CADTH. Rapid Response Report: Peer-Reviewed Summary with Critical Appraisal. Canadian Agency for Drugs and Technologies in Health

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1 Canadian Agency for Drugs and Technologies in Health Agence canadienne des médicaments et des technologies de la santé Rapid Response Report: Peer-Reviewed Summary with Critical Appraisal CADTH A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema May 2012 Supporting Informed Decisions

2 Cite as: Fortin, P., Mintzes, B., and Innes, M. A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema [Internet]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2012 (Rapid Response Report: Peer-Reviewed Summary with Critical Appraisal). Available from: Production of this report is made possible by financial contributions from Health Canada and the governments of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Prince Edward Island, Saskatchewan, and Yukon. The Canadian Agency for Drugs and Technologies in Health takes sole responsibility for the final form and content of this report. The views expressed herein do not necessarily represent the views of Health Canada, or any provincial or territorial government. Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CADTH. CADTH is funded by Canadian federal, provincial, and territorial governments. Legal Deposit 2012 Library and Archives Canada ISSN: (online) Project # RD0028 May 2012

3 Canadian Agency for Drugs and Technologies in Health A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema Patricia Fortin, MLibSc, MSc (Health Informatics) 1 Barbara Mintzes, BSc, PhD 1 Mike Innes, MSc (Epid), PharmD 2 May University of British Columbia, Vancouver, British Columbia 2 Canadian Agency for Drugs and Technologies in Health (CADTH), Ottawa, Ontario

4 Health technology assessment agencies face the challenge of providing quality assessments of medical technologies in a timely manner to support decision-making. Ideally, all important deliberations would be supported by comprehensive health technology assessment reports, but the urgency of some decisions often requires a more immediate response. The Rapid Response Service provides Canadian health care decision-makers with health technology assessment information, based on the best available evidence, in a quick and efficient manner. Inquiries related to the assessment of health care technologies (drugs, devices, diagnostic tests, and surgical procedures) are accepted by the service. Information provided by Rapid Response Service is tailored to meet the needs of decision-makers, taking into account the urgency, importance, and potential impact of the request. Consultations with the requestor of this Rapid Response assessment indicated that a review of the literature would be beneficial. The research question and selection criteria were developed in consultation with the requestor. The literature search was carried out by an information specialist using a standardized search strategy. The review of evidence was conducted by one internal reviewer. The draft report was internally reviewed and externally peer-reviewed by two or more peer reviewers. All comments were reviewed internally to ensure that they were addressed appropriately.

5 This report is a review of existing public literature, studies, materials, and other information and documentation (collectively the source documentation ) that are available to CADTH. The accuracy of the contents of the source documentation on which this report is based is not warranted, assured, or represented in any way by CADTH, and CADTH does not assume responsibility for the quality, propriety, inaccuracies, or reasonableness of any statements, information, or conclusions contained in the source documentation. CADTH takes sole responsibility for the final form and content of this report. The statements and conclusions in this report are those of CADTH and not of reviewers. Disclaimer: This report was prepared by the Canadian Agency for Drugs and Technologies in Health (CADTH). CADTH is an independent, not-for-profit organization funded by the federal, provincial, and territorial governments of Canada. CADTH is one of Canada s leading sources of information and advice about the effectiveness and efficiency of drugs, medical devices, and other health technologies. The report contains a comprehensive review of the existing public literature, studies, materials, and other information and documentation (collectively the source documentation) available to CADTH at the time of report preparation, and was guided by expert input and advice throughout its preparation. The information in this report is intended to help health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services within the Canadian health care systems. The information in this report should not be used as a substitute for the application of clinical judgment in respect to the care of a particular patient or other professional judgment in any decision making process, nor is it intended to replace professional medical advice. While CADTH has taken care in the preparation of this document to ensure that its contents are accurate, complete, and up to date, as of the date of publication, CADTH does not make any guarantee to that effect. CADTH is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in the source documentation. CADTH is not responsible for any errors or omissions or injury, loss or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the information in this document or in any of the source documentation. CADTH takes sole responsibility for the final form and content of this report subject to the limitations noted above. The statements, conclusions, and views expressed herein do not necessarily represent the view of Health Canada or any Canadian provincial or territorial government. Production of this report is made possible by financial contributions from Health Canada and the governments of Alberta, British Columbia, Manitoba, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Prince Edward Island, Saskatchewan and Yukon. A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema i

6 Copyright: CADTH (May 2012). You are permitted to make copies of this document for non-commercial purposes provided it is not modified when reproduced and appropriate credit is given to CADTH. Links: This document may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the owners own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. ii A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema

7 ACRONYMS AND ABBREVIATIONS AE adverse events AMD age-related macular degeneration ARR absolute risk reduction BCVA best-corrected visual acuity CATT Comparison of Age-Related Macular Degeneration Treatment Trials CSME clinically significant macular edema DME diabetic macular edema DR diabetic retinopathy DRCRN Diabetic Retinopathy Clinical Research Network ETDRS Early Treatment Diabetic Retinopathy Study HR hazard ratio logmar logarithm of the minimum angle of resolution ME macular edema MEDCAC Medicare Evidence Development & Coverage Advisory Committee NNH number needed to harm NNT number needed to treat RCT randomized controlled trial RR relative risk SAE serious adverse events SD standard deviation VEGF vascular endothelial growth factor WDAE withdrawal due to adverse events A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema iii

8 TABLE OF CONTENTS ACRONYMS AND ABBREVIATIONS...III EXECUTIVE SUMMARY CONTEXT AND POLICY ISSUES: RESEARCH QUESTION: KEY MESSAGES: METHODS: Literature Search Strategy Selection Criteria and Methods Exclusion Criteria Article Selection Data Extraction Strategy Critical Appraisal of Individual Studies Data Analysis Methods RESULTS: Quantity of Research Available Study Characteristics Data Analyses and Synthesis Critical Appraisal of Individual Studies DISCUSSION Summary of Evidence Comparison With Other Literature Limitations CONCLUSIONS AND IMPLICATIONS FOR DECISION- OR POLICY-MAKING: REFERENCES:...32 APPENDIX 1: SUMMARY OF EVIDENCE ON ADVERSE EVENTS WITH INTRAVITREAL BEVACIZUMAB: A SUPPLEMENTAL SAFETY REVIEW...37 APPENDIX 2: GLOSSARY OF SELECTED TERMS...45 APPENDIX 3: LITERATURE SEARCH STRATEGY...46 APPENDIX 4: SELECTION OF INCLUDED STUDIES (PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES [PRISMA] FLOW CHART)...49 APPENDIX 5: LIST OF INCLUDED STUDIES...50 APPENDIX 6: LIST OF EXCLUDED STUDIES...51 APPENDIX 7: CHARACTERISTICS OF INCLUDED AND EXCLUDED STUDIES...52 APPENDIX 8: CRITICAL APPRAISAL OF INCLUDED STUDIES...56 APPENDIX 9: SUMMARY OF STUDY FINDINGS...57 iv A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema

9 TITLE: A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema DATE: 4 May 2012 EXECUTIVE SUMMARY Context and Policy Issues Diabetic retinopathy (DR) and diabetic macular edema (DME) are microvascular complications of diabetes that are a leading cause of blindness in the diabetic population. DME which is swelling of the retina due to leakage of fluid from blood vessels within the macula, the central portion of the retina may occur at any time during the progression of DR. 1 The goal of treatment is to preserve current visual acuity and reduce the chances of progression to visual loss. Successful laser treatment reduces moderate visual loss but has limited effects on improving visual acuity. 2 Intravitreal injection of corticosteroids, such as triamcinolone acetate, may also moderately improve visual acuity, but these generally offer only short-term improvements in acuity in cases of DME refractory to laser treatment. 3,4 Moreover, triamcinolone is not licensed by Health Canada for this indication. Ranibizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF). It is the only pharmacological therapy licensed in Canada for the treatment of DME. Bevacizumab (Avastin), also derived from a recombinant humanized monoclonal IgG1 antibody that inhibits VEGF, is used clinically in the treatment of DME, although it does not have a Notice of Compliance (NoC) from Health Canada for this indication. It is approved as an antineoplastic, not for the condition under consideration. This systematic review was undertaken to evaluate the effects of intravitreal bevacizumab for the treatment of diabetic macular edema. Research Question In randomized controlled trials (RCTs), does intravitreal injection of bevacizumab provide a therapeutic advantage in the effects on visual acuity, morbidity, and/or mortality, in comparison with other standard therapy (intravitreal injection of triamcinolone, pegaptanib, or ranibizumab, or other drug therapies; and laser photocoagulation), sham treatment, or placebo in the treatment of diabetic macular edema? Methods Literature Search Strategy A peer-reviewed literature search was conducted using the following bibliographic databases: Ovid MEDLINE, Embase, and The Cochrane Library. Grey literature (literature that is not commercially published) was identified by a focused Google search. No filters were applied to limit the retrieval by study type. The original search was conducted November 16, 2011, and there was no restriction by date or language. A second update search was completed April 2, 2012, and included all the same sources originally searched, with the addition of PubMed and grey literature from relevant sections of the Grey Matters checklist ( No filters were applied to this second search to limit the retrieval by study type; however, this update was limited to English language documents published between October, and April 2, Regular alerts were A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema 1

10 established to update the search until May 1, Where possible, retrieval was limited to the human population for both searches. See Appendix 3 for the detailed search strategies. A supplemental review based on a non-systematic literature search was conducted to further identify evidence regarding the safety of intravitreal bevacizumab use in ocular conditions (Appendix 1). This search also considered observational studies and post-marketing surveillance safety data. Selection Criteria and Methods Only randomized controlled trials (open-label, single-masked, or double-masked) comparing intravitreal bevacizumab with placebo/sham or other treatments in patients with DME were included in this systematic review. One reviewer independently screened the titles and abstracts resulting from the search strategies. If there were any doubts about the abstract/article meeting inclusion criteria, a second reviewer screened the abstract/article. Two reviewers selected articles based on the inclusion criteria. Data were extracted by one reviewer and verified by a second reviewer. Two independent reviewers assessed the risk of bias of all included trials and prepared a Risk of Bias Table. Outcomes were analyzed in order of clinical importance, with the greatest weight placed on allcause mortality and serious adverse events (SAE), validated visual acuity measures, activities of daily living, and quality of life. Meta-analysis was carried out whenever possible. Risk of bias was assessed according to standardized criteria and helped to inform conclusions. Data synthesis and analyses were done using the Cochrane Review Manager software, RevMan 5.0. For dichotomous outcomes, the relative risk and/or the risk differences were calculated. Where continuous scales of measurement were used, the mean difference was used. A standard chi-square statistic for heterogeneity was used to test for heterogeneity of treatment effect between the 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 the random effects model was used. Results Ten trials met the inclusion criteria: one of bevacizumab versus sham injections; 5 five versus laser therapy; 6-10 and four versus intravitreal triamcinolone Three studies included primarily patients with type 2 diabetes mellitus; 6,7,9 the remaining trials did not report whether patients had type 1 or type 2 diabetes. One study 9 included a mix of patients with either focal or diffuse DME, and three studies only included patients with diffuse disease. Four studies recruited treatment-naive patients, 8,10,12,13 and three studies included patients with DME refractory to at least one previous laser treatment. 5,9,11 No trials compared intravitreal bevacizumab with ranibizumab in patients with DME. Mortality and serious adverse events (SAEs) did not differ versus any comparator, with two deaths out of 369 eyes treated with bevacizumab compared with five deaths out of 314 eyes treated with comparators (P = 0.20), and 29/369 SAEs on bevacizumab versus 20/314 for comparators (P = 0.45). None of the trials reported on activities of daily living or quality of life. 2 A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema

11 Bevacizumab Versus Sham: Ahmadieh et al (n = 78 eyes; duration = 24 weeks) compared bevacizumab with sham treatment in patients with DME refractory to laser therapy. Improvement in best-corrected visual acuity (BCVA) was not seen with bevacizumab at week six, but differed significantly from sham at weeks 12 to 24. The logarithm of the minimum angle of resolution (logmar) difference was 0.21 ± 0.7 (P = 0.01) at 24 weeks; this equates to an improvement of approximately 11 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters with bevacizumab versus sham. Central macular thickness was decreased versus sham at six and 24 weeks, but results were not significant at 12 and 18 weeks. No withdrawals due to adverse events (WDAE), increased intraocular pressure, or infections were reported in either group. Few adverse events (AE) were reported: eight eyes with mild anterior chamber reactions and one eye progressing to fibrous proliferation were reported in the bevacizumab group. Leakage on fluorescein angiography was not reported. 5 Bevacizumab Versus Laser: Five trials compared bevacizumab to laser photocoagulation, n = 396 eyes in total (metaanalysis of Michaelides et al., Soheilian et al., and Diabetic Retinopathy Clinical Research Network [DRCRN]). 6,8,9 Three RCTs measured 15-letter (three-line) gain in BCVA ETDRS at six, 12 to 16, 6,8 and 36 to 52 weeks. 8,9 Bevacizumab outperformed laser: absolute benefit increase was 12% (number needed to treat [NNT] = 8), 16% (NNT = 6), and 12% (NNT = 8) at six, 12 to 16, and 36 to 52 weeks, respectively. 6,8,9 Three RCTs measured BCVA logmar at six weeks and found that bevacizumab provided a significant improvement versus laser: mean difference 0.17 (95% CI: 0.03 to 0.31; P = 0.02). (meta-analysis of Faghihi et al., Soheilian et al., Solaiman et al.). 7,8,10 This difference is approximately equivalent to nine ETDRS letters. The difference was not statistically significant at weeks 12, 16, or 24. 7,8,10 One trial (Michaelides et al.) reported visual acuity at 12 months: a median gain of eight letters in the bevacizumab group (interquartile range: 1 to 10) versus a median loss of 0.5 letters in the laser group (interquartile range: 15 to 5), P = Over all five trials, four eyes had increased intraocular pressure in the bevacizumab group versus none in the laser group. One eye developed endophthalmitis in the bevacizumab group. In total, 48/223 (22 %) AEs were reported in the bevacizumab group versus 20/173 (12%) in the laser group: risk ratio 1.86 (95% CI: 1.15 to 3.20; P = 0.01), absolute risk increase = 10%, NNH = 10. 8,9 Mean change in central macular thickness did not differ significantly between bevacizumab and laser at week six. At week 24, laser performed better than bevacizumab: mean difference µm (95% CI: to 57.70; P = 0.002). This outcome was measured in two trials, but results mainly reflect one trial (Solaiman et al.) with 84% of the weight. 10 Median change in central macular thickness was reported in two trials (Michaelides et al., and DRCRN), and did not differ between bevacizumab and laser. 9,15 One trial (Solaiman et al.) reported on macular leakage: there was a 62% decrease in macular leakage in the bevacizumab group versus a 53% decrease in the laser group (P = 0.56). 10 Bevacizumab Versus Triamcinolone: Four RCTs compared bevacizumab with triamcinolone (n = 209 eyes in total). Shahin and El- Lakkany (n = 48 eyes) reported on two-line improvement (ETDRS); this occurred in 58% of eyes on triamcinolone versus none on bevacizumab. 12 Shahin and El-Lakkany also reported A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema 3

12 deterioration in one line in three bevacizumab eyes and zero triamcinolone eyes. This trial had inadequate masking and allocation concealment, resulting in a high risk of bias. 12 Two trials (Paccola et al., and Marey and Ellakwa) reported that BCVA logmar was significantly better on triamcinolone than bevacizumab at weeks 6, 12, and 24: mean difference 0.16 (95% CI: 0.07 to 0.24; P = ); 0.12 (95% CI: 0.02 to 0.22; P = 0.02); and 0.10 (95% CI: 0.00 to 0.20; P = 0.04), respectively; in other words, approximate mean differences of eight, six, and five ETDRS letters, respectively. 11,13 Both trials had either inadequate allocation concealment and masking, or inadequate reporting on methods. The one-line ETDRS gain (five letters, 0.1 logmar) for triamcinolone at week 24 is of questionable clinical significance, as the minimum clinically important difference cited in the literature is generally two lines or greater Increased intraocular pressure occurred in 8/50 (16%) eyes on triamcinolone versus zero on bevacizumab in two trials (Shahin and El-Lakkany, Lim et al.). 12,14 Two other trials compared the mean change in intraocular pressure (Paccola et al., Marey and Ellakwa). 11,13 Results favoured bevacizumab, with 1.67 mmhg (95% CI: 2.81 to 0.53; P = 0.004) change in intraocular pressure on bevacizumab at week six versus triamcinolone, and no significant differences at week 12: 0.29 mmhg (95% CI: 1.16 to 0.59; P=0.52). 11,13 No infections were reported. One anterior chamber reaction was reported as an AE in the triamcinolone group. Leakage on fluorescein angiography was not reported in any of the trials. Critical Appraisal: Of the 10 included randomized controlled trials, three trials versus laser had low risk of bias (DRCRN, Michaelides et al. and Soheilian et al.). 6,8,9 These three trials measured ETDRS line improvement and consistently found a benefit for bevacizumab over laser, both for greater improvement and less deterioration. The two other trials versus laser (Faghihi et al. and Solaiman et al.) had a high risk of bias due to problems with research methods and reporting. 7,10 Solaiman et al. did not adequately report on randomization, allocation concealment, or masking. 10 This trial was also responsible for heterogeneity at six weeks for both the BCVA logmar and central macular thickness measurements. All trials comparing bevacizumab versus triamcinolone either had inadequate masking and concealment of treatment allocation or inadequate reporting of these aspects of trial methods. Six trials (one versus sham, 5 two of five versus laser, 7,10 and three of four versus triamcinolone ) failed to report on early withdrawals and loss to follow-up, and only selectively reported common and serious adverse events. It is unclear whether reported results for these trials reflected the full patient population or only those who completed all assessments. Supplemental Safety Evaluation: Given the relative paucity of high quality safety evidence reported in the trials included in the systematic review, a supplemental search of the literature was conducted to further evaluate the evidence for the safety of intravitreal bevacizumab among patients with DME and other ocular conditions. This supplemental (non-systematic) safety review (see Appendix 1) included two systematic reviews, 20,21 one head-to-head RCT comparing bevacizumab with ranibizumab in treating AMD, 22,23 two retrospective cohort analyses, and a multicentre case series. 27 In the two systematic reviews of intravitreal bevacizumab, safety, study designs, and the number of patients in reviewed studies were generally insufficient to detect rare AEs such as endophthalmitis due to bevacizumab. A systematic review comparing ocular and systemic AEs associated with bevacizumab and ranibizumab used in patients with age-related macular degeneration (AMD) did not show important differences in the frequency of events between the drugs. 21 However, the results of the review were compromised by relatively lower quality 4 A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema

13 evidence for bevacizumab compared with that for ranibizumab. A head-to-head, randomized, non-inferiority trial between bevacizumab and ranibizumab in patients with AMD reported similar rates of AEs between the treatments, including total SAEs after one year: 166/586 (28.3%) on bevacizumab versus 143/599 on ranibizumab (23.9%), P = 0.08; 28 total cumulative SAEs have not been reported for the full two-year study period. 23 In a secondary analysis, the authors note more serious systemic AEs (234/586 [39.9%] on bevacizumab versus on ranibizumab (190/599 [31.7%] at two years; relative risk, 1.30 [95% CI: 1.07 to 1.57], P = 0.009). 23 The authors noted the excess systemic events were largely those not previously associated with systemic therapy with anti-vegf agents. It was unclear whether this imbalance in serious systemic events arose from factors unaccounted for in the trial design and analysis, by chance, or truly reflects an important safety signal for bevacizumab versus ranibizumab. Additionally, the rate of endophthalmitis for bevacizumab was almost twice that of ranibizumab (7/586 [1.2%] on bevacizumab versus 4/599 [0.7%] on ranibizumab) at two years; however, the difference was not statistically significant (P = 0.45) and may have occurred by chance. 22,23 One large retrospective analysis of insurance claims data failed to show a difference between bevacizumab and ranibizumab in the rate of serious systemic events in the treatment of AMD. 26 Similarly, a case series involving greater than 12,000 and 14,000 injections of intravitreal bevacizumab and ranibizumab, respectively, reported no difference in the crude incidence proportions of endophthalmitis between these anti-vegfs in the treatment of DME and AMD. These systemic adverse events and ocular infection data are in contrast to a manufacturersupported analysis that reported a higher risk of overall mortality, hemorrhagic cerebrovascular accident, ocular inflammation, and cataract surgery following AMD treatment with bevacizumab versus ranibizumab. 24,25 However, the latter analysis may have been confounded by a lack of sufficient adjustment for important confounding factors, such as socioeconomic status and health factors (smoking, lipid and blood pressure levels). Conclusions and Implications for Decision- or Policy-Making There is insufficient evidence to draw conclusions on the effects of bevacizumab on mortality, serious morbidity, activities of daily living, and quality of life. Bevacizumab has been shown to improve visual acuity in patients with DME refractory to laser therapy. A clinically significant mean difference was observed in visual acuity of 0.21 ± 0.7 versus sham treatment, which is the equivalent of a two-line (10-letter) gain on the ETDRS scale. In patients who have not yet undergone laser therapy, bevacizumab significantly improved visual acuity versus laser therapy in trials lasting up to one year. The absolute benefit increase ranged from 15% to 19% over six to 52 weeks. However, patients experienced more adverse events on bevacizumab than laser. There is insufficient evidence that bevacizumab improves visual acuity to an equal or greater extent than triamcinolone. The trials that compared bevacizumab to triamcinolone had a high risk of bias, as measured both by design features such as lack of masking of patients of those providing treatment or of those assessing outcomes, and inadequate reporting. There is also a lack of robust evidence as to the long-term safety profile of intravitreal bevacizumab, particularly due to sparse AE reporting and short study follow-up periods. The single head-to-head randomized trial between bevacizumab and ranibizumab (for the treatment of AMD) suggested an excess risk of non-specific serious systemic adverse events for bevacizumab-treated patients over the two year period of the trial. However, the importance of this difference remains unclear. There is conflicting evidence from large health claim database analyses, with one study failing to find a difference in AEs between bevacizumab and A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema 5

14 ranibizumab, and a manufacturer-sponsored analysis finding greater harm with bevacizumab than ranibizumab. As well, the lack of post-marketing surveillance compounds the situation. The results of this systematic review align with those of another recently published health technology assessment performed for the U.S. Medicare Evidence Development and Coverage Advisory Committee (MEDCAC), which assessed the effects of anti-vegfs for treating DME. 29 In that review, pairwise indirect comparisons between anti-vegf agents suggested bevacizumab is not significantly different from ranibizumab for improving visual acuity in patients with DME. Compared with this review, differences in study inclusion criteria and use of indirect comparisons methodology may, in part, explain the more definitive conclusion of the MEDCAC health technology assessment that intravitreal bevacizumab has benefit in the treatment of DME. However, both reviews echo the relative paucity of evidence available for bevacizumab versus ranibizumab, especially regarding safety profiles. Large, well-conducted randomized controlled trials of sufficient duration are needed to provide better evidence of the effects of intravitreal bevacizumab compared with other treatments used for DME. As well, such studies would better define the optimal dose, timing, and duration of treatment with intravitreal bevacizumab for DME. 6 A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema

15 1 CONTEXT AND POLICY ISSUES: Diabetic retinopathy (DR) and diabetic macular edema (DME) are microvascular complications in diabetes that are a leading cause of blindness in this population. DME is swelling of the retina due to leakage of fluid from blood vessels within the macula and may occur at any time during the progression of diabetic retinopathy. 1 The 10-year incidence of DME is approximately 7% to 10% in type 1 diabetes. In patients with type 1 diabetes 20 years, the incidence increases to 25% to 30%. Patients with type 2 diabetes have a five- and 20-year incidence of DME of 5% and 15%, respectively. Approximately half of patients with DME will lose two or more lines of visual acuity within two years. 30 The Early Treatment Diabetic Retinopathy Study (ETDRS) a National Eye Institute randomized controlled trial enrolled patients with bilateral (n = 1,124) or unilateral (n = 754) mild to moderate diabetic retinopathy. 2 The first stage of randomization was to immediate photocoagulation or deferral; those randomized to photocoagulation went through a second randomization to two forms of photocoagulation. The authors found that eyes assigned to laser photocoagulation of clinically significant macular edema (CSME) were half as likely to lose 15 or more letters on the ETDRS chart compared with eyes assigned to deferred photocoagulation. Laser treatment also increases the chance of visual improvement and decreases the frequency of persistent macular edema. CSME is the threshold level at which laser photocoagulation is indicated. CSME as defined by the ETDRS includes the following characteristics: retinal edema within 500 μm of the centre of the fovea hard exudates within 500 μm of the centre of the fovea, if associated with adjacent retinal thickening (which may be outside the 500 μm limit) one disc area of retinal edema (1,500 μm or larger), any part of which is within a one disc diameter of the centre of the fovea. 2 DME is classified into focal and diffuse types. Focal macular edema is caused by foci of vascular abnormalities, which are primarily microaneurysms and have high permeability. Diffuse macular edema is caused by dilated retinal capillaries throughout the posterior pole. Widespread retinal non-perfusion results in compensatory dilation of the remaining capillary bed. Cystoid retinal edema is also more common in diffuse macular edema. The distinction is important as each requires a different photocoagulation technique, with focal edema using focal laser treatment and diffuse edema using grid laser treatment. 30 The goal of treatment is to preserve or improve current visual acuity and to reduce the chances of progressing to visual loss. However, it is noted that successful laser treatment reduces moderate visual loss, but the ETDRS showed that only 3% of laser-treated eyes gained three or more lines of visual acuity. 2 Intravitreal corticosteroids have been used to treat DME. Evidence suggests that intravitreal triamcinolone results in improved visual acuity compared with no treatment, and it can offer short-term improvements in acuity in eyes with DME refractory to laser treatment. 3,4 However, long-term benefits alone or in combination with laser are inconclusive. 31,32 Furthermore, the risk of elevated intraocular pressure and cataracts are increased with intravitreal steroid use. A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema 7

16 Currently, ranibizumab (Lucentis) is the only pharmacologic therapy licensed by Health Canada for the treatment of DME. However, bevacizumab (Avastin) is also being used by ophthalmologists to treat DME, although it does not have a Notice of Compliance (NoC) from Health Canada for this indication (bevacizumab is authorized for intravenous administration for cancer therapy). Such use has become widespread because of evidence that bevacizumab is as effective as ranibizumab in the treatment of a related condition for which ranibizumab is also approved; that is, age-related macular degeneration. 22 The two drugs bevacizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody, of which ranibizumab is a fragment share the same mechanism of action (inhibition of the biologic activity of human vascular endothelial growth factor [VEGF]), but bevacizumab is much less costly than ranibizumab. The optimal dose and duration of therapy of bevacizumab for use in DME are unknown, although generally it is administered at 1.25 mg intravitreally (0.05 ml volume), with regimens varying from a single injection at baseline and subsequent injections at six-week intervals, as required. The ETDRS set the guidelines for the treatment of DME. Since that time, the standard of treatment for DME has been glycemic control, as demonstrated by the Diabetes Control and Complications Trial; optimal blood pressure control, as demonstrated by the United Kingdom Prospective Diabetes Study; and macular focal/grid laser photocoagulation. 33 This paradigm may shift now that there is an approved pharmacological therapy available. Although bevacizumab does not have an indication for treatment of DME, there is considerable interest in its use for this condition. Hence, there is a need for an assessment of the comparative benefits and risks of bevacizumab in DME to inform clinical and policy decisions. 2 RESEARCH QUESTION: In randomized controlled trials (RCTs), does intravitreal injection of bevacizumab provide a therapeutic advantage in the effects on visual acuity, morbidity, and/or mortality in comparison with other standard therapy (intravitreal injection of triamcinolone, pegaptanib, or ranibizumab, or other drug therapies; and laser photocoagulation), sham treatment or placebo in the treatment of diabetic macular edema? 3 KEY MESSAGES: Although bevacizumab does not have an indication for treatment of diabetic macular edema, there is considerable interest in its use for this condition. This review found bevacizumab improved vision compared to laser therapy, insufficient evidence comparing bevacizumab to triamcinolone and lack of robust evidence for the long-term safety profile of bevacizumab. There were no trials that directly compared bevacizumab with ranibizumab for the treatment of DME, although a recently published indirect comparison suggested that they may have similar efficacy. Large, well-conducted trials are needed to provide better evidence of the effects of bevacizumab compared with other options, as well as to better define the optimal dose, timing, and duration of bevacizumab treatment in diabetic macular edema. 8 A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema

17 4 METHODS: 4.1 Literature Search Strategy A peer-reviewed literature search was conducted to obtain published literature for this review. The following bibliographic databases were searched: Ovid MEDLINE with In-Process records and daily updates through Ovid (1948 to present), Embase through Ovid (1980 to present), and The Cochrane Library through Wiley. Grey literature (literature that is not commercially published) was identified by a focused Google search. The search strategy consisted of both controlled vocabulary, such as the National Library of Medicine s MeSH (Medical Subject Headings), and keywords. The main search concepts were Avastin [intervention] and ocular conditions [indication/population]. No filters were applied to limit the retrieval of the search by study type. The original search was conducted November 16, 2011, and there were no restrictions by date or language. A second update search was completed April 2, 2012, and included all the same sources originally searched, with the addition of PubMed and grey literature from relevant sections of the Grey Matters checklist ( No filters were applied to this second search to limit the retrieval by study type; however, this update was limited to English language documents published between October, and April 2, Regular alerts were established to update the search until May 1, Where possible, retrieval was limited to the human population for both searches. See Appendix 3 for the detailed search strategies. A supplemental review based on a non-systematic literature search was conducted to further identify evidence regarding the safety of intravitreal bevacizumab use in ocular conditions (Appendix 1). See Appendix 1 for a brief description of the separate (non-systematic) literature search strategy used. 4.2 Selection Criteria And Methods Only randomized controlled trials were eligible for inclusion in the systematic review (Table 1). Abstracts were not considered unless the full trial report was available. The study population involved patients with either type 1 or type 2 diabetes with a diagnosis of DME; no limits were imposed a priori on disease severity. The intervention was the administration of intravitreal bevacizumab. The comparators were intravitreal injection of triamcinolone, pegaptanib, or ranibizumab, or other drug therapies; laser photocoagulation; sham treatment or placebo. The outcomes of interest were hierarchically arranged as shown in Table 1, and include several surrogate outcomes. A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema 9

18 Table 1: Table of Selection Criteria Population Intervention Comparator Outcomes Study Designs Patients with either type 1 or type 2 diabetes with a diagnosis of DME Intravitreal bevacizumab for DME Intravitreal injection of: Triamcinolone Pegaptanib Ranibizumab Other drug therapies used clinically for treatment of DME Laser photocoagulation Sham treatment or placebo All-cause mortality Non-fatal SAEs Proportion of eyes with improvement or deterioration of BCVA of 15 letters (3 lines) on the ETDRS chart at 4 metres or any improvement/deterioration Mean visual acuity in the treated eye at 6 months and any other followup times reported Ability to carry out activities of daily living, as measured on a validated scale Quality of life as measured on a validated scale WDAEs Increased intraocular pressure Infections Any other AEs The number of additional interventions administered Surrogate outcomes (presence of macular edema with stereoscopic fundus photography of biomicroscopy; objective assessment of ME regression measured by change in mean retinal thickness on optical coherence tomography; presence of leakage on fluorescein angiography) RCTs published and unpublished AEs = adverse events; BCVA = best-corrected visual acuity; DME = diabetic macular edema; ETDRS = Early Treatment Diabetic Retinopathy Study; ME = macular edema; RCT = randomized controlled trial; SAEs = serious adverse events; WDAEs = withdrawal due to adverse events. 10 A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema

19 4.3 Exclusion Criteria Studies were excluded if: they did not meet the selection criteria the comparison group also received bevacizumab the methods section was incomplete they were duplicate publications, narrative reviews, or editorials. 4.4 Article Selection One reviewer independently screened the titles and abstracts resulting from the search strategies. Abstracts/articles were rejected on initial screening if it was judged from the title or the abstract that the article was not a report of a randomized controlled trial. If there were any doubts about the abstract/article meeting inclusion criteria, the second reviewer screened the abstract/article. The full texts of the remaining articles were then retrieved. Once full-text articles were retrieved, one reviewer selected studies for inclusion and the second reviewer verified the selections. The bibliographies of pertinent articles, reviews, and texts were searched for additional citations. 4.5 Data Extraction Strategy Relevant data from each of the individual studies were extracted by one reviewer and verified by a second reviewer. All numeric calculations and graphic interpolations were confirmed by a second reviewer. 4.6 Critical Appraisal of Individual Studies The Cochrane Collaboration Risk of Bias Tool was used to assess the quality of the trials included in this systematic review. 34 Two independent reviewers assessed the risk of bias of all included trials and prepared a Risk of Bias Table (Appendix 8). 4.7 Data Analysis Methods Data synthesis and analyses were done using the Cochrane Review Manager software, RevMan 5.0. The relative risk and/or the risk difference were calculated for dichotomous outcomes (adverse events, serious adverse events, number of patients with improvement on visual charts). Where continuous scales of measurement were used (BCVA logarithm of the minimum angle of resolution [logmar], changes in central macular thickness), the mean difference was used. A standard chi-square statistic for heterogeneity was used to test for heterogeneity of treatment effect between the 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 the random effects model was used. 5 RESULTS: 5.1 Quantity of Research Available The electronic literature search identified 464 citations, and one additional citation was identified through the search of other sources. From these, 111 duplicates were removed to yield 354 citations for screening. Upon screening titles and abstracts, 342 citations were excluded, and 12 potentially relevant articles were retrieved for full-text review. Of the 12 potentially relevant reports, two reports did not meet the inclusion criteria. Ten publications were included in this A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema 11

20 review. The study selection process is presented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart (Appendix 4).The included and excluded studies are listed in Appendices 5 and 6, respectively. Of the 10 RCTs that met the inclusion criteria for this review, one compared bevacizumab versus placebo (sham injection; Ahmadieh et al.), 5 and nine versus active treatment: Five studies compared intravitreal bevacizumab therapy with laser photocoagulation (DRCRN, Faghihi et al., Soheilian et al., Michaelides et al., and Solaiman et al.) Four studies compared bevacizumab with intravitreal triamcinolone therapy (Paccola et al., Shahin and El-Lakkany, Marey and Ellakwa, and Lim et al.) No studies compared bevacizumab with ranibizumab (Lucentis), the only drug licensed for the treatment of DME in Canada. 5.2 Study Characteristics Characteristics of the included studies are summarized in Table 7.1, Appendix 7. The included studies were published between 2007 and 2011 and were conducted in the United States, 15 Iran, 5,7,8 Egypt, 10,12,13 Korea, 14 Brazil, 11 and the United Kingdom. 9 The number of eyes injected ranged from 28 (28 patients, Paccola et al.) 11 to 150 (129 patients, Soheilian et al.). 8 Patient Characteristics Studies included patients with type 1 or type 2 diabetes mellitus, or both, with most patients having a diagnosis of CSME in at least one eye. Studies were variable in terms of the minimum central macular thickness or BCVA criteria for study enrollment, and with regard to whether patients had treatment-naive or refractory disease. Three studies included mostly or all type 2 diabetics, 6,7,9 while the other studies did not report the percentage of patients with type 1 or type 2 diabetes mellitus. One study 9 included a mix of patients with either focal or diffuse DME, and three studies only included patients with diffuse disease; the remaining studies did not indicate whether patients had focal or diffuse DME. Four studies 8,10,12,13 recruited treatment-naive patients, three studies 5,9,11 included patients with DME refractory to at least one previous laser treatment, and in one study 15 the majority of patients had received prior treatment for DME. Only two studies 9,11 provided information (such as HbA1C values) on the degree of control of underlying diabetes. Interventions and Comparators Most studies consisted of three treatment groups, 5,7,8,10,13,14 whereas three studies were twogroup comparisons. 9,11,12 The DRCRN study consisted of five treatment groups. 15 All of the studies used a bevacizumab dose of 1.25 mg, except one study in which the dose was 1.5 mg, 11 and another study where one of the comparator groups received 2.5 mg. 15 Studies in which triamcinolone was used as a comparator treatment or as an adjunct to bevacizumab generally used a dose of 2 mg; 5,7,8,14 however, two studies used a dose of 4 mg. 11,12 One study that used triamcinolone as both a comparator and as an adjunct to bevacizumab used doses of 4 mg and 2 mg, respectively. 13 Outcomes In general, change from baseline in central macular thickness and/or change from baseline in BCVA logmar were the outcomes reported in the included trials. One study also reported the percentage of patients gaining 10 ETDRS letters and the percentage of patients who lost < A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema

21 ETDRS letters. 9 All of the studies reported on safety assessments; however, relatively sparse data were presented for this outcome. 5.3 Data Analyses and Synthesis Results are presented by bevacizumab comparators (sham, laser, and triamcinolone) according to the outcome hierarchy described previously. Detailed data extraction tables on all outcomes for individual trials are included in Appendix 9. Bevacizumab Versus Sham (one trial: Ahmadieh et al. 5 ): 1. All-cause mortality: Sham control group: One death was reported (reason not provided). 2. Serious adverse events: Bevacizumab group: One marked anterior chamber reaction occurred in one eye and was considered a serious adverse event (SAE). 3. BCVA ETDRS 15-letter (three lines) improvement: This outcome was not reported in the Ahmadieh et al. trial, which reported mean (standard deviation [SD]) change from baseline in BCVA logmar. 4. BCVA ETDRS 15-letter (three lines) deterioration: This outcome was not reported in the Ahmadieh et al. trial, which reported mean (SD) change from baseline in BCVA logmar. Mean difference BCVA logmar Versus Sham: 6 weeks: 0.07 ± 0.04, P = weeks: 0.18 ± 0.06, P = weeks: 0.18 ± 0.06, P = weeks: 0.21 ± 0.07, P = Mean visual acuity change at six months or other follow-up times: Outcome not reported. 6. Activities of daily living: Outcome not reported. 7. Quality of life: Outcome not reported. 8. Withdrawal due to adverse events: No WDAEs were reported in the Ahmadieh et al. trial in either treatment arm. 9. Increased intraocular pressure: No increased intraocular pressure was reported in the Ahmadieh et al. trial in either treatment arm. 10. Infections: No infections were reported in either group. A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema 13

22 11. Other adverse events: Ahmadieh et al. reported mild anterior chamber reactions in eight (19.5%) eyes, and one (2.4%) eye with progression of fibrous proliferation in the bevacizumab group. This was the only AE not listed previously that was reported in this trial (under other AEs). No other AEs were reported for the sham group. 12. Additional interventions: Ahmadieh et al. reported using topical corticosteroid and cycloplegic drops to treat marked anterior chamber reaction in one eye in the bevacizumab group. 13. Presence of macular edema and mean change in central macular thickness: Mean difference in central macular thickness (µm) versus sham, as measured by optical coherence tomography: 6weeks: 90 ± 27, P = weeks: 65 ± 29, P = weeks: 48 ± 38, P = weeks: 120 ± 42, P = Leakage on fluorescein angiography: This outcome was not reported. Bevacizumab versus laser (five trials: DRCRN, Faghihi et al., Soheilian et al., Michaelides et al., Solaiman et al.) 6-10 : 1. All-cause mortality: Faghihi et al. reported that no serious mortality or morbidity occurred during the trial. 7 DRCRN 15 : Bevacizumab group: n = 2 deaths: One fatal myocardial infarction (78-year-old male 73 days after 1.25 mg bevacizumab, history of coronary bypass surgery); one death due to pancreatic cancer. Soheilian et al. 8 : Laser group: n = 2 deaths (reason not provided). Michaelides et al. 9 : Laser group: n = 2 deaths (reason not provided). This outcome was not reported in Solaiman et al Serious adverse events: There was no difference in the SAE rate between these comparators. DRCRN 15 : Bevacizumab groups: n = 14/68 (21%): n=1 non-fatal myocardial infarction (69-year-old male five days after 2.5 mg bevacizumab with history of coronary bypass surgery); n = 1 congestive heart failure in 56-year-old female with a history of three similar episodes, 40 days after a second injection of 1.25 mg bevacizumab; n = 3 with blood pressure elevation, one with history of hypertension; n = 1 peripheral vascular disease, n = 1 syncope; n = 3 worsening of renal function; n = 4 with worsening of anemia. 14 A Systematic Review of Intravitreal Bevacizumab for the Treatment of Diabetic Macular Edema