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1 Lincolnshire Knowledge and Resource Service Please find below the results of your literature search request. If you would like the full text of any of the abstracts included, or would like a further search completed on this topic, please let us know. Google can bring you back 100,000 answers, a librarian can bring you back the right one. Neil Gaiman Literature Search Results Search request date: 18 th April 2013 Search completion date: 22 nd April 2013 Search completed by: Alison Price Enquiry Details Clinical and cost effectiveness of avastin (bevacizumab )for iris rubeosis and rubeotic glaucoma. Neovascular glaucoma (NVG) is classified as a secondary glaucoma. First documented in 1871, historically, it has been referred to as hemorrhagic glaucoma, thrombotic glaucoma, congestive glaucoma, rubeotic glaucoma, and diabetic hemorrhagic glaucoma. Disclaimer Every effort has been made to ensure that this information is accurate, up-to-date, and complete. However it is possible that it is not representative of the whole body of evidence available. No responsibility can be accepted for any action taken on the basis of this information. It is the responsibility of the requester to determine the accuracy, validity and interpretation of the search results. All links from this resource are provided for information only. A link does not imply endorsement of that site and the Lincolnshire Knowledge and Resource Service does not accept responsibility for the information displayed there, or for the wording, content and accuracy of the information supplied which has been extracted in good faith from reputable sources. 1

2 Opening Internet Links The links to internet sites in this document are live and can be opened by holding down the CTRL key on your keyboard while clicking on the web address with your mouse Full Text Papers Links are given to full text resources where available. For some of the papers, you will need a free NHS Athens Account. If you do not have an account you can register by following the steps at: You can then access the papers by simply entering your username and password. If you do not have easy access to the internet to gain access, please let us know and we can download the papers for you. Guidance on Searching within Online Documents Links are provided to the full text of each of these documents. Relevant extracts have been copied and pasted into these Search Results. Rather than browse through often lengthy documents, you can search for specific words and phrases as follows: Portable Document Format / pdf. / Adobe Click on the Search button (illustrated with binoculars). This will open up a search window. Type in the term you need to find and links to all of the references to that term within the document will be displayed in the window. You can jump to each reference by clicking it. You can search for more terms by pressing search again. Word documents Select Edit from the menu, the Find and type in your term in the search box which is presented. The search function will locate the first use of the term in the document. By pressing next you will jump to further references. 2

3 Guidelines NICE report on the feasibility of appraising the use of bevacizumab (Avastin) to treat eye conditions December 2010 NICE explored the feasibility of advising the NHS on the clinical and cost effectiveness of bevacizumab (Avastin, Genentech/Roche) to treat wet age-related macular degeneration (AMD), the leading cause of blindness in the UK, and other conditions affecting the eye. The main conclusion of the report is that there is support for an appraisal of intravitreal bevacizumab for eye conditions. Stakeholders agreed that an appraisal would need to be conditional on, or incorporate the assessment of, the safety and quality of intravitreal bevacizumab by a regulatory body or through the involvement of regulatory expertise. Furthermore, arrangements for safety monitoring / pharmacovigilance will need to be explored. The next step is for the Department of Health to decide whether or not to refer bevacizumab to NICE for consideration as part of its technology appraisal programme. Bevacizumab works by stopping tumour growth by preventing the formation of new blood vessels. It does this by targeting and inhibiting the function of a natural protein called vascular endothelial growth factor that stimulates new blood vessel formation. Bevacizumab is currently being used as a treatment for eye conditions by some NHS trusts as an alternative to ranibizumab (Lucentis), which is licensed for AMD and which NICE recommended for use in August 2008 ( Bevacizumab for age-related macular degeneration and other eye conditions: an assessment of published evidence and ongoing trials Scoping report commissioned by the NIHR HTA Programme Produced by Southampton Health Technology Assessments Centre There are other eye disorders that cause visual impairment because they damage the blood vessels supplying retina, macular or other parts of the eye. These include retinal vein occlusion (either central or branch retinal vein occlusion, CRVO and BRVO respectively), which is the second most common type of retinal vascular disorder after diabetic retinal disease.6 Damaged or blocked blood vessels such as those found in diabetic retinopathy, CRVO and BRVO may lead to the stimulation of new blood vessel growth and cause an uncommon type of glaucoma known as neovascular glaucoma. This type of glaucoma is caused when new blood vessels develop in the angle of the eye preventing normal drainage and leading to an increase in intra-ocular pressure. Damaged, blocked and fragile newly formed blood vessels may cause fluid to build up within the retina in the macula area. This is known as macular oedema and is associated with an impaired central vision. One RCT in neovascular glaucoma compared intracameral bevacizumab at different doses of 1.25 mg and 2.5 mg in combination with trabeculectomy (n=19). Yazdani S, Hendi K, Pakravan M, Mahdavi M, Yaseri M. Intravitreal bevacizumab for neovascular glaucoma: a randomized controlled trial. Journal of Glaucoma 2009;18:

4 Bevacizumab (Avastin) for eye conditions Report of findings from a workshop held at NICE on 13 July 2010 Summary Findings: There are clinical and financial reasons why bevacizumab is currently used as an intravitreal injection to treat age-related macular degeneration (AMD) and non-amd eye conditions. Doing nothing would not improve the current situation which is seen as unsatisfactory for patients. The safety and quality of the product that results from serial dilution have not been subject to regulatory review. There is concern that the product might not be manufactured to the standards used for ophthalmic products. It is important to establish what the characteristics of bevacizumab are when it is used at a low dose in an intravitreal injection; particularly concerning dosing. Evidence from existing records of intravitreal bevacizumab in clinical use is available and provides relevant information for the patient population in the NHS. Safety concerns should be reviewed as part of, or before an appraisal. The necessary expertise should be enlisted to consider the safety of intravitreal bevacizumab If an appraisal resulted in a positive recommendation, the guidance would have to be supported by adequate ongoing safety surveillance. Conclusion There is support for an appraisal of intravitreal bevacizumab for eye conditions. Stakeholders agreed that an appraisal would need to be conditional on, or incorporate the assessment of, the safety and quality of intravitreal bevacizumab by a regulatory body or through the involvement of regulatory expertise. It was suggested that options for commissioning the relevant skills and expertise for this purpose be explored. Arrangements for safety monitoring / pharmacovigilance will need to be explored. 4

5 Interim Guidelines for Management of Retinal Vein Occlusion Royal College of Ophthalmologists, December Management of established neovascular glaucoma The aim of management of this condition in a blind eye is to keep the eye pain free. This is usually achieved by topical steroids and atropine. However, if the eye has any visual potential intraocular pressure should be controlled with topical pressure-lowering agents,cyclo-ablative procedures or filtering surgery Intravitreal and intracameral bevacizumab has been shown to cause regression of iris new vessels and decrease angle obstruction. 40,41 Comparative case series indicate that iris new vessels regress faster after intravitreal bevacizumab with PRP than with PRP alone. 36,42 The reports also suggest that bevacizumab may reduce the need for surgical interventions and serve as a useful adjunct to filtering surgery. 37,44 Evidence level C: A body of evidence including studies rated as well conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as high quality systematic reviews of case-control or cohort studies. Bevacizumab: The pan-vegf blocker, bevacizumab is unlicensed for intraocular use. Several case series (without controls) indicate that approximately 50% of subjects with non-ischaemic CRVO improve 2 or more lines with intravitreal bevacizumab, whilst 90% of eyes showed vision stabilization by 12 months However, the dosing schedule is unclear and the long-term outcomes remain unclear. The SmPC for bevacizumab has recently been altered to include cases of severe intraocular inflammation following intravitreal administration of the drug. Evidence Level D: Evidence from non-analytic studies, e.g. case reports, case series or expert opinion Bevacizumab: Currently, increasing short-term data support the fact that multiple intravitreal bevacizumab injections reduce macular oedema secondary to branch retinal vein occlusion including those that had failed previous laser treatment. 57,59,60,77-79 The most common treatment regimen is two to three injections over the first 5-6 months. However, further randomized, controlled trials are required to assess long term safety and efficacy of intravitreal bevacizumab. No recommendations on the use of intravitreal bevacizumab can be made at this time. Evidence level C: A body of evidence including studies rated as well conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as high quality systematic reviews of case-control or cohort studies. 5

6 Evidence NHS Evidence 2010 Annual Evidence Update on Retinal Vein Occlusion There are several case series with short follow-ups that show that rubeosis can be decreased or even abolished transiently with anti-vegf agents (ranibizumab and bevacizumab), representing an emerging knowledge around recent developments in clinical practices for which there is as yet no evidence base. [ 6, 7, 8, 9 ]. No RCTs are currently available. 6. Brouzas D, Charakidas A, Moschos M, Koutsandrea C, Apostolopoulos M, Baltatzis S. Bevacizumab (Avastin) for the management of anterior chamber neovascularization and neovascular glaucoma. Clinical Ophthalmology 2009;3: PURPOSE: To establish the efficacy and safety of intravitreal bevacizumab in reducing iris and anterior chamber angle neovascularization and managing neovascular glaucoma. DESIGN: Prospective interventional case series. PATIENT AND METHODS: Eleven eyes of 11 patients with iris and anterior chamber angle neovascularization with refractory intraocular pressure were treated with intravitreal injection of 1.25 mg bevacizumab (Avastin((R))). The study group included eight males and three females aged 23 to 77 years (average, 62 years). Out of the 11 cases, five had proliferative diabetic retinopathy, of whom two had undergone vitrectomy for tractional retinal detachment and vitreous hemorrhage, and six were secondary to ischemic central retinal vein occlusion (CRVO). All patients were followed for eight to 16 months (average, 10 months). RESULTS: Iris and anterior chamber angle neovascularization receded in all eyes after one to three injections at monthly intervals. In five eyes, neovascularization recurred during the follow-up period. The intraocular pressure normalized in one eye. Four eyes were controlled with anti-glaucoma drops. A cyclodestructive procedure was required in two eyes. An Ahmet drainage valve was implanted in four eyes, including one controlled with additional antiglaucoma drops and one in which the intraocular pressure remained high while on maximum antiglaucoma medication and a cyclodestructive procedure was scheduled. CONCLUSIONS: Bevacizumab appears to be effective in reducing iris and anterior chamber angle neovascularization and is likely to extend our therapeutic options in the management of neovascular glaucoma Martínez-Carpio PA, Bonafonte-Márquez E, Heredia-García CD, Bonafonte-Royo S. [Efficacy and safety of intravitreal injection of bevacizumab in the treatment of neovascular glaucoma: systematic review]. [Article in Spanish]. Archivos de la Sociedad Espanola Oftalmologia Oct;83(10): Moraczewski AL, Lee RK, Palmberg PF, Rosenfeld PJ, Feuer WJ. Outcomes of treatment of neovascular glaucoma with intravitreal bevacizumab. British Journal of Ophthalmology May;93(5): Epub 2008 Dec Davidorf FH, Mouser JG, Derick RJ. Rapid improvement of rubeosis iridis from a single bevacizumab (Avastin) injection. Retina Mar;26(3):

7 Management of established neovascular glaucoma The aim of management of this condition in a blind eye is to keep the eye pain free. This is usually achieved by topical steroids and atropine. However, if the eye has any visual potential intraocular pressure should be controlled with topical pressure-lowering agents or cyclo-ablative procedures, [ 4, p.11 ]. Other interventions: Intravitreal and intracameral bevacizumab has been shown to cause regression of iris new vessels and decrease angle obstruction. Comparative case series indicate that iris new vessels regress faster after intravitreal bevacizumab with PRP than with PRP alone. The reports also suggest that bevacizumab may reduce the need for surgical interventions and may also serve as a useful adjunct to filtering surgery, [ 10 and 11 ]. These represent emerging knowledge around recent developments in clinical practices for which there is as yet no evidence base. 10. Gupta V, Jha R, Rao A, Kong G, Sihota R. The effect of different doses of intracameral bevacizumab on surgical outcomes of trabeculectomy for neovascular glaucoma. European Journal of Ophthalmology 2009 May;19(3): PURPOSE: To prospectively evaluate the effect of 1.25 mg and 2.5 mg intracameral bevacizumab on surgical outcomes of trabeculectomy for neovascular glaucoma (NVG), with primary outcome measures being the regression of neovascularization of iris (NVI) and reduction of intraocular pressure (IOP). METHODS: Consecutive patients with neovascular glaucoma from December 2006 to March 2007 were randomized into two cohorts assigned to receive 1.25 mg (Group 1) or 2.5 mg (Group 2) intracameral bevacizumab prior to undergoing mitomycin C (MMC) trabeculectomy. Surgical outcome measures were evaluated following initial injection and during follow-up post-surgery. RESULTS: The most common causes for iris neovascularization were central retinal vein occlusion (47.3%) and proliferative diabetic retinopathy (36.8%). Following intracameral bevacizumab, there was a reduction in IOP compared to baseline in both treatment groups (Group 1, n=9: /-4.5 mmhg, p=0.57; Group 2, n=10: /-5.5 mmhg, p=0.1). The reduction in IOP was not statistically significant between the two groups (p=0.55). None of the eyes underwent further retinal ablation post trabeculectomy. Reappearance of NVI was seen in three eyes (Group 1, n=2; Group 2, n=1) after 3 months. There was no statistically significant difference in regression of NVI grade between the treatment groups (p=0.1). CONCLUSIONS: The efficacy of an intracameral dose of 2.5 mg of bevacizumab prior to trabeculectomy for eyes with NVG is not significantly different from a 1.25 mg dose. Intracameral bevacizumab followed by trabeculectomy results in good surgical outcomes. Longer follow-up would be needed to evaluate differences in recurrence rates of iris neovascularization using different dosages. 11. Beutel J, Peters S, Luke M, Aisenbrey S, Szurman P, Spitzer MS, et al. Bevacizumab as adjuvant for neovascular glaucoma. Acta Ophthalmol 2008 Sep 20. [Epub ahead of print] 7

8 Bevacizumab in Eye Conditions: Issues Related to Quality, Use, Efficacy and Safety Report by the Decision Support Unit August, 2012 Edith Poku, John Rathbone, Emma Everson-Hock, Munira Essat, School of Health and Related Research, University of Sheffield 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 settings Research supporting Avastin use in rubeotic glaucoma 8

9 Service Examples Bevacizumab (Avastin ) for neovascular glaucoma secondary to ischaemic central retinal vein occlusion NHS North East Treatment Advisory Group, Apr 2011 Bevacizumab in NVG has been reported in a large and increasing number of studies. However these are generally of low quality with small patient numbers, no randomisation and no control group. None have been specifically performed in NVG secondary to CRVO although the evidence indicates that outcomes are not different compared with other NVG cohorts. Relief of glaucoma and pain is often rapid. A benefit in terms of reduced need for, or facilitation of, laser therapy or other established therapies has not been demonstrated. Effects on visual acuity, whilst not the primary aim of treatment, are inconsistent. The safety of intravitreal bevacizumab has been established in many thousands of patients, although few specifically with NVG. The studies of bevacizumab in NVG did not realise any new or unexpected safety concerns. Intravitreal bevacizumab is a costly treatment at about 720 per dose with the majority of costs due to the cost of admission. It is not clear how many doses will be required per patient. An accompanying treatment algorithm specifies that after two doses subsequent doses should only be administered after individual application. The cost-effectiveness of bevacizumab for NVG has not been demonstrated. Clinical evidence indicates that it provides a useful new therapeutic option compared with existing treatments. Full Text Attached 9

10 Research Systematic Reviews Title: Efficacy and safety of intravitreal injection of bevacizumab in the treatment of neovascular glaucoma: Systematic review [Spanish] Eficacia y seguridad de la inyeccion intravitrea de bevacizumab en el tratamiento del glaucoma neovascular: Revision sistematica Citation: Archivos de la Sociedad Espanola de Oftalmologia, 2008, 83/10( ) Author(s): Martinez-Carpio P.A., Bonafonte-Marquez E., Heredia-Garcia C.D., Language: Spanish Abstract: Purpose: Systematic review on efficacy and safety of intravitreal bevacizumab (IVB) in the treatment of neovascular glaucoma (NVG). All original papers published in Medline (prior to August 2008) were included. Methods: Search and selection of information on the internet and in Medline, validated by Kappa Index (K). Statistical and clinical study of the results in the selected articles on a one by one basis. Results: 26 original papers analyzed the efficacy and safety of the procedure in case reports and short series of cases (127 eyes). The efficacy calculated in the sample was 68.7% and the recurrence rate was 18.6% in 4.2 months of follow-up. All studies were after 2006 and none of them was a clinical randomized controlled assay. Ophthalmic complications were under 0.78% and no systemic complications were found. Conclusions: The use of bevacizumab demonstrates that intravitreal injections may be effective and useful to manipulate growth factors in the anterior chamber. IVB could serve as a first line treatment for NVG. Clinical trials are needed to confirm these results before its use is authorized. 10

11 Literature Reviews Title: Anterior segment ischemia with rubeosis iridis after a circular buckling operation treated successfully with an intravitreal bevacizumab injection: a case report and review of the literature. Citation: Bulletin de la Societe Belge d Ophtalmologie, 2012, vol./is. /319(5-9) Author(s): Janssens K, Zeyen T, Van Calster J Abstract: PURPOSE: To report a case of anterior segment ischemia (ASI) with rubeosis iridis after circular buckling surgery in a highly-myopic patient which was successfully treated with a second intravitreal bevacizumab injection.methods: Case report and review of the literature.discussion: ASI is a rare but potentially serious complication of posterior segment surgery. Finally it leads to neovascular glaucoma as a result of rubeosis iridis. An encircling band can compromise anterior segment circulation in different ways: by manipulation or disinsertion of the recti muscles, by occlusion of the vortex veins through compression or by changes in the blood supply of iris and ciliary body. This patient developed rubeosis iridis secondary to ASI. There was a remarkable regression of rubeosis iridis one month after a second intravitreal bevacizumab injection. Other case reports of bevacizumab use in neovascular glaucoma have shown clinical improvements of these patients, with intraocular pressure control and reduction of the neovascularization process. CONCLUSION: We describe a highly-myopic patient who developed ASI with rubeosis iridis after a circular buckling operation. Slit-lamp examination and gonioscopy can show very little rubeosis iridis and can be misleading. Iris fluorescein angiography is the most sensitive technique for evaluation of iris vessel abnormalities and is of considerable value in the early detection of rubeosis iridis. This report demonstrates the rapid resolution of rubeosis iridis on iris fluorescein angiography after a second intravitreal injection of bevacizumab. How long this regression will persist is unknown and repeated injections of bevacizumab may be necessary if rubeosis reappears. Title: Bevacizumab in glaucoma: A review Citation: Canadian Journal of Ophthalmology, December 2007, vol./is. 42/6( ), Author(s): Ichhpujani P., Ramasubramanian A., Kaushik S., Pandav S.S. Abstract: Recent research has shown that a large number of growth factors are responsible for neovascularization. Vascular endothelial growth factor has been identified as playing a key role in ocular angiogenesis. Bevacizumab, a humanized monoclonal antibody that binds to all isoforms of vascular endothelial growth factor, has shown promising results in regression of neovascularization. The use of bevacizumab has been reported extensively in various retinal pathologies, including proliferative diabetic retinopathy, cystoid macular edema, neovascular age-related macular degeneration, and neovascular glaucoma, but the clinical use in glaucoma is not yet clear. Glaucoma filtering surgery entails fashioning an external filter for aqueous drainage, and a prerequisite to its optimum functioning is a patent filtering bleb. Since fibroblast function and growth of new vessels is a component of healing of the bleb, there have been attempts to retard this healing by the use of bevacizumab. This article reviews current clinical studies documenting the use of bevacizumab in glaucoma. 11

12 Title: Bevacizumab: off-label use in ophthalmology. Citation: Indian Journal of Ophthalmology, November 2007, vol./is. 55/6(417-20) Author(s): Grisanti S, Ziemssen F Abstract: Bevacizumab is a full-length, humanized monoclonal antibody directed against all the biologically active isoforms of vascular endothelial growth factor (VEGF- A). The antibody was initially designed and studied as an anti-angiogenic strategy to treat a variety of solid tumors. After approval by the US Food and Drug Administration, bevacizumab gained access into ophthalmology to treat various types of neovascular diseases. Since the first report in 2005 more than 100 publications share the experience with bevacizumab in ophthalmology. Two authors independently assessed the research results from Pubmed to April The reference list is a selection of key publications related to the issue. Currently, there is no well-designed randomized controlled trial yet to establish the efficacy and safety of intraocular bevacizumab for any ocular disease in spite of its assumed characteristics representing the most cost-effective VEGF inhibitor. Randomised Trials Title: Clinical and electrophysiologic outcome in patients with neovascular glaucoma treated with and without bevacizumab Citation: European Journal of Ophthalmology, July 2012, vol./is. 22/4( ), Author(s): Wittstrom E., Holmberg H., Hvarfner C., Andreasson S. Abstract: PURPOSE. To investigate the clinical and electrophysiologic effect of a single intravitreal injection of bevacizumab for neovascular glaucoma (NVG) after ischemic central retinal vein occlusion (icrvo). METHODS. Nineteen eyes from 19 patients with NVG secondary to icrvo were randomly allocated to either an intravitreal bevacizumab injection and panretinal photocoagulation (PRP) (10 eyes) or PRP alone (9 eyes). The primary outcome measure was the change in the total retinal function 6 months after treatment, demonstrated by full-field electroretinography (ERG). Secondary outcomes included visual acuity, intraocular pressure (IOP), glaucoma medication, additional IOPlowering treatment, and the presence of ocular neovascularization before treatment, and 1 week, 2 months, and 6 months after treatment. RESULTS. The regression of ocular neovascularization in the bevacizumab/prp group was confirmed 1 week after injection. Patients in both study groups had very poor visual acuity at baseline. This remained unchanged. There was no significant difference in the mean IOP between the groups at any point in time. The a-wave amplitudes of combined rod-cone response were significantly decreased after 6 months in the bevacizumab/prp group (p=0.028), compared with the baseline values. The a- and b-wave amplitudes of combined rodcone response and the b-wave amplitudes of the 30-Hz flicker response were also markedly reduced compared with the PRP group (-60%, -43%, -47% vs +23%, -36%, - 16%, respectively). CONCLUSIONS. This study suggests that intravitreal injection of bevacizumab is valuable in the treatment of NVG by hastening the resolution of neovascularization, while the full-field ERG results indicate that bevacizumab may reduce the photoreceptor function in NVG patients Wichtig Editore. 12

13 Title: Bevacizumab for macular edema in central retinal vein occlusion: a prospective, randomized, double-masked clinical study. Citation: Ophthalmology, June 2012, vol./is. 119/6(1184-9), ; Author(s): Epstein DL, Algvere PV, von Wendt G, Seregard S, Kvanta A Abstract: PURPOSE: To evaluate the efficacy of intraocular injections with bevacizumab in patients with macular edema (ME) secondary to central retinal vein occlusion (CRVO).DESIGN: Prospective, randomized, sham injection-controlled, doublemasked clinical trial.participants: Sixty patients with ME secondary to CRVO.METHODS: At baseline, patients were randomized 1:1 to receive intraocular injections of bevacizumab or sham injections every 6 weeks for 6 months.main OUTCOME MEASURES: The primary outcome measure was the proportion of patients gaining at least 15 letters at 6 months. Secondary outcome measures included mean change from baseline best-corrected visual acuity (BCVA), foveal thickness, and neovascular glaucoma.results: At the end of follow-up, 18 of 30 patients (60.0%) in the study group had gained >=15 letters compared with 6 of 30 patients (20.0%) in the control group (P=0.003). The BCVA improved by 14.1 letters at 24 weeks compared with a decrease of 2.0 letters in the control group (P < 0.003). The mean decrease in central retinal thickness (CRT) was significantly greater in the study group (426 um) than in the control group (102 um) at all time points up to week 24 (P < 0.001). No residual edema, defined as CRT <300 um at 24 weeks, was found in 26 of 30 patients (86.7%) in the treatment group compared with 6 of 30 patients (20%) in the control group (P < 0.001). In the sham group, 5 of 30 patients (16.7%) had developed iris rubeosis at week 24. No patients in the study group had rubeosis at week 24 (P=0.052). There were no events of endophthalmitis, retinal tear, or retinal detachment during the 24-week treatment period. No serious non-ocular adverse events were reported. CONCLUSIONS: Intraocular injections of bevacizumab given every 6 weeks for 6 months improve visual acuity (VA) and reduce ME significantly compared with sham. Title: Intravitreal bevacizumab for neovascular glaucoma: a randomized controlled trial Citation: Journal of glaucoma, October 2009, vol./is. 18/8( ), X (2009 Author(s): Yazdani S., Hendi K., Pakravan M., Mahdavi M., Yaseri M. Abstract: PURPOSE: To determine the effect of intravitreal bevacizumab (IVB) on neovascular glaucoma (NVG) in terms of iris neovascularization (NVI), intraocular pressure (IOP), and visual acuity. METHODS: This randomized controlled trial included 26 eyes of 26 patients with NVG. All eyes received conventional treatment for NVG and were randomly allocated to three 2.5 mg IVB injections at 4-week intervals or a sham procedure (subconjunctival normal saline) at similar time intervals and in the same setting. RESULTS: Overall, 14 eyes of 14 patients received IVB and 12 eyes of 12 subjects were allocated to the sham procedure and followed for a mean period of 5.9+/- 1.4 months. The IVB group demonstrated significant reduction in IOP from a baseline value of 33.4+/-14.5 mm Hg to 21.8+/-13.7 mm Hg (P=0.007), 25.1+/-20 mm Hg (P=0.058), and 23.9+/-18.7 mm Hg (P=0.047) at 1, 3, and 6 months after intervention, respectively. NVI was also significantly reduced from a mean baseline value of 347+/-48 degrees to 206+/-185 degrees (P=0.01), 180+/-187 degrees (P=0.004), and 180+/-180 degrees (P=0.004) at 1, 3, and 6 months after intervention. In contrast, IOP and NVI remained unchanged or increased insignificantly at all follow-up intervals in the control group. No significant change in visual acuity was observed within the study groups at any time interval. The study groups were comparable in terms of requirement for additional interventions such as panretinal photocoagulation and cyclodestructive procedures. 13

14 CONCLUSIONS: Intravitreal injections of bevacizumab seem to reduce NVI and IOP in NVG and may be considered as an adjunct to more definitive surgical procedures for NVG. The effect of different doses of intracameral bevacizumab on surgical outcomes of trabeculectomy for neovascular glaucoma. Gupta V, Jha R, Rao A, Kong G, Sihota R. European Journal of Ophthalmology 2009 May;19(3): PURPOSE: To prospectively evaluate the effect of 1.25 mg and 2.5 mg intracameral bevacizumab on surgical outcomes of trabeculectomy for neovascular glaucoma (NVG), with primary outcome measures being the regression of neovascularization of iris (NVI) and reduction of intraocular pressure (IOP). METHODS: Consecutive patients with neovascular glaucoma from December 2006 to March 2007 were randomized into two cohorts assigned to receive 1.25 mg (Group 1) or 2.5 mg (Group 2) intracameral bevacizumab prior to undergoing mitomycin C (MMC) trabeculectomy. Surgical outcome measures were evaluated following initial injection and during follow-up post-surgery. RESULTS: The most common causes for iris neovascularization were central retinal vein occlusion (47.3%) and proliferative diabetic retinopathy (36.8%). Following intracameral bevacizumab, there was a reduction in IOP compared to baseline in both treatment groups (Group 1, n=9: /-4.5 mmhg, p=0.57; Group 2, n=10: /-5.5 mmhg, p=0.1). The reduction in IOP was not statistically significant between the two groups (p=0.55). None of the eyes underwent further retinal ablation post trabeculectomy. Reappearance of NVI was seen in three eyes (Group 1, n=2; Group 2, n=1) after 3 months. There was no statistically significant difference in regression of NVI grade between the treatment groups (p=0.1). CONCLUSIONS: The efficacy of an intracameral dose of 2.5 mg of bevacizumab prior to trabeculectomy for eyes with NVG is not significantly different from a 1.25 mg dose. Intracameral bevacizumab followed by trabeculectomy results in good surgical outcomes. Longer follow-up would be needed to evaluate differences in recurrence rates of iris neovascularization using different dosages. 14

15 Trials Title: Intravitreal becacizumab treatment the neovascular glaucoma as an adjunct method Citation: International Journal of Ophthalmology, 2010, vol./is. 10/10( ) Author(s): Wang L.-L., Jin L.-Y., Li L.-J., Zhang W., Huo M. Language: Chinese Abstract: * AIM: To observe the clinical effect of the intravitreal bevacizumab (IVB) combined with vitrectomy, retinal photocoagulation and trabeculectomy as a multtreatment for the neovascular glaucoma(nvg). * METHODS: Totally 27 patients 27 eyes which had the NVG secondary from central retinal vein occlusion(crvo) were enrolled. All eyes accepted the vitrectomy, retinal photocoagulation combined with trabeculectomy 7 days after IVB (0.05mL/1.25mg). The visual acuity, the condition of the new vessels on the iris and the angle of anterior chamber and the intraocular pressure (IOP) were observed 12 months postoperatively. * RESULTS: The new vessels on the iris and the angle of anterior chamber regressed completely in 25 eyes(93%), 7 days after IVB and thinned obviously in 2 eyes but not regressed(7%). The mean IOP before the IVB (55.81+/-4. 65mmHg) and the after (42.07+/-7.49mmHg) had significant difference(t = , P < 0.01), but still higher than normal level (28-50mmHg). The mean IOP1 month, 3, 6, 9 and 12 months after the vitrectomy, retinal photocoagulation and trabeculectomy (14.85+/-4.56, /-3.73, /-6.58, /-4.74, /-4.12, respectively) mmhg and 7 days after IVB had significant difference (P<0.01). The IOP were controlled completely in 22 eyes (82%), partly controlled in 3 eyes (11%), and not controlled in 2 eyes (7%). The visual acuity of all the eyes was stable and rise slightly. * CONCLUSION : IVB as an adjunct method combined with vitrectomy, retinal photocoagulation and trabeculectomy can make the new vessels on the iris and the angle of anterior chamber regression and to lower the IOP, thus it can increase the achievement ratio of the operation and decrease the complication. And the long-term effect is better to cure the protopathy at the same time. Title: Intracameral bevacizumab (avastin) for neovascular glaucoma: A pilot study in 6 patients Citation: Journal of Glaucoma, February 2009, vol./is. 18/2( ), Author(s): Duch S., Buchacra O., Milla E., Andreu D., Tellez J. Abstract: PURPOSE: To describe the use of intracameral bevacizumab (ICB) Avastin in neovascular glaucoma (NVG) as the first maneuver before pan retinal photocoagulation and/or filtering surgery. METHODS: Between June 2006 and May 2007, 6 consecutive patients with NVG underwent intracameral injection of bevacizumab (1.25 mg/0.05 ml) as the initial treatment of NVG. Pre-ICB and post-icb anterior segment photography, iris fluoresceingraphy when possible, gonioscopy with peripheral anterior synechiae (PAS), neovascular membrane (NVM) extension grading, as well as intraocular pressure (IOP) changes during treatment were recorded. All patients were followed for at least 7 months. RESULTS: ICB resulted in a marked regression of anterior segment neovascularization with IOP control without filtering surgery in 2 cases. When PAS extended <330 degrees without previous glaucoma, no filtering surgery was needed to control IOP<18 mm Hg. Iris neovascularization extension had no prognostic value in terms of IOP control. After vascular regression following the administration of ICB, filtering surgery with drainage implants or trabeculectomy were performed when needed with no added difficulties owing to the underlying NVG. No macroscopic signs of corneal toxicity were detected, even when ICB injection had to be repeated. In this case, the 15

16 time elapsed for the neovascular membrane to reappear at the anterior segment was 3 months. CONCLUSION: ICB resulted in a rapid regression of the iris and angle neovascularization, which permitted to halt the progression of PAS process. This pilot study shows that intracameral injection of bevacizumab may be a helpful adjunct for the surgical treatment of NVG Lippincott Williams & Wilkins, Inc. Title: Intraocular avastin (bevacizumab) for neovascularisation of the iris and neovascular glaucoma Citation: Annals of the Academy of Medicine Singapore, 2008, vol./is. 37/1(72-74) Author(s): Cheng J.Y.C., Wong D.W.K., Chong L.A. Abstract: Introduction: The aim of this study was to determine the effectiveness of intraocular injections of bevacizumab for neovascularisation of the iris and neovascular glaucoma. Clinical Picture: Three patients with neovascularisation of the iris due to various causes were recruited. Treatment: Patients were treated with intraocular bevacizumab. Outcome: Neovascularisation of the iris was noted to have completely regressed as early as 3 days after the injection and in all the patients (100%) within 8 days after injection. They were followed up for at least 1 month with no clinical evidence of recurrence. Visual acuity remained stable or improved, and the intraocular pressure was controlled in all the 3 patients' eyes. Vitreous haemorrhage also cleared. No signs of inflammation or complications were observed. Conclusion: Intraocular injection of bevacizumab is effective and safe for patients with neovascularisation of the iris and neovascular glaucoma with or without vitreous haemorrhage. Title: Intravitreal bevacizumab for neovascular glaucoma Citation: Acta Clinica Croatica, September 2008, vol./is. 47/3( ), Author(s): Andrijevic-Derk B., Vatavuk Z., Bencic G., Novak-Laus K., Mandic Z. Abstract: The aim of the study was to assess short-term efficacy of intravitreal bevacizumab in a series of patients with neovascular glaucoma. Eleven patients with neovascular glaucoma and symptomatic elevation of intraocular pressure were treated with 1.25 mg/0.1 ml of bevacizumab. In three patients, intravitreal bevacizumab was administered preoperatively, one day before pars plana vitrectomy. Additional therapy was only performed if topical medication failed to result in satisfactory control of intraocular pressure. Patients were followed-up for a minimum of 8 weeks. In all study patients, intravitreal application of bevacizumab resulted in marked regression of iris neovascularization within the first three postoperative days. Appropriate control of intraocular pressure was achieved in seven patients, whereas four patients required additional therapy for intraocular pressure regulation. No side effects of intravitreal bevacizumab were recorded. Thus, intravitreal bevacizumab seems to be a potent adjunct in the management of neovascular glaucoma. Additional studies of bevacizumab long-term safety and efficacy are warranted. Title: Intravitreal bevacizumab (Avastin) injection for neovascular glaucoma: A survey on 23 cases throughout 12-month follow-up Citation: British Journal of Clinical Pharmacology, November 2008, vol./is. 66/5(667- Author(s): Costagliola C., Cipollone U., Rinaldi M., Della Corte M., Semeraro F., Abstract: AIMS: Neovascular glaucoma (NVG) represents one of the most severe forms of secondary glaucoma, caused by a number of ocular and systemic conditions, which share the common element of retinal ischaemia/hypoxia that initiates the subsequent release of angiogenesis factors, with consequent development of new abnormal vessels 16

17 through the ciliary body. The aim was to examine the potential efficacy and safety of intravitreal injection of bevacizumab (IVB) (Avastin) in the treatment of NVG in patients who had already undergone the standard retinal ablative procedure. METHODS: This was a prospective pilot trial. Clinical data of 26 eyes from 23 patients, including diagnosis, visual acuity, iris fluorescein angiography stage and intraocular pressure (IOP), were collected. Three injections of bevacizumab were scheduled for each recruited eye at 4-week intervals from the start. All investigations were repeated the day before the IVB (1.25 mg/0.05 ml) and at the 1-, 3-, 6-, 9- and 12-month follow-up. RESULTS: Regression of corneal oedema together with significant pain reduction was achieved in all eyes already after the first IVB, without any noteworthy improvement of visual acuity. At the end of the scheduled protocol (three IVB), regression of iris neovascularization was documented in all patients, together with significant improvement of visual acuity. The IOP reduction from baseline ranged from 30 to 0 mmhg (12.1 +/- 8 mmhg). CONCLUSIONS: Intravitreal bevacizumab, as adjunctive treatment to the standard retinal ablative procedure, seems promising for the management of conditions responsible of retinal ischaemia/hypoxia associated with Prospective Evaluation of Cases Title: Effect on anterior chamber bevacizumab injection combined with seton implantation in treatment of rubeosis iridis in neovascular glaucoma. Citation: Cutaneous & Ocular Toxicology, June 2012, vol./is. 31/2(124-7) Author(s): Altintas AG, Arifoglu HB, Tutar E, Koklu G, Ozcan PY Abstract: OBJECTIVE: To evaluate the effect of anti-vegf (bevacizumab) injection to the posterior chamber (BIPC) behind the iris combined with seton implantation in treatment of neovascular glaucoma (NVG).METHODS: Twenty-eight eyes with NVG who underwent BIPC, prospectively evaluated. Anterior segment photographs were taken for grading of neovascularization on anterior segment in pretreatment period and at each follow-up. Grading and regression of rubeosis iridis was classified according to Teich and Walsh grading system and glaucoma filtration surgery with drainage device was performed following BIPC.RESULTS: The mean pre-bipc IOP was /-7.09 mmhg, post-bipc IOP in the 1st, 2nd day, 1st week, 1st, 3rd, 6th month were 19.7+/-8.9 mmhg, 13.5+/-6.7 mmhg, 9.9+/-3.4 mmhg, /-5.3 mmhg, 16.6+/-5.03 mmhg, 18.5+/-3.8 mmhg, respectively. Twenty seven eyes underwent seton implantation surgery. No one had anterior segment bleeding during surgery. The pre-bipc grades were Grade 4: 67.58%, Grade 3: 28.57%, Grade 2: 3.57%, no one had Grade 1or Grade 0, while post BIPC grade were at the 1st week Grade 1: 64.28%, Grade 0: 35.71%, no one had Grade 2 or more, at 1st month Grade 2: 3.57%, Grade 1: 39.28%, Grade 0: 57.14%, at 3rd month Grade 2: 17.85% Grade 1: 28.57%, Grade 0: 53.57%, no one had Grade 3 or more both in first and the third month, at 6th month Grade 3: 7.14%, Grade 2: 28.57%, Grade 1: 42.85%, Grade 0: 21.42%. and no one had Grade 4. CONCLUSION: Significant reduction of NV was observed during the first week. Minimal increasement was seen in third month, significant regression effect persisted for 6 months. BIPC inhibited the peroperative risk of anterior segment bleeding, increased the surgical comfort and prevented the failure of filtration procedure by inhibiting reproliferation. 17

18 Title: Intravitreal bevacizumab in refractory neovascular glaucoma: A prospective, observational case series Citation: Archives of Ophthalmology, February 2011, vol./is. 129/2( ) Author(s): Kotecha A., Spratt A., Ogunbowale L., Dell'Omo R., Kulkarni A., Bunce C., Abstract: Objective: To examine the efficacy of intravitreal bevacizumab for pain relief in eyes with refractory neovascular glaucoma. Methods: In this prospective case series, 52 eyes with neovascular glaucoma were administered intravitreal bevacizumab, 1.25 mg, and monitored for 6 months. The primary outcome measure was change in subjective pain score. Intraocular pressure and iris neovascularization were evaluated at each visit. Surgical intervention for control of intraocular pressure was performed according to clinical need. Results: Forty-two patients (44 eyes) completed the 6-month follow-up. Subjective pain score was reduced significantly 1 week after intravitreal bevacizumab injection and lasted throughout the follow-up period (median [interquartile range]: baseline, 3 [0-6]; week 1, 1 [0-3]; month 1, 0 [0-1]; month 3, 0 [0-1]; and month 6, 0 [0-0]; Kruskal-Wallis chi² 31.03; P<.001). A rapid, yet relatively transient, reduction in iris neovascularization was also noted (iris neovascularization grade at baseline, 4.0 [3-4]; week 1, 2.5 [1-4]; month 1,2.0 [1-4]; month 3, 3.0 [2-4]; and month 6, 3.0 [2-4], chi² 23.33; P<.001). Four eyes (8%) required more than 1 injection to facilitate further intraocular surgery. Conclusions: Intravitreal bevacizumab is a useful adjunct in the management of refractory neovascular glaucoma, producing rapid relief of pain. However, we found no evidence to suggest that intravitreal bevacizumab lowers intraocular pressure in eyes with angle closure; conventional medical, laser, and surgical treatment are still needed in these eyes. Title: Intravitreal bevacizumab and aqueous shunting surgery for neovascular glaucoma: Safety and efficacy Citation: Canadian Journal of Ophthalmology, August 2009, vol./is. 44/4( ), Author(s): Eid T.M., Radwan A., El-Manawy W., El-Hawary I. Abstract: Objective: To study the safety and efficacy of intravitreal injection of bevacizumab followed by aqueous shunting tube surgery for the management of neovascular glaucoma (NVG). Study Design: A prospective, non-randomized study with a historical control group. Participants: Twenty eyes of 20 patients with intractable NVG were treated with intravitreal injection of bevacizumab followed by aqueous shunting surgery (IVB group). A historical group of 10 NVG eyes treated with panretinal photocoagulation followed by aqueous shunting surgery without bevacizumab injection was used for comparison (PRP group). Methods: Injection of bevacizumab (1.25 mg/0.05 ml) was performed under topical anesthesia. An Ahmed valve was implanted in all cases after 1-2 weeks. In the IVB group, 10 eyes received postoperative panretinal photocoagulation (subgroup 1A), and 10 eyes were followed without further photocoagulation (subgroup 1B). Minimum follow-up was 1 year or when failure was diagnosed. Results: Mean preoperative intraocular pressure (IOP) was 46.5 mm Hg in the IVB group and 49.2 mm Hg in the PRP group (p = 0.5). After bevacizumab injection, iris neovessels regressed markedly. The final IOP after aqueous shunting tube surgery was 18.8 mm Hg in the IVB group and 15.9 mm Hg in the PRP group (p = 0.2). Postsurgical complications were comparable between the groups. The success rate was 85% and 70% in the 2 groups, respectively. Two eyes were considered failures, and 3 required repeated bevacizumab injections in subgroup 1B as compared with 1 in subgroup 1A. Conclusion: Intravitreal bevacizumab is a useful preparatory step to safely and effectively implant an aqueous shunting tube in NVG. Panretinal photocoagulation after bevacizumab injection promotes the success rate of aqueous shunt surgery by permanent ablation of the ischemic retina. 18

19 Title: Intravitreal bevacizumab in the treatment of neovascular glaucoma [French] Injection intravitreenne de Bevacizumab (Avastin) dans le traitement du glaucome neovasculaire Citation: Journal Francais d'ophtalmologie, February 2009, vol./is. 32/2( ), Author(s): Ouhadj O., Chergui I., Mendil L., Nouri M.T. Language: French Abstract: Purpose: To report the effect of an intravitreal injection of 1.25 mg (0.05 ml) of bevacizumab (IVB) as symptomatic treatment for neovascular glaucoma. Patients and method: This prospective study included 13 eyes of 12 patients presenting neovascular glaucoma, in two cases secondary to ischemic central retinal vein occlusion and, in ten cases, to proliferative diabetic retinopathy. Each patient received an intravitreal injection of 1.25 mg (0.05 ml) of bevacizumab, in combination with other procedures such as panretinal photocoagulation to treat retinal ischemia and transscleral cyclocryoapplication as glaucoma treatment. Their mean age was 58 years (range, years). The mean intraocular pressure (IOP) was 40 mmhg +/- 10 mmhg. The mean follow-up was 6 months. Results: IVB resulted in a marked regression of anterior segment neovascularization and relief of symptoms within 48 h. IOP decreased substantially in eight eyes; in four eyes, adjuvant cyclocryoapplication was necessary. The last eye was affected by a retinal detachment 1 month after IVB. No side effects were observed. Discussion: We observed that the intravitreal injection of bevacizumab enabled the total regression of iris and angle neovascularization but had only a partial action on intraocular hypertension. Conclusion: Intravitreal injection of 1.25 mg (0.05 ml) of bevacizumab contributes to a better management of neovascular glaucoma Bevacizumab (Avastin) for the management of anterior chamber neovascularization and neovascular glaucoma. Brouzas D, Charakidas A, Moschos M, Koutsandrea C, Apostolopoulos M, Baltatzis S. Clinical Ophthalmology 2009;3: PURPOSE: To establish the efficacy and safety of intravitreal bevacizumab in reducing iris and anterior chamber angle neovascularization and managing neovascular glaucoma. DESIGN: Prospective interventional case series. PATIENT AND METHODS: Eleven eyes of 11 patients with iris and anterior chamber angle neovascularization with refractory intraocular pressure were treated with intravitreal injection of 1.25 mg bevacizumab (Avastin((R))). The study group included eight males and three females aged 23 to 77 years (average, 62 years). Out of the 11 cases, five had proliferative diabetic retinopathy, of whom two had undergone vitrectomy for tractional retinal detachment and vitreous hemorrhage, and six were secondary to ischemic central retinal vein occlusion (CRVO). All patients were followed for eight to 16 months (average, 10 months). RESULTS: Iris and anterior chamber angle neovascularization receded in all eyes after one to three injections at monthly intervals. In five eyes, neovascularization recurred during the follow-up period. The intraocular pressure normalized in one eye. Four eyes were controlled with anti-glaucoma drops. A cyclodestructive procedure was required in two eyes. An Ahmet drainage valve was implanted in four eyes, including one controlled with additional antiglaucoma drops and one in which the intraocular pressure remained high while on maximum antiglaucoma medication and a cyclodestructive procedure was scheduled. CONCLUSIONS: Bevacizumab appears to be effective in reducing iris and anterior chamber angle neovascularization and is likely to extend our therapeutic options in the management of neovascular glaucoma. 19