoffmann Visual acuity ≥20/40, history of Authors have no financial La Roche Ltd Basel, cataract surgery within the past 6 conflicts of interested. months, prior intraocular injection or vitrectomy, glaucoma or ocular hypertension, proliferative diabetic retinopathy were excluded. DRCRN 200727
Type 1 or 2 Diabetes; ETDRS 1: Bevacizumab:
Laser at baseline (n =19)
Central macular thickness VA letter score ≥ 24 (20/320 or (1.25 mg) at baseline better) and ≤78 (2/32 or worse); Authors have financial safety assessments (No IVB preparation details) central macular thickness ≥ 275 interests with Genentech μm; no previous treatment for 2: Bevacizumab:
DMO within last 3 months (2.5 mg) at baseline,
week 6 (n = 24 eyes)
3: Bevacizumab:
(1.25 mg) baseline,
sham at week 6
(n = 22 eyes)
(Total N=68 eyes)
Faghihi 200828
Type 2 diabetes with DMO; IVB mean age =59 years Bevacizumab: 1.25 mg (no
Laser (n = 47 eyes)
BCVA improvement BCVA ≤ 20/40; CMT ≥ 250 μm; Laser mean age=56 years further details) (n = 42 eyes) Central macular thickness patients with history of treatment (No IVB preparation details) for diabetic retinopathy were Financial conflicts of interest not reported Author, year, country, No. of
Inclusion criteria /exclusion
Baseline data, Sponsor
Comparators
Outcomes
eyes (patients), IVB
criteria
Preparation
Mansourian 201124
Patients with previous panretinal No baseline details Bevacizumab: 1.25 mg (no
Laser (n=33)
Change in central or focal laser photocoagulation, Financial conflicts of further details) (n=32) macular thickness; prior intraocular surgery or interest not reported (No IVB preparation details) injection, history of glaucoma or ocular hypertension, VA of 20/40 or better or worse than 20/300, presence of iris neovascularization, high-risk proliferative diabetic retinopathy, and significant media opacity were excluded Michaelides 201026
Type 1 or 2 diabetes; BCVA IVB mean age: 64 years. Bevacizumab: 1.25 mg at
Laser: at baseline and
between 35 and 69 letters on Laser mean age:63 years. baseline, and at 6 and 12 retreatment at 4-month ETDRS at 4 m; patients with any weeks. Subsequent injections review, if required (IVB prepared by Moorfields, ocular condition that may affect Authors have no financial administered until a stable (weeks 16, 32, and 48) macular oedema or alter VA conflicts of interested. gaining ≥10 ETDRS during the course of the study thickness attained: minimum letters; % who lost of 3 and maximum of 9 over 12 months (n = 42 eyes) letters; safety assessments Solaiman 201030
Diffuse diabetic macular oedema; Mean age 57 years. Bevacizumab: 1.25 mg
Laser once at baseline (n =
Changes in central macular central macular thickness ≥ 350 thickness; changes in BCVA; Authors have no financial (No IVB preparation details) No history of intravitreal conflicts of interested. injection, surgical intervention, or Soheilian 201229
Patients with DMO based on IVB mean age: 60 years. Bevacizumab: 1.25 mg at
Laser (n = 50 eyes)
Change in BCVA (logMAR; ETDRS with no previous laser Laser: mean age 61 years. baseline (n= 50 eyes) central macular thickness treatment, or intraocular surgery. Retreatment based on changes; safety assessments (IVB prepared by F Hoffmann Authors have no financial persistence of clinically La Roche Ltd Basel, conflicts of interested. significant macular oedema according to ETDRS criteria APPENDIX 5
Table A 8: Design and patient characteristics of included studies: RVO review of efficacy - Study characteristics
Author, year, country, number
Inclusion criteria /exclusion criteria
Sponsor / Disclosures
Interventions [treatment
Comparators
Outcomes
of eyes (patients), IVB
protocol]
preparation
Epstein 201231
Inclusion: CRVO with a duration of ≤ 6 months
Authors have financial Change in BCVA (number of BCVA between 15–65 ETDRS letters (Snellen interests with Alcon, equivalent approx 20/50 to 20/500) Allergan, Bayer and (1.25mg/0.05ml) at (IVB prepared at the hospital Mean central subfield thickness ≥ 300μm as measured Novartis. baseline and at weeks 6, pharmacy under sterile by OCT (Cirrus OCT) 12 and 18 (n = 30 eyes) Exclusion: CRVO with neovascularisation
Any previous treatment for CRVO Sham at baseline and at Intraocular surgery during the previous 3 months weeks 6, 12 and 18 (n = Vascular retinopathy of other causes Glaucoma with advanced visual field defect or uncontrolled ocular hypertension >25mmHg despite full therapy Myocardial infarction or stroke during the last 12 months Habibabadi 200732 (abstract)
Inclusion: Patients with CRVO
Financial conflicts of BCVA (no further details) interest not reported. Note group 2 (concentration and number excluded as (No IVB preparation details) of injections not reported) bevacizumab augmented with Bevacizumab combined intravitreal with triamcinolone triamcinolone (concentration and number
of injections not reported)
Group 3:
Sham (number of
injections not reported)
Author, year, country, number
Inclusion criteria /exclusion criteria
Sponsor / Disclosures
Interventions [treatment
Comparators
Outcomes
of eyes (patients), IVB
protocol]
preparation
Habibabadi 200833 (abstract)
Inclusion: Patients with CRVO
Financial conflicts of BCVA (no further details) interest not reported. Note group 2 (concentration not excluded as (No IVB preparation details) reported) at baseline, 6 bevacizumab augmented with intravitreal Bevacizumab combined triamcinolone with triamcinolone
(concentration not
reported) at baseline, then
just bevacizumab at 6 and
12 weeks
Group 3:
Sham (number of
injections not reported)
Moradian 200735 (abstract)
Inclusion: acute BRVO
Financial conflicts of BCVA (no further details) interest not reported. (1.25mg/0.05ml) at (No IVB preparation details) baseline and 6 weeks (n =
34)
Group 2:
Sham at baseline and 6
weeks (n = 36)
Moradian 201134
Inclusion: acute BRVO and a best-corrected
BCVA measured with a Snellen visual acuity (BCVA) equal to or less than 20/50 financial conflicts of chart then transformed to Exclusion: One-eyed patients
(1.25mg/0.05ml) at logMAR; adverse events (No IVB preparation details) Surgical candidate eyes baseline and 6 weeks (n = Intraocular surgery in the past 6 months Macular thickening less than 250 μm by optical coherence tomography (OCT) Sham at baseline and 6 Ocular media haziness that precluded evaluation by OCT and funduscopy Any new vessel formation Accompanying arterial obstruction Signs of chronicity (vascular shunts) Other macular diseases that affect central vision Pregnancy Patient incompliance Uncontrolled hypertension or any recent history of myocardial infarction or cerebral vascular accident within the past 6 months Table A 9: Design and patient characteristics of included studies: RVO review of efficacy - Patient characteristics at baseline
Author, year
Mean age (SD)
Condition
Previous treatment [for
Mean BCVA, EDTRS
Mean BCVA (logMAR±SD)
Habibabadi 200732 (abstract) Habibabadi 200833 (abstract) Moradian 200735 (abstract) Abbreviations: IVB: intravitreal bevacizumab; RVO – retinal vein occlusion; CRVO – central retinal vein occlusion; BRVO – branch retinal vein occlusion APPENDIX 6
Table A 10: Summary of efficacy outcomes for the RVO review - Bevacizumab monotherapy versus sham injection
Author, year
Mean change in
Percentage of eyes
Percentage of eyes
Percentage of eyes
Percentage of eyes (patients)
point (weeks)
BCVA (±SD)
(patients) with
(patients) achieving
(patients) with stable
with worsening BCVA
improvement in
improvement in
BCVA, ≥ 15 letters (3
BCVA of 10 -15
lines), EDTRS
letters, EDTRS
Habibabadi 200732 Habibabadi 200833 Moradian 200735 (abstract) 0.19±0.24 logMAR 0.31±0.30 logMAR 0.08±0.25 logMAR 0.15±0.03 logMAR Abbreviations: EDTRS - Early Treatment Diabetic Study; SD – standard deviation; BCVA- visual acuity; NR – not reported APPENDIX 7: MEDLINE SEARCH STRATEGY – SAFETY REVIEW
Search date: 24 May 2012 Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) <1946 to Present> 1. bevacizumab.mp. 9. (cancer$ or neoplas$ or oncolog$ or malignan$ or tumo?r$ or carcinoma$ or adenocarcinoma$).ti,ab. 11. ((side or adverse or undesirable) adj2 (event$ or effect$ or reaction$ or outcome$)).ab,ti. 13. (safe or safety).ab,ti. 14. (treatment adj emergent).ab,ti. 15. tolerability.ab,ti. 16. toxicity.ab,ti. 19. (cancer$ or neoplas$ or oncolog$ or malignan$ or tumo?r$ or carcinoma$ or adenocarcinoma$).ti,ab. 21. exp Endophthalmitis/ci 22. endophthalmiti$.ab,ti. 23. (intraocular adj2 (pressure$ or tension$)).ab,ti. 24. hypotony.ab,ti. 25. exp Cataract/ci 26. cataract$.ab,ti. 27. Retinal Detachment/ci 28. (retina$ adj2 detach$).ab,ti. 29. exp Retinal Artery Occlusion/ci [Chemically Induced] 30. retina$ artery occlu$.ab,ti. 32. vitreoretinal fibros$.ab,ti. 33. discomfort.ab,ti. 35. corneal abrasion.ab,ti. 36. lens injur$.ab,ti. 37. Uveitis/ci [Chemically Induced] 38. uveitis.ab,ti. 39. infection$.ab,ti. 40. itch$.ab,ti. 41. (vision adj2 (loss or reduced or subnormal or diminished or abnormal)).ab,ti. 42. (subconjunctival adj (haemorrhag$ or hemorrhag$)).ab,ti. 43. ((subretinal or retina$) adj (haemorrhag$ or hemorrhag$)).ab,ti. 44. (retina$ adj3 tear$).ab,ti. 45. rpe tears.ab,ti. 46. blood pressure.ab,ti. 47. Venous Thrombosis/ci [Chemically Induced] 48. Ischemic Attack, Transient/ci [Chemically Induced] 49. Stroke/ci [Chemically Induced] 50. Myocardial Infarction/ci [Chemically Induced] 54. (cancer$ or neoplas$ or oncolog$ or malignan$ or tumo?r$ or carcinoma$ or adenocarcinoma$).ti,ab. 58. limit 57 to yr="2009 -Current" APPENDIX 8
Table A 11: Study characteristics of RCTs included in safety review
Author, year, country,
Inclusion criteria /exclusion
Baseline details
Interventions [treatment
Comparators
Outcomes
number of eyes (patients)
criteria
protocol], IVB
preparation
Ahmadieh (2008)25
Patients with significant macular Total mean age = 59 Bevacizumab 1.25 mg at
Sham injection (n=37 eyes)
oedema, refractory to previous laser baseline and weeks 6, 12 Marked anterior chamber reaction treatment were included. Visual Progression of fibrous proliferation (IVB prepared by F Hoffmann acuity ≥20/40, history of cataract Outcomes at 24 weeks La Roche Ltd Basel, surgery within the past 6 months, financial conflicts of prior intraocular injection or vitrectomy, glaucoma or ocular hypertension, proliferative diabetic retinopathy were excluded. Bashshur 200769
Neovascular AMD. BCVA 20/50 and IVB mean age 75 years; Bevacizumab: 2.5mg,
Laser therapy: mean 2.3
Systemic adverse events 20/200. Submacular hemorrhage not Laser mean age 74 mean 2.4 injections (n=32) No. eyes NR 62 subjects. involving the fovea. prior treatment Outcomes at 6 months Authors report no conflicts of for CNV associated AMD excluded. IVB prepared in hospital Biswas 201144
CNV associated AMD, age >50 Bevacizumab: 1.25mg
Ranibizumab: 0.5mg (n=30),
Significant adverse events years, BCVA between 25-70 ETDRS (n=30), 3 monthly 3 monthly injections (mean Outcome at 18 months 60 eyes in 60 patients. letters, treatment naive CNV. Co- injections (mean 4.3). Conflicts of interest not existing ocular pathologies, history of CVA, MI were excluded. Methods of IVB preparation not reported CATT 201245
Eligible eyes had active choroidal IVB mean age 80 years; Bevacizumab: 1.25mg,
Ranibizumab: 0.5mg
neovascularization secondary IVR mean age 79 years. (monthly or as needed) (monthly or as needed) Endophthalmitis, to AMD, no previous treatment, One author received financial visual acuity between 20/25 and Adverse events associated with anti- support from Genentech 20/320, and neovascularization, fluid, or haemorrhage under the fovea. Arteriothrombotic adverse events Outcomes at 2 years Cekic 201042
Patients with macular oedema due to IVB mean age 60 years; Bevacizumab:1.25 mg
Triamcinolone: 4mg,
Endophthalmitis, uveitis, branch retinal vein occlusion. IVT mean age 66 years; mean 1.6 injections (n=14) mean1.4 injections (n=17) thromboembolic events 52 eyes in 52 subjects Included if visual acuity 20/40 or duration of BRVO Methods of IVB preparation Outcomes at 6 months Conflicts of interest not worse, and CMT of 250 or greater. IVB=5.6 months; IVT Author, year, country,
Inclusion criteria /exclusion
Baseline details
Interventions [treatment
Comparators
Outcomes
number of eyes (patients)
criteria
protocol], IVB
preparation
Ding 201146
Patients with macular oedema IVB mean age 53 years; Bevacizumab:1.25 mg
Triamcinolone: 4mg (n=16)
secondary to RVO, older than 18 duration 12 weeks. Outcomes at 9 months 32 eyes in 31 subjects. years, BCVA worse than 20/40 IVT mean age 55 years; Methods of IVB preparation No financial conflicts of (logarithm of the minimal angle of duration18 weeks. resolution [logMAR] =0.3), clinically detectable ME involving fovea with a thickness of >250µm; no history of previous treatments. Exclusion criteria intraocular pressure (IOP) >21mmHg, previous intraocular surgery within the past 2 years or grid photocoagulation for MO., DRCRN (2007)27
Type 1 or 2 Diabetes; ETDRS 1: Bevacizumab:
Laser at baseline (n =19)
VA letter score ≥ 24 (20/320 or (1.25 mg) at baseline better) and ≤78 (2/32 or worse); Authors have financial Outcomes at 12 weeks (No IVB preparation details) central macular thickness ≥ 275 μm; Safety over a 70 week period no previous treatment for DMO Genentech (Avastin) 2: Bevacizumab:
within last 3 months (2.5 mg) at baseline,
week 6 (n = 24 eyes)
3: Bevacizumab:
(1.25 mg) baseline,
sham at week 6
(n = 22 eyes)
(Total N=68 eyes)
Epstein (2012)31
Inclusion: CRVO with a duration of Sham injection: at baseline
≤ 6 months BCVA between 15–65 differences in baseline (1.25mg/0.05ml) at baseline and at weeks 6, 12 and 18 (n= 60 eyes in 60 subjects. ETDRS letters (Snellen equivalent characteristics between and at weeks 6, 12 and 18 Retinal detachment Author consultant for Novartis approx 20/50 to 20/500); Mean No serious non-ocular adverse events central subfield thickness ≥ 300μm. Outcomes at 6 months Exclusion: CRVO with IVB prepared in hospital neovascularisation pharmacy by dividing a vial Any previous treatment for CRVO of bevacizumab (Avastin) Intraocular surgery during the into small vials for each previous 3 months Vascular retinopathy of other causes Glaucoma with advanced visual field defect or uncontrolled ocular hypertension >25mmHg despite full therapy Myocardial infarction or stroke during the last 12 months Author, year, country,
Inclusion criteria /exclusion
Baseline details
Interventions [treatment
Comparators
Outcomes
number of eyes (patients)
criteria
protocol], IVB
preparation
Faghihi (2008)28
Type 2 diabetes with DMO; BCVA ≤ IVB mean age =59 Bevacizumab: 1.25 mg (no
Laser (n = 47 eyes)
Safety assessment 20/40; CMT ≥ 250 μm; patients with further details) (n = 42 Vitreous haemorrhage history of treatment for diabetic Laser mean age=56 Ocular hypertension (≥23 mmHg) Financial conflicts of interest retinopathy were excluded. No IVB preparation details Outcome 16 weeks Gharbiya 201047
Pathologic myopia, defined as IVB mean age 59. yrs Bevacizumab: 1.25 mg, as
Ranibizumab: 0.5 mg as
Systemic adverse events axial length more than 26.5 IVT mean age 60 yrs; needed, after the first needed, after the first Endophthalmitis, 32 eyes in 32 subjects, one mm;subfoveal or juxtafoveal Foveal center thickness Retinal detachment author received unrelated choroidal neovascularisation. IVB 237; IVT 251; no Methods of IVB preparation Vitreous haemorrhage Novartis fellowship; no significant differences conflicts stated by other characteristics between Outcomes at 6 months IVAN 201248
Adults ≥50 years old with previously IVB mean age 77 years; Bevacizumab: 1.25mg
Ranibizumab: 0.5mg
Serious adverse events untreated neovascular AMD in the IVR mean age 77 years. study eye and best corrected visual Baseline characteristics discontinuous treatment) discontinuous treatment) Arteriothrombotic events Author(s) have conflicts of acuity ≥25 letters on the Early similar across groups Transient ischaemic attack interest with Novartis Treatment Diabetic Retinopathy Commercially obtained Hospitalized for angina Study chart were eligible. IVB. Bevacizumab was Outcomes at 1 year repackaged in prefilled syringes in an aseptic facility Lazic 200749
Minimally classic or occult CNV Baseline characteristics Bevacizumab: 1.25 mg
1. Laser therapy: according
Pigment epithelial tears due to AMD in 1 or both eyes were (age, gender, size of the to recommended standard Posterior vitreous detachment 165 eyes in 165 subjects. procedures (N=55) Thromboembolic events of the fellow eye, and Methods of IVB preparation Cataract progression Authors have no commercial Excluded the subjects with cataract CNV type) showed no 2. Combination treatment
Outcomes at 3 months. or proprietary interest or media opacities that could relevant differences significantly interfere with optic between the 3 groups coherence tomography imaging & image analysis (inadequate signal strength & quality). Author, year, country,
Inclusion criteria /exclusion
Baseline details
Interventions [treatment
Comparators
Outcomes
number of eyes (patients)
criteria
protocol], IVB
preparation
Lim 201250
Diabetic macular oedema (ETDRS) IVB mean age 61 years Bevacizumab: 1.25mg
1. Triamcinolone: 2mg,
criteria, macular oedema with central IVT mean age 59 years Thromboembolic AE 120 eyes in 110 subjects, macular thickness of at least 300µm Serious ocular complications Authors have no commercial by optical coherence tomography 2. IVB + IVT (n=37) conflicts of interest Outcomes at 1 year. Exclusion criteria : unstable medical status, including glycaemic control and blood pressure, any previous treatment for diabetic macular oedema, including intravitreal, sub-Tenon injection or macular photocoagulation, history of vitreoretinal surgery, uncontrolled glaucoma, proliferative diabetic retinopathy with active neovascularization, previous panretinal photocoagulation. Marey 201151
Clinically significant DMO based on Mean age in IVB 57 Bevacizumab: 1.25mg
1. Triamcinolone: 4mg,
(ETDRS) Exclusion criteria were: 90 eyes in 90 subjects previous laser treatment, previous Mean age in IVT 57 Methods of IVB preparation Outcomes at 12 weeks Authors have no commercial intraocular injection, previous 2. IVB + IVT (n=30) conflicts of interest intraocular surgery, history of glaucoma or ocular hypertension, and significant media opacity. Michaelides 201026
Type 1 or 2 diabetes; BCVA between IVB mean age: 64 Bevacizumab: 1.25 mg at
Laser: at baseline and
35 and 69 letters on ETDRS at 4 m; baseline, and at 6 and 12 retreatment at 4-month Ocular hypertension patients with any ocular condition Laser mean age:63 weeks. Subsequent review, if required Loss of 30 ETDRS letters Authors have no financial that may affect macular oedema or injections administered until (weeks 16, 32, and 48) Vitreous haemorrhage conflicts of interested. alter VA during the course of the a stable central macular Cerebrovascular accident study were excluded. (IVB prepared by thickness attained: Outcomes at 12 months Moorfields, London) minimum of 3 and maximum of 9 over 12 months (n = 42 eyes) Author, year, country,
Inclusion criteria /exclusion
Baseline details
Interventions [treatment
Comparators
Outcomes
number of eyes (patients)
criteria
protocol], IVB
preparation
Moradian 201134
Inclusion: acute BRVO and a best- Sham injection: at baseline
Foveal haemorrhage differences in baseline (1.25mg/0.05ml) at baseline and 6 weeks (n = 39) visual acuity (BCVA) equal to or less characteristics between and 6 weeks (n = 42) Outcomes at 12 weeks Exclusion: One-eyed patients Methods of IVB preparation Surgical candidate eyes Intraocular surgery in the past 6 Macular thickening less than 250 μm by optical coherence tomography (OCT) BCVA≥20/40 Ocular media haziness that precluded evaluation by OCT and funduscopy Any new vessel formation Accompanying arterial obstruction Signs of chronicity (vascular shunts) Other macular diseases that affect central vision Pregnancy Patient incompliance Uncontrolled hypertension or any recent history of myocardial infarction or cerebral vascular accident within the past 6 months Patwardhan 201152
Vitreous haemorrhage of 0-3 months IVB mean age 26 years. Bevacizumab: 1.25 mg
Control no treatment:
Retinal detachment duration (grade 3 or 4), secondary to Control mean age 25 every four weeks. Outcomes at 12 weeks 20 eyes of 20 subjects. Earls disease. Patients with retinal Authors have no commercial detachment at presentation, history Methods of IVB preparation or proprietary interest on any intervention , undergone proior surgery or laser photocoagulation were excluded. Schimid-Kubista 201153
Neovascular age related macular IVB median age 77 Bevacizumab: 1.0 mg x3
Pegaptanib: 0.3 mg x3
No significant IOP increase degeneration.excluded if any prior injections (n=13) injections (n=18) No significant BP increase 48 eyes in 48 subjects. treatment for CNV. Pegaptanib median age 2. Combination treatment: Outcomes at 6 months Authors have no commercial Methods of IVB preparation or proprietary interest regarding the products Author, year, country,
Inclusion criteria /exclusion
Baseline details
Interventions [treatment
Comparators
Outcomes
number of eyes (patients)
criteria
protocol], IVB
preparation
Shahin 201054
Diffuse diabetic macular oedema, Bevacizumab: single
Triamcinolone: single 4mg
IOP (≥23-43 mmHG) without previous laser therapy injection (n=24) Visually significant cataract 48 eyes, in 32 subjects. Outcomes at 3 months Conflicts of interest not Methods of IVB preparation
Soheilian 201229
Patients with DMO based on ETDRS IVB mean age: 60 Bevacizumab: 1.25 mg at
Laser (n = 50 eyes)
with no previous laser treatment, or baseline (n= 50 eyes) intraocular surgery. Laser: mean age 61 Ocular hypertension (IVB prepared by F Hoffmann High risk proliferative diabetic La Roche Ltd Basel, Switzerland) Authors have no Outcomes at 2 years financial conflicts of interested.
Tufail 201055
Age related macular degeneration; IVB mean age 79 years. Bevacizumab: 1.25 mg,
1. Laser therapy: (n=38)
aged at least 50, have a lesion in the Groups (1,2,3) mean three loading injections at 2. Pegaptanib: 0.3mg, mean
No. eyes NR (n=131) study eye with a total size of less six week intervals followed injections 8.9 (n=16) Retinal detachment Author(s) involvement with than 12 optic disc areas for baseline measures by further treatment if 3. Sham injection: (n=12)
Novartis advisory boards minimally classic or occult lesions; similar in all groups. required at six week Vitreous haemorrhage have BCVA of 6/12 to approximately intervals (mean injections 7.1 range 3-9) (n=65). Myocardial infarction equivalent), assessed with the use of charts from (ETDRS) (70 to 25 Methods of IVB preparation Cerebral infarction ETDRS 1 m equivalent letter scores. Death Outcomes at one year Yazdani 200956
Neovascular glaucoma; excluded IVB mean age 57, Bevacizumab: 2.5mg, 3
Sham injection: (n=12)
monocular subjects, BCVA better Sham mean age 62. injections at monthly Injection related adverse events 26 eyes in 26 subjects. than 20/200, presence of infectious intervals (n=14). Outcomes at 6 months Authors report no conflicts of Methods of IVB preparation not reported APPENDIX 9
Table A 12: Study characteristics of observational studies included in safety review

Study type
Condition
Baseline
Number of
Follow-up
Information
reference
included
injections/
patients
patients
(yes/no/
including
patients
preparation
[mean age
unknown/not
frequency
in years]
applicable)
of dosing
bevacizumab
Arevalo-Coutinho in Ophthalmology, Venezuela Prevent Blindness, New York American University of Beirut Medical 1.5 during second year) Sociedade Portuguesa de Oftalmologia, Hospitalde Sao Joao, CNV secondary to AMD [76.9 ] f Azad 2008105 studied patients with the following conditions: AMD,CNV due to myopic degeneration idiopathic and other secondary causes ,cystoid or diffuse MO from CRVO, BRVO, diabetes, uveitis and retinitis pigmentosa proliferative retinopathies g Population included patients CNV due to AMD;DMO;DR;MO due to RVO or autoimmune retinopathy Study type
Condition
Baseline
Number of
Follow-up
Information
reference
included
injections/
patients
patients
(yes/no/
including
patients
preparation
[mean age
unknown/not
frequency
in years]
applicable)
of dosing
bevacizumab
Sociedade Portuguesa Increased rate of ATEs in de Oftalmologia, IVB group compared to IVT Hospitalde Sao Joao, (secondary analyses Swiss National Foundation and Walter & Gertrud Sienenthaler Foundation Patients received IOP- lowering treatment during follow-up period if IOP ≥ Anterior paracentesis was performed before IVB to reduce ocular pressure. Author's conclusion: IVB better than IVT Reported as a dose escalation study but difficult to tell how Research Support of many doses each participant the State of São was given and how far apart Exclusion criteria included previous history of thromboembolic events; uncontrolled hypertension, BP >150/90mmHg. Topical antibiotics prescribed for 3 days, after injection. Study type
Condition
Baseline
Number of
Follow-up
Information
reference
included
injections/
patients
patients
(yes/no/
including
patients
preparation
[mean age
unknown/not
frequency
in years]
applicable)
of dosing
bevacizumab
Research agreement Patient data were censored between OSI Eyetech when at the time when a and Duke University treatment which was different from initially assigned intervention was received. Between July and December 2006, study population was limited to treatment-naïve patients who received bevacizumab or ranibizumab. from 122 injections for 70 patients) Number of injections not monthly injections then as needed First injection only selected 3 initial injections h Forty-seven patients out of a study population of 71 received bevacizumab. NOTE: Some patients received all 3 anti-VEGF medications while others received just one treatment type. However, authors reported that only the first anti-VEGF injection was considered in the study. iGamulescu 2010186 included a control group that received ranibizumab. Study type
Condition
Baseline
Number of
Follow-up
Information
reference
included
injections/
patients
patients
(yes/no/
including
patients
preparation
[mean age
unknown/not
frequency
in years]
applicable)
of dosing
bevacizumab
subretinal fluid observed. Hazard ratios adjusted for baseline comorbidities, demographics and socio-economic status patients lost to follow-up] j Re-injection in 5 eyes, 1 or 2 months after first injection at physician discretion k Good 201178 included a control group that received ranibizumab. l 101 eyes received bevacizumab only, 96 eyes received ranibizumab only, 18 eyes received bevacizumab and ranibizumab Study type
Condition
Baseline
Number of
Follow-up
Information
reference
included
injections/
patients
patients
(yes/no/
including
patients
preparation
[mean age
unknown/not
frequency
in years]
applicable)
of dosing
bevacizumab
(84.6%); DMO (6.7%); Other including ocular histoplasmosis (8.7%) [76] Re-injection considered after Education, Culture, 2 to 3 months if fluorescein Sports Science and leakage in angiograam or Technology of Japan; subretinal fluid persisted Health and Labor Sciences Research of Japan This study reported incidence of infectious endophthalmitis associated with 2% topical lidocaine gel anaesthesia. No information on conditions being treated or patient During the 1-year follow-up, an average of 2.4 re-injections (range, 0–5) administered, with a mean of 1.6 re-injections within the 6 months (weeks 6 to 24) and a further 0.8 re-injections the latter 6 months (weeks 30 Study type
Condition
Baseline
Number of
Follow-up
Information
reference
included
injections/
patients
patients
(yes/no/
including
patients
preparation
[mean age
unknown/not
frequency
in years]
applicable)
of dosing
bevacizumab
Queen's University, 40 days (range 19 to 170 days) 534 re-injections dispensing service In all cases, optimum control of intraocular was achieved by the time IVB active neovascularisation) received triamcinolone acetonide) Grant from Kyung study (prospective, consecutive) mPopulation included patients AMD, diabetes, retinal vein occlusion and other eye conditions Study type
Condition
Baseline
Number of
Follow-up
Information
reference
included
injections/
patients
patients
(yes/no/
including
patients
preparation
[mean age
unknown/not
frequency
in years]
applicable)
of dosing
bevacizumab
case – control L. Boltzmann Institute based on OCT and FA findings; 3 intravitreal injections disease [median 33] ≥1.5 months NR Follow-up was 6-weekly and Macula Foundation Same-day bilateral injections dispensing service n Kiss 200663 included a control group that received triamcinolone acetonide. o Krishnan 2009111 included a control group that received ranibizumab. pPopulation included patients with AMD, BRVO, CRVO and myopic choroidal neovascularisation. Study type
Condition
Baseline
Number of
Follow-up
Information
reference
included
injections/
patients
patients
(yes/no/
including
patients
preparation
[mean age
unknown/not
frequency
in years]
applicable)
of dosing
bevacizumab
University research grant, New York. No. of eyes/patients refers to Authors reported that nti- VEGF related reflux was not associated with a sub- therapeutic effect causes of CMO [68.6] (IVB injections) IVR patients were on average Novartis (and part- funded by Canadian older than IVB patients (78.7 Institutes for Health 0.01) and had slightly worse baseline vision (6/76 versus 6/64, p 0.013). 195 out of the 351 patients that received IVR, had been treated previously with IVB (mean, 4.3 injections per patient). Prior treatment in IVB group unclear. q Population included patients with neovascular age-related macular degeneration; branch retinal vein occlusion, central retinal vein occlusion; cystoid macular oedema; proliferative diabetic retinopathy; diabetic macular oedema. rRasier 200977 studied between-group comparison of hypertensive / nonhypertensive patients. Study type
Condition
Baseline
Number of
Follow-up
Information
reference
included
injections/
patients
patients
(yes/no/
including
patients
preparation
[mean age
unknown/not
frequency
in years]
applicable)
of dosing
bevacizumab
treatment until no intraretinal or subretinal fluid on optical coherence tomography. Treatment intervals determined by signs of exudation Sciences Research Ministry of Health, Labour and Welfare, Japan Grants 19390441 and 19659445 from the Japan Society for the Promotion of Science, No significant difference in adverse events between 1-montly intervals Gachon Univeristy, s Conditions included AMD, DR, CNV, BRVO, CRVO and other pathologies (unspecified). t Control group received triamcinolone acetonide Study type
Condition
Baseline
Number of
Follow-up
Information
reference
included
injections/
patients
patients
(yes/no/
including
patients
preparation
[mean age
unknown/not
frequency
in years]
applicable)
of dosing
bevacizumab
Institute for Medicine research grant of Kosin University College of Medicine Of 27 patients, 3 were lost to follow-up/protocol violation) every 12 weeks until week 48 weeks. Frequency not reported Academic institution Of the 40 patients included in the study, 14 received IVR u Control group received triamcinolone acetonide Study type
Condition
Baseline
Number of
Follow-up
Information
reference
included
injections/
patients
patients
(yes/no/
including
patients
preparation
[mean age
unknown/not
frequency
in years]
applicable)
of dosing
bevacizumab
case series (prospective) Abbreviations: AMD-age-related macular degeneration, BRVO-branch retinal vein occlusion, CRVO-central retinal vein occlusion, CME-cystoid macular oedema, CNV-choroidal neovascularization, DMO-diabetic macular oedema, DR-diabetic retinopathy, DRT-diffuse retinal thickening, IVB-intravitreal bevacizumab, IVP-intravitreal pegaptinib, IVR-intravitreal ranibizumab, MO- macular oedema, NA-not applicable, NR –not reported, RVO-retinal vein occlusion, PED-pigment epithelium detachment, SRD-serous retinal detachment APPENDIX 10: ADVERSE EVENT RATES FROM OBSERVATIONAL STUDIES
Table A 13: Systematic adverse events in included observational studies

Study reference
Death (%)
Non-ocular
Arterial
Myocardial
Transient
accident(%)
ischaemic
attack(%)
[n/N]
2007104 Arevalo 200871 One patient required coronary pass surgery for unstable angina. It was reported that the association between treatment and event could not be established. Authors reported that the two cases repeat injections) accident occurred in women over 70 years of age who had other risk factors. The event occurred 3 weeks after IVB when systemic concentrations of bevacizumab are considered to be lower. Study reference
Death (%)
Non-ocular
Arterial
Myocardial
Transient
accident(%)
ischaemic
attack(%)
[n/N]
Arterial thromboembolic events-12.4% [12/97] included peripheral thromboembolic events (n=1), sudden death (n=1), TIA (n=1), MI (n=2), unstable angina (n=1)], and stroke (n=6 of which 2 were lethal). Authors reported that IVB increased the risk of arterial thromboembolic events (ATE) when compared with ranibizumab (i.e. 3 events: stroke, n=2; and MI, n=1). However, in an elderly population with multiple cardiovascular risk factors, new ATEs may not be attributed exclusively to IVB administration Study reference
Death (%)
Non-ocular
Arterial
Myocardial
Transient
accident(%)
ischaemic
attack(%)
[n/N]
No systemic adverse events such as thrombosis or hypertension No systemic or serious adverse events were observed. 200982 Curtis 201058 2007110 Fintak 200883 One death due to MI 6 weeks after 3rd IVB injection (history of hypertension), other was due to upper respiratory tract infection, 2 months after 3rd IVB injection (no medical history) 2010186 Gomi 200857 Goverdhan 200873 Study reference
Death (%)
Non-ocular
Arterial
Myocardial
Transient
accident(%)
ischaemic
attack(%)
[n/N]
than for IVR(HR: demographics and socio-economic status. Haemorrhagic cerebrovascular accident rates reported – no difference for ischemic events. 200768 Higashide 2012114 Authors reported that no cases experienced systemic side effects including myocardial infarction and cerebrovascular accidents within 3 months after bevacizumab injection. Hollands 2007187 This study reported incidence of infectious endophthalmitis associated with anaesthetic procedure. Study reference
Death (%)
Non-ocular
Arterial
Myocardial
Transient
accident(%)
ischaemic
attack(%)
[n/N]
Authors reported that no obvious bevacizumab-related ocular or systemic adverse events were apparent. Authors reported that there were no adverse events related to IVB nor to the injection procedure. Authors reported that ‘no general complications' were observed. Authors reported that ‘no other systemic complications such as cardiovascular events or cerebral accidents were encountered.' Authors reported (Patients were on anti-hypertensives systemic or drug- related adverse events were observed during the follow-up period. Study reference
Death (%)
Non-ocular
Arterial
Myocardial
Transient
accident(%)
ischaemic
attack(%)
[n/N]
200864 Krishnan 2009111 No inflammation, infection, thrombo-embolic events or ocular toxicity were reported. 200961 Lorenz 201084 Manayath 2009190 No obvious systemic adverse events were observed. Study reference
Death (%)
Non-ocular
Arterial
Myocardial
Transient
accident(%)
ischaemic
attack(%)
[n/N]
[3/222] (see note) presented per number of injections. Arterial thromboembolism was defined as an emergency room visit within 1 month of injection in which the patient was diagnosed with a myocardial infarction, ischemic stroke, transient ischemic attack, or pulmonary embolism. Authors reported that no adverse ocular or systemic events were observed. Authors reported that no adverse ocular or systemic events were observed. xxii Incidence of systemic adverse events was reported for patients with addresses within the greater Kingston region (n=222/693 injections) Study reference
Death (%)
Non-ocular
Arterial
Myocardial
Transient
accident(%)
ischaemic
attack(%)
[n/N]
Other reported complications : facial skin redness (n = 1) - 0.14%; itchy diffuse rash (n = 1- 0.14%; and menstrual irregularities (n = 3) - 0.42%. Authors reported that ‘no serious ocular or nonocular adverse events were noted'. 2012194 Valmaggia 200987 NR 200797 Wickremasinghe 2008195 Wu 2008106 Abbreviations: n-number, NR-not reported, IVB-intravitreal bevacizumab Table A 14: Ocular adverse events in included observational studies
Infectious
Anterior
Lens damage(%)
Visual loss(%)
reference
reaction(%)
None of the patients with intraocular inflammation required treatment and inflammatory cells spontaneously resolved. Adverse events reported 1 patient with hypopyon was pre-treated. No ocular side effects Incidence of subretinal macular haemorrhage reported. Vision loss was attributed to subretinal fibrosis n=2) and atrophy of the retinal pigment epithelium (n=4) 201190 Cavalcante Submacular haemorrhage Costa 200681 – haemorrhage considered. No uveitis observed. Costa 200681 – haemorrhage considered. No uveitis observed. Costa 200681 – haemorrhage considered. No uveitis observed. Infectious
Anterior
Lens damage(%)
Visual loss(%)
reference
reaction(%)
200982 Curtis 201058 IOP >30 mm Hg at 10 Culture positive Staphylococcus epidermidis endophthalmitis IOP > 40mmHg spike (0-2 min) Authors described anterior chamber reaction as sterile endophthalmitis and also referred to blurred vision after IVB treatment. 2010186 Gomi 200857 Submacular haemorrhage. Visual loss of 6 lines or 30 ETDRS letters Hazard ratios adjusted for baseline comorbidities, ranibizumab (HR: demographics and socio- economic status. Ocular inflammation for ACR. Infectious
Anterior
Lens damage(%)
Visual loss(%)
reference
reaction(%)
Authors reported that no cases had marked inflammation, lens injuries, marked vitreous haemorrhage, retinal detachment, or endophthalmitis Authors reported that IVB injection is safe with respect to short-term IOP changes, as almost all patients (97.1%) IOP returned to a safe range (<25 mm Hg) within 30 minutes. Elevated IOP at 30 minutes after injection does occur, rarely, thus clinicians should consider checking IOP after injection as a precaution. Transient extreme IOP elevations occur in a significant percentage of patients, but the consequences of these events are unknown. Authors reported that two eyes developed chemosis at the injection site one day after IVB that resolved with a topical steroid treatment in one week. One eye developed a retinal detachment two months after IVB; however, the relationship between IVB and the detachment was questionable. Infectious
Anterior
Lens damage(%)
Visual loss(%)
reference
reaction(%)
Authors reported that no cases of endophthalmitis, retinal detachment or any other severe procedure-related complications were observed in a total of 78 injections. Authors reported that IVB is associated with a low but significant risk of acute intraocular inflammation and may result in significant visual loss. Authors reported that the rate of infectious endophthalmitis after an IVB injection of 1.5mg may be approximately 1:1000. Two patients in the IVB group developed progressive cataract following treatment. Authors reported that there were no adverse events related to IVB nor to the injection procedure. Infectious
Anterior
Lens damage(%)
Visual loss(%)
reference
reaction(%)
Authors reported that no inflammatory response was detected clinically and by laser flare meter after IVB administration. It was suggested that the slight reduction in anterior chamber flare could be due to known anti-inflammatory effect of anti-VEGF. Authors stated that none of the patients experienced severe local adverse events. Association between visual loss and IVB administration was unclear. Reported as pigment 2009190 Rasier 200977 Nine patients had minor local AEs listed as conjunctival hyperaemia and subconjunctival haemorrhage, but no numbers given for each one Infectious
Anterior
Lens damage(%)
Visual loss(%)
reference
reaction(%)
Adverse event rates reported per injection.xx Safety study- Reported no adverse ocular or systemic events observed. complications also included corneal abrasion (n = 2) - 0.28%; chemosis (n = 2) - 0.28%; ocular inflammation (n = 2) - 0.28%. Acute visual loss occurred in a patient with PDR Authors reported that no [11/24; injections] serious ‘drug-related' ocular adverse events occurred. Ocular bleeding referred to subconjunctival haemorrhage at the injection site. One of the four patients with retinal tear developed visual loss. Patients included in this study had underlying pigment epithelium detachment. xxiii This rate is based on the total number of IVB injections evaluated (n=693). Infectious
Anterior
Lens damage(%)
Visual loss(%)
reference
reaction(%)
2012194 Weinberger 17.4%(n=31/178) patients treated with IVB had initial PED at presentation. Vitreous haemorrhage [19/1278] Per injection 71.52[839/1,173] The cultures of patients with bacterial endopthalmitis yielded 5 cases of coagulase negative staphylococci and one case each of Staphylococcus aureus and Streptococcus pneumoniae. It is uncertain whether reported visual loss 0.51[6/1,173] was an efficacy outcome or safety outcome. Note: Visual loss was not listed under ocular complications (see Table 4 of published paper). Abbreviations: AE-adverse event, n-number, ETDRS-Early treatment diabetic retinopathy study, NR-not reported, PDR-proliferative diabetic retinopathy, PED-pigment epithelium detachment APPENDIX 11

Table A 15: Safety review - table of excluded studies with reasons

Eligibility critera
Study references
Total number
Population not relevant Ahmadieh 2011201 Aisenbrey 2007202 Algvere 2008203 Arevalo 200972 Arias 2007107 Arias 2008204 Arias 2008103 Avery 2006205 Bae 2011206 Bashshur 2006207 Beutel 2010208 Bonin-Filho 2009209 Brouzas 2009210 Cervantes-Castandea 2009211 Chan 2009212 Chau 2009213 Chen 2011214 Cheng 2011215 Chiang 2012216 Cavalcante 2010198 Davis 2010217 Ehlers 2011218 Ehrlich 2008219 Fang 2008220 Finger 2008221 Finger 2012222 Forte 2011223 Funk 2010224 Garg 2008225 Gelisken 2009226 Ghanem 2009227 Gharbiya 2009228 Ghazi 2010229 Gregori 2008230 Hasanreisoglu 2009231 Honda 2008232 Hou 2009233 Hung 2010234 Jiang 2009235 Jonas 2011236 Kim 2011237 Kook 2008238 Kotecha 201176 Kramer 2010239 Kumar 2007240 Kuo 2011241 Lupinacci 2008242 Moradian 2008243 Nielsen 2012244 Nuti 2011245 Roh 2009246 Roh 2010247 Ronan 2007248 Roth 2009249 Ruiz-Moreno 2010250 Schadlu 2008251 Seo 2009252 Shetty 2008253 Shimura 2008254 Eligibility critera
Study references
Total number
Skaat 2011255 Soheilian 2010173 Soliman 2008256 Song 2009257 Spielberg 2009258 Stahl 2009259 Stergiou 2011260 Subramanian 2010175 Synek 2011177 Tao 2010261 Tran 2008262 Tseng 2012263 Wang 2011178 Warid Al-Laftah 2010264 Weiss 2009265 Wu 2012266 Yamaike 2009267 Yeung 2010268 Zhang 2011183 Intervention not relevant Arevalo 2011270 Arias 2010271 Cleary 2011272 Curtis 201058 Dayani 2007273 Frenkel 2007274 Furino 2009275 Hariprasad 2006276 Hernandez da Mota 2010154 Kopecna 2011277 Koss 2010278 Moraczewski 2008279 Myung 2010280 Suzuki 2010281 Takahashi 2010282 Tao 2010283 Treumer 2010284 Udaondo 2011285 Vasudev 2009286 Voykov 2010287 Wakabayashi 2008288 Wong 2008289 Wu 2009290 Yamashiro 2010291 Yoon 2010292 Study type not relevant Abdallah 2009294 Al-Qureshi 2012295 Avastin and Lucentis are equally effective…296 Battaglia 2009297 Beaumont 2011298 Blair 2012299 Campochiaro 2012300 Chang 2007301 Cheung 2012302 Chung 2010303 First reports of serious adverse reactions 2009304 First reports of serious adverse reactions 2009305 First reports of serious adverse reactions 2010306 Food and Drug Administration 2009307 Fung 200621 Gunther 2009308 Kernt 2007309 Martin 2011310 Martinez-Ferez 2011311 Schouten 2009312 Eligibility critera
Study references
Total number
Schultz 2011313 Schwartz 2009314 Schwartz 2009315 Seet 2012316 Soiberman 2010317 Spitzer 2008318 Summary of recent evidence… 2011319 Utman 2008320 Veritti 2012321 Waisbourd 2011322 WHO 2011323 Wu 2009324 Ziemssen 2009325 Case reports/case series/case control studies <10 patients Alkuraya 2008327 Amselem 2009328 Anto 2012329 Arriola-Villalobos 2008330 Artunay 2010331 Bae 2010332 Bakri 2006333 Bakri 200888 Baskin 2011334 Brouzas 2009335 Byeon 2009336 Chen 2009337 Chieh 2007338 Chilov 2007339 Forooghian 2008340 Freund 2006341 Gamulescu 2007342 Gelisken 2006343 Gibran 2007344 Guthoff 2010345 Hannan 2007346 Jalil 2007347 Jonas 2009348 Kawashima 2008349 Kim 2008350 Kopel 2008351 Maier 2009352 Mathews 2007353 Mennel 2007354 Meyer 2006355 Meyer 2007356 Mitamura 2008357 Montero 2008358 Neri 2008359 Nicolo 2006360 Peng 2009361 Piermici 2006362 Rodrigues 2007363 Rosenfeld 20051 Sayanagi 2009364 Shah 2011365 Shah 2011366 Shaikh 2007367 Shan 2006368 Shimura 2010369 Shoeibi 2011370 Song 2010371 Subramanyam 2007372 Tarantola 2010373 Teixeira 2010374 Tranos 2007375 Wiegand 2009376 Eligibility critera
Study references
Total number
Wu 2009377 Yenerel 2008378 Yoon 2009379 Foreign language Angulo Bocco 2008380 Baeteman 2009381 Bidot 2011382 Demircelik 2009383 Dithmar 2009384 Dolezalova 2010385 Fukami 2011108 Guthoff 2011386 Guthoff 2011387 Hasler 2008388 Hoh 2008389 Hong 2010390 Horn 2008391 Jamrozy-Witkowska 2011392 Malgorzata 2010393 Meng 2009394 Meyer 2007395 Meyer 2008396 Meyer 2008397 Schaal 2009398 Schaal 2009399 Schaal 2009400 Schiano 2009401 Sekeryapan 2011402 Sun 2010403 The Lucentis Avastin story 2009404 Vidinova 2009405 Yu 2010406 Zhou 2010407 Zwaan 2009408

Source: http://www.nicedsu.org.uk/Bevacizumab%20report%20-%20NICE%20published%20version%2011.04.13.pdf