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Anti–Vascular Endothelial Growth Factor Treatment for Retinal Conditions: A Systematic Review and Meta-analysis
Journal: BMJ Open ManuscriptFor ID peerbmjopen-2018-022031 review only Article Type: Research
Date Submitted by the Author: 29-Jan-2018
Complete List of Authors: Pham, Ba; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program Thomas, Sonia; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program Lillie, Erin; Li Ka Shing Knowledge Institute, St Michael's Hospital, Knowledge Translation Program Lee, Taehoon; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program Hamid, Jemila; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program; McMaster University, Department of Clinical Epidemiology and Biostatistics
Richter, Trevor; Canadian Agency for Drugs and Technologies in Health, http://bmjopen.bmj.com/ Janoudi, Ghayath; Canadian Agency for Drugs and Technologies in Health Agarwal, Arnav; McMaster University, Department of Clinical Epidemiology and Biostatistics; University of Toronto, Faculty of Medicine Sharpe, Jane ; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program Scott, Alistair; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program Warren, Rachel; Li Ka Shing Knowledge Institute, St. Michael’s Hospital,
Knowledge Translation Program on September 24, 2021 by guest. Protected copyright. Brahmbhatt, Ronak; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program Macdonald, Erin; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program; University of Toronto, Institute of Health Policy, Management and Evaluation Straus, Sharon; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program; University of Toronto, Department of Geriatric Medicine Tricco, Andrea; Li Ka Shing Knowledge Institute, St Michael's Hospital; University of Toronto, Epidemiology Division, Dalla Lana School of Public Health
ranibizumab, bevacizumab, aflibercept, anti-vascular endothelial growth Keywords: factor, age-related macular degeneration, diabetic macular edema
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29
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1 2 3 1 Anti–Vascular Endothelial Growth Factor Treatment for Retinal Conditions: A Systematic 4 5 6 2 Review and Meta-analysis 7 8 9 1 10 3 Ba’ Pham PhD, MSc Email: [email protected] 11 12 4 Sonia M. Thomas MSc1 Email: [email protected] 13 14 5 Erin Lillie MSc1 Email: [email protected] 15 16 For1 peer review only 17 6 Taehoon Lee MD, MPH Email: [email protected] 18 19 7 Jemila S. Hamid PhD, MSc1,2 Email: [email protected] 20 21 8 Trevor Richter PhD, MSc3 Email: [email protected] 22 23 3 24 9 Ghayath Janoudi MD, MSc Email: [email protected] 25 26 10 Arnav Agarwal HBSc2,4 Email: [email protected] 27 28 11 Jane P. Sharpe BSc1 Email: [email protected] 29
30 1 http://bmjopen.bmj.com/ 31 12 Alistair Scott BSc Email: [email protected] 32 1 33 13 Rachel Warren MA Email: [email protected] 34 35 14 Ronak Brahmbhatt MBBS, MPH1 Email: [email protected] 36 37 15 Erin Macdonald MSc, HBSc1,5 Email: [email protected]
38 on September 24, 2021 by guest. Protected copyright. 39 1,6 40 16 Sharon E. Straus MD, MSc Email: [email protected] 41 42 17 Andrea C. Tricco PhD, MSc1,7,* Email: [email protected] 43 44 45 46 18 1 Li Ka Shing Knowledge Institute, St. Michael’s Hospital, 209 Victoria Street, East Building, 47 48 49 19 Toronto, Ontario, M5B 1W8, Canada 50 51 20 2 Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main 52 53 21 Street West, Hamilton, Ontario, L8S 4K1, Canada 54 55 1 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 22 3 Canadian Agency for Drugs and Technologies in Health (CADTH), 865 Carling Avenue, 4 5 6 23 Ottawa, Ontario, K1S 5S8, Canada 7 4 8 24 Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 9 10 25 1A8, Canada 11 12 26 5 Institute of Health Policy, Management and Evaluation, University of Toronto, 6th floor, 155 13 14 15 27 College Street, Toronto, Ontario, M5T 3M7, Canada 16 For peer review only 17 28 6 Department of Geriatric Medicine, University of Toronto, 27 King’s College Circle, Toronto, 18 19 29 Ontario, M5S 1A1, Canada 20 21 7 22 30 Epidemiology Division, Dalla Lana School of Public Health, University of Toronto, 6th Floor, 23 24 31 155 College Street, Toronto, Ontario, M5T 3M7, Canada 25 26 27 28 32 * Corresponding Author 29
30 http://bmjopen.bmj.com/ 31 33 Dr. Andrea C. Tricco 32 33 34 Scientist, Knowledge Translation program 34 35 35 Li Ka Shing Knowledge Institute, St. Michael’s Hospital 36 37 36 209 Victoria Street, East Building, Toronto, Ontario, M5B 1W8, Canada
38 on September 24, 2021 by guest. Protected copyright. 39 40 37 Phone: 416 864 6060 ext. 77521, e mail: [email protected] 41 42 43 44 38 Word count: 285/300 (Abstract), 3397/4000 (Main text), 1 figure, 4 tables, 2 supplementary 45 46 39 files 47 48 49 50 51 52 53 54 55 2 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 4 40 ABSTRACT 5 6 7 8 41 Objectives: To evaluate the comparative effectiveness and safety of intravitreal bevacizumab, 9 10 42 ranibizumab, and aflibercept for patients with choroidal neovascular age related macular 11 12 43 degeneration (cn AMD), diabetic macular edema (DME), macular edema due to retinal vein 13 14 44 occlusion (RVO ME) and myopic choroidal neovascularization (m CNV). 15 16 For peer review only 17 45 Design: Systematic review and random effects meta analysis. 18 19 46 Methods: Multiple databases were searched from inception to August 17th, 2017 (MEDLINE, 20 21 47 Embase, Cochrane Central). Eligible head to head randomized controlled trials (RCTs) 22 23 24 48 comparing the anti VEGF drugs in patients aged ≥18 years with the retinal conditions of interest. 25 26 49 Two reviewers independently extracted data and assessed risk of bias using the Cochrane risk of 27 28 50 bias tool. 29
30 http://bmjopen.bmj.com/ 31 51 Results: Nineteen RCTs involving 7459 patients with: cn AMD (n=12), DME (n=3), RVO ME 32 33 52 (n=2), and m CNV (n=2) were included. Vision gain was not significantly different in patients 34 35 53 with cn AMD, DME, RVO ME, and m CNV treated with bevacizumab versus ranibizumab. 36 37 54 Similarly, vision gain was not significantly different between cn AMD patients treated with
38 on September 24, 2021 by guest. Protected copyright. 39 40 55 aflibercept versus ranibizumab. In DME patients treated for 2 years, vision gain was as likely to 41 42 56 be attained with aflibercept as with ranibizumab or bevacizumab; however, in the first year of 43 44 57 treatment, patients treated with aflibercept were more likely to attain vision gain than patients 45 46 47 58 with ranibizumab or bevacizumab. Rates of systemic serious harms were similar among 48 49 59 bevacizumab, ranibizumab, and aflibercept. For cn AMD patients, compared to monthly 50 51 60 treatment, an as needed treatment regimen (6 9 injections per year) was associated with a 52 53 54 61 mortality increase of 1.8% (RR: 2.0, [1.2, 3.5], 2 RCTs, 1795 patients) in a post hoc analysis. 55 3 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 62 Conclusions: With few exceptions, intravitreal bevacizumab was a reasonable alternative to 4 5 6 63 ranibizumab and aflibercept in patients with wet cn AMD, DME, RVO ME and m CNV. 7 8 64 However, the choice of anti VEGF drugs may depend on the specific retinal condition, baseline 9 10 65 visual acuity, and treatment regimen. 11 12 66 Trial registration: PROSPERO CRD 42015022041 13 14 15 67 16 For peer review only 17 68 Keywords: ranibizumab, bevacizumab, aflibercept, anti vascular endothelial growth factor, age 18 19 69 related macular degeneration, diabetic macular edema, retinal vein occlusion, myopic choroidal 20 21 22 70 neovascularization 23 24 25 26 27 28 29
30 http://bmjopen.bmj.com/ 31 32 33 34 35 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 4 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 4 71 STRENGTHS AND LIMITATIONS OF THIS STUDY 5 6 7 8 72 • Our systematic review serves as an update to existing systematic reviews of individual retinal 9 10 73 conditions, including recent head to head trials in patients with RVO ME and DME, and 11 12 74 long term follow up data for patients with cn AMD. We consolidated the evidence for 13 14 15 75 treatment choice of all common retinal conditions, allowing the interpretation of the strength 16 For peer review only 17 76 of the evidence of benefits and harms of the anti VEGF drugs across conditions. 18 19 77 • We summarized information regarding treatment regimens (e.g., 3 initial monthly intravitreal 20 21 22 78 injections and as needed monthly retreatment, treat and extend), as needed retreatment 23 24 79 criteria, and the reconstitution of bevacizumab. We examined the influence of the choice of 25 26 80 treatment regimens on the benefits and harms of the anti VEGF drugs for specific retinal 27 28 81 conditions. 29
30 http://bmjopen.bmj.com/ 31 82 • We limited our review to English studies. We found a limited number of RCTs evaluated the 32 33 83 anti VEGF drugs in patients with RVO ME and m CNV. Our sensitivity and subgroup 34 35 84 analyses were not specified a-priori and should be interpreted with caution. 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 5 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 85 BACKGROUND 4 5 6 7 86 Retinal conditions due to neovascular abnormality are common in older adults. Choroidal 8 9 87 neovascular age related macular degeneration (cn AMD) is the leading cause of irreversible 10 11 88 blindness in individuals aged 50 years or older in high income countries.1 2 If left untreated, 12 13 89 potentially irreversible visual impairment can also be caused by diabetic macular edema (DME) 14 15 3 5 16 90 and macular edema Fordue to retinal peer vein occlusion review (RVO ME). only Choroidal neovascularization 17 18 91 secondary to pathologic myopia (myopic CNV) is another major cause of blindness and visual 19 20 92 impairment worldwide.6 7 Together, these retinal diseases cause substantial reduction in quality 21 22 8 23 93 of life, and are a significant burden on healthcare systems. 24 25 94 Ranibizumab, off label use of repackaged bevacizumab, and aflibercept are widely used anti 26 27 95 vascular endothelial growth factor (anti VEGF) drugs for intravitreal treatment of retinal 28 29 96 conditions. Multiple systematic reviews have evaluated the comparative effectiveness of anti 30 http://bmjopen.bmj.com/ 31 9 12 32 97 VEGF drugs in patients with cn AMD, DME, RVO ME, and m CNV; but given the 33 34 98 publication of new trials in patients with RVO ME13 and DME,14 and long term follow up data 35 36 99 for patients with cn AMD,15 an update is necessary. We aimed to conduct a systematic review to 37
38 on September 24, 2021 by guest. Protected copyright. 39 100 evaluate the comparative effectiveness and safety of bevacizumab, ranibizumab, and aflibercept 40 41 101 for patients with cn AMD, DME, RVO ME, and m CNV. 42 43 44 102 METHODS 45 46 47 48 103 A systematic review regarding the comparative efficacy and safety of the anti VEGF drugs was 49 50 104 planned in response to a query from the Canadian Drug Safety and Effectiveness Network 51 52 105 (PROSPERO CRD 42015022041), for which a preliminary report was prepared to inform listing 53 54 55 6 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 106 recommendations.16 17 The report included a meta analysis of pairwise comparisons of the anti 4 5 6 107 VEGF drugs for individual retinal conditions, as well as a network meta analysis to evaluate the 7 8 108 anti VEGF drugs in cn AMD patients. This paper summarizes results of the meta analysis; a 9 10 109 separate paper is underway for the network meta analysis results. 11 12 110 The current review was conducted using the Cochrane Handbook for Systematic Reviews and 13 14 18 15 111 reported using the PRISMA statement (Additional file 1). The methods are outlined briefly 16 For peer review only 17 112 below, as they are described in greater detail in Additional file 2: Appendix 1 and a related 18 19 113 therapeutic review report.17 20 21 22 23 114 Data Sources and Searches: 24 25 115 MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched. Studies 26 27 28 116 that are not widely available or commercially published (i.e., grey literature), were identified 29 19 30 117 using an established approach. Additional studies were identified by searching reference lists of http://bmjopen.bmj.com/ 31 32 118 included studies, and email correspondence with expert clinicians and anti VEGF drug 33 34 35 119 manufacturers. 36 37 120 An information specialist developed the search strategy, which was peer reviewed by another
38 on September 24, 2021 by guest. Protected copyright. 39 121 information specialist using the PRESS statement.20 The MEDLINE strategy can be found in 40 41 th 42 122 Additional file 2: Appendix 1. The search was conducted on May 27 , 2015 and updated on 43 th 44 123 August 17 , 2017. 45 46 47 124 Study Selection: 48 49 50 125 Eligible studies were randomized controlled trials (RCTs) that directly compared intravitreal 51 52 126 bevacizumab, ranibizumab, and/or aflibercept for the treatment of patients (aged ≥18 years) with 53 54 55 7 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 127 cn AMD, DME, RVO ME or m CNV. Due to time and resource constraints, we only included 4 5 6 128 studies published in English. 7 8 129 Eligible RCTs reported one of the following benefits and harms outcomes: vision gain, defined 9 10 130 as a gain in Best Corrected Visual Acuity (BCVA) letter score of ≥15 on the Early Treatment 11 12 131 Diabetic Retinopathy Study (ETDRS) chart;21 vision loss, defined as a loss in BCVA letter score 13 14 15 132 of ≥15; mean change in BCVA from baseline; legal blindness (BCVA of 20/200 or worse 16 For peer review only 17 133 measured on a standard Snellen chart, or worse than 20/100 visual acuity measured on ETDRS 18 19 134 chart); vision related function according to the 25 item National Eye Institute Visual Function 20 21 22 22 135 Questionnaire (NEI VFQ 25; serious adverse events; all cause mortality; arterial 23 24 136 thromboembolic events (TEs); venous TEs; bacterial endophthalmitis; and retinal detachment. 25 26 137 All titles/abstracts and potentially relevant full text articles were screened by two reviewers, 27 28 29 138 independently. Discrepancies were discussed and if necessary, resolved with input from a third
30 http://bmjopen.bmj.com/ 31 139 reviewer. When multiple reports of the same trial were identified, the main report was included, 32 33 140 and the others were treated as companion reports.23 34 35 36 141 Data Extraction and Quality Assessment: 37
38 on September 24, 2021 by guest. Protected copyright. 39 142 Data extraction forms were developed with input from three clinicians, pilot tested, and refined 40 41 42 143 twice. Data extraction was conducted by two reviewers, independently. Discrepancies were 43 44 144 discussed and if necessary, resolved with input from a third reviewer. A similar approach was 45 46 145 followed for quality assessment using the Cochrane risk of bias tool for RCTs.24 47 48 49 146 Synthesis of study results 50 51 52 147 Study results were synthesized with respect to benefits and harms of treatment, treatment 53 54 55 8 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 148 regimen (e.g., monthly and as needed regimens), and trends in BCVA improvement over time. 4 5 6 149 With respect to visual acuity improvement, meta analyses were conducted with studies reporting 7 8 150 BCVA letter score as measured on the ETDRS chart. For studies reporting visual acuity in 9 10 151 logMAR and decimal values, the values were converted to approximate ETDRS letter scores,25 11 12 152 with approximate standard deviations.26 Pairwise comparisons of drugs were assessed at the 13 14 15 153 longest treatment duration, allowing for the inclusion of trials in the meta analysis that reported 16 For peer review only 17 154 outcome data at different time points. Subgroup analyses were conducted at 12 months and 24 18 19 155 months, as these were the most frequently reported time points. A post hoc analysis was 20 21 22 156 conducted to compare different treatment regimens across the drugs. For DME patients, 23 24 157 treatment effect estimates were obtained for all patients as well as subgroups based upon baseline 25 26 158 BCVA, which were pre specified in the DRCR.net trial.27 The meta analysis was conducted 27 28 29 159 using a random effects model, as we assumed treatment effects varied across trials. A sensitivity
30 http://bmjopen.bmj.com/ 31 160 analysis was conducted by restricting results to trials determined to be at low risk of selection 32 33 161 bias. Between study heterogeneity was assessed using the I² statistic, with values above 75% 34 35 162 indicating substantial heterogeneity.28 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 163 RESULTS 40 41 42 164 Literature search 43 44 45 165 After screening 3176 titles/abstracts and 440 full text articles, 19 head to head RCTs of the anti 46 47 166 VEGF drugs were included, with 7459 patients, including 12 RCTs for cn AMD, 3 RCTs for 48 49 167 DME, 2 RCTs for RVO ME, and 2 RCTs for m CNV (Figure 1, Additional file 2: Appendix 50 51 27 29 42 52 168 1). Given our inclusion criteria, we excluded RCTs that compared anti VEGF drugs with 53 54 169 placebo or laser photocoagulation.43 49 55 9 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 170 Study and patient characteristics 4 5 6 171 Studies were completed between 2010 and 2017 with an average sample size of 393 patients per 7 8 172 trial (range: 28, 1240) (Table 1, Additional file 2: Appendix 2 3). The mean age ranged from 9 10 11 173 approximately 60 to 80 years, and females accounted for 5% to 76% of the patients. The average 12 13 174 follow up duration was 13 months (range: 6 24 months). RCTs were conducted in Europe (n=8), 14 15 175 North America (n=5), Asia (n=4), Africa (n=1) and across multiple continents (n=1); most were 16 For peer review only 17 18 176 multi centre RCTs (n=13), in addition to 6 single centre RCTs. 19 20 21 177 Risk of bias assessment 22 23 24 178 Random sequence generation and allocation concealment were unclear for 12/19 (63.2%) and 25 26 179 9/19 (47.4%) of the included RCTs, respectively, suggesting the potential for selection bias 27 28 180 (Additional file 2: Appendix 4 5). The RCTs were at low risk with respect to blinding of 29
30 http://bmjopen.bmj.com/ 31 181 participants and trial personnel 18/19 (94.7%), blinding of outcome assessment 18/19 (94.7%), 32 33 182 incomplete outcome data 13/19 (68.4%), and selective reporting 13/19 (68.4%). Two of the 19 34 35 183 RCTs (10.5%) were industry funded.38 36 37 38 184 Patients with cn-AMD on September 24, 2021 by guest. Protected copyright. 39 40 41 42 185 Comparative effectiveness of bevacizumab and ranibizumab 43 44 45 186 Results from 10 RCTs (3302 patients) showed that approximately 22% of patients attained vision 46 47 187 gain with treatment, and patients treated with bevacizumab were as likely to attain vision gain as 48 49 50 188 those treated with ranibizumab (Risk Ratio (RR): 1.05; [95% confidence interval (CI), 0.93, 51 52 189 1.19], Table 2, Additional file 2: Appendix 6 7). Over an average treatment duration of 16 53 54 190 months, approximately 94% of patients maintained their vision, with no statistical difference 55 10 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 191 between patients treated with bevacizumab or ranibizumab (RR of vision loss: 0.91 [95% CI, 4 5 6 192 0.70, 1.19]). Patients treated with bevacizumab or ranibizumab gained an average of 7 letters in 7 8 193 terms of mean BCVA with no statistical difference between the drugs (mean difference [MD] 9 10 194 0.03 letters [95% CI, 1.02, 1.08]). Approximately 2 4% patients treated with bevacizumab or 11 12 195 ranibizumab became legally blind (RR: 2.04 [95% CI, 0.32 to 12.50], 3 trials, 1823 patients). 13 14 15 196 Overall, the results were consistent across the 10 trials and did not change with the sensitivity 16 For peer review only 17 197 analyses restricted to trials determined to be at low risk of selection bias and with different 18 19 198 follow up lengths (Additional file 2: Appendix 6, 8 9). 20 21 22 23 199 Treatment regimens 24 25 26 200 Additional file 2: Appendix 10 provides detailed information regarding the treatment regimens 27 28 201 in the included trials, the as needed re treatment criteria and the reconstitution of bevacizumab 29
30 http://bmjopen.bmj.com/ 31 202 for intravitreal injections. The treatment regimens varied widely, and are summarized in Table 3 32 33 203 along with the mean number of injections per year for each treatment regimen. The number of 34 35 204 reported treatment regimens varied by condition (cn AMD (n=6), DME (n=3), RVO ME (n=2), 36 37 205 and m CNV (n=1)). In cn AMD patients, the two most commonly reported regimens for
38 on September 24, 2021 by guest. Protected copyright. 39 40 206 bevacizumab and ranibizumab included monthly injections (~11 injections/year) and 3 monthly 41 42 207 injections followed by as needed treatment (~6 injections/year). Aflibercept was most commonly 43 44 208 administered using a monthly regimen (~11 injections/year). 45 46 47 209 Results of our post hoc analysis comparing as needed versus monthly treatment in cn AMD 48 49 210 patients are summarized in Table 4. The as needed treatment regimen with ranibizumab or 50 51 211 bevacizumab was less effective than the monthly regimen in improving mean BCVA (MD: 1.9 52 53 54 212 letters [95% CI, 0.5 to 3.3 letters], 2 RCTs, 1622 patients) and vision gain (RR: 0.73 [95% CI, 55 11 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 213 0.55 to 0.95]). When the regimens were assessed for non inferiority at 1 year with an inferiority 4 5 6 214 margin of 5 points, monthly bevacizumab was equivalent to monthly ranibizumab (MD: 0.5 7 8 215 [95% CI, 3.9, 2.9]), as needed bevacizumab was equivalent to as needed ranibizumab (MD: 0.8 9 10 216 [95% CI, 4.1, 2.5]), as needed ranibizumab was equivalent to monthly ranibizumab (MD: 1.7 11 12 217 [95% CI, 4.7, 1.3]) but monthly bevacizumab was not equivalent to as needed bevacizumab 13 14 50 15 218 (MD: 2.1 [95% CI, 5.7, 1.6]). Compared to the monthly regimen, the as needed regimen was 16 For peer review only 17 219 associated with a significant increase in mortality of 1.8% (95% CI, 0.1% to 3.4%) [RR, 2.0; 18 19 220 95% CI, 1.2 to 3.5]. 20 21 22 23 221 Comparative effectiveness of aflibercept and ranibizumab 24 25 26 222 Results from 2 RCTs (1815 patients; Table 2, and Additional file 2: Appendix 6) showed that 27 28 223 approximately 32% of patients attained vision gain with treatment, and patients treated with 29
30 http://bmjopen.bmj.com/ 31 224 aflibercept were as likely to attain vision gain as patients treated with ranibizumab (RR: 0.99 32 33 225 [95% CI, 0.81 to 1.22]). Over an average assessment and treatment duration of 12 months, 34 35 226 approximately 95% of patients maintained their vision, and aflibercept patients were as likely to 36 37 227 maintain vision as ranibizumab patients (RR of vision loss: 0.90 [95% CI, 0.60 to 1.35]). With
38 on September 24, 2021 by guest. Protected copyright. 39 40 228 respect to mean BCVA, patients gained on average 9 letters (MD: 0.05 [95% CI, 2.5, 2.4]). 41 42 229 Compared to baseline, patients gained some visual related function, with an average of 5 points 43 44 230 on the NEI VFQ 25 questionnaire (MD: 2.2 [95% CI, 0.6, 5.1]). 45 46 47 48 231 Harms 49 50 51 232 Over an average of 14 months (range: 12 24 months), mortality was reported in 4% and 3% of 52 53 233 patients treated with bevacizumab or ranibizumab, respectively (RR: 1.14 [95% CI, 0.72 to 54 55 12 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 234 1.79], 6 RCTs, 2941 patients, Additional file 2: Appendix 6). Serious adverse events were 4 5 6 235 reported in 19 and 18% of patients treated with bevacizumab or ranibizumab, respectively (RR: 7 8 236 1.09 [95% CI, 0.93 to 1.27], 5 RCTs, 3026 patients). Arterial thromboembolic events were 9 10 237 reported in 4% and 3%of patients treated with bevacizumab or ranibizumab, respectively (RR: 11 12 238 0.86 [95% CI, 0.51, 1.47], 4 RCTs, 2033 patients). Venous thromboembolic events, bacterial 13 14 15 239 endophthalmitis and retinal detachment were reported in <1% of patients treated with either 16 For peer review only 17 240 drug. In the trials evaluating aflibercept and ranibizumab, arterial thromboembolic events were 18 19 241 reported in 2% of patients treated with aflibercept or ranibizumab (RR: 0.96 [95% CI, 0.45, 20 21 22 242 2.04], 2 RCTs, 1818 patients), and venous thromboembolic events were reported in <1% of 23 24 243 patients treated with either drug. Data on other harms were not available. 25 26 27 244 Patients with DME 28 29
30 http://bmjopen.bmj.com/ 31 245 Comparative effectiveness of ranibizumab, bevacizumab and aflibercept 32 33 34 246 Results from the trial by the Diabetic Retinopathy Clinical Research Network (DRCR.net trial, 35 36 247 620 patients) showed that over 2 years of treatment, patients were as likely to attain vision gain 37
38 248 with ranibizumab (37%), bevacizumab (35%), or aflibercept (39%) bevacizumab versus on September 24, 2021 by guest. Protected copyright. 39 40 41 249 ranibizumab: RR: 0.94 [95% CI, 0.72, 1.23]; aflibercept versus bevacizumab: RR: 1.06 [95% CI, 42 43 250 0.80, 1.38]; and aflibercept versus ranibizumab: RR: 1.06 [95% CI, 0.82, 1.37]; Table 2) Over 2 44 45 251 years of treatment, approximately 98% of patients maintained their vision with all 3 drugs. 46 47 48 252 Patients’ mean BCVA improved by 13 letters with aflibercept, 10 letters with bevacizumab and 49 50 253 12 letters with ranibizumab (aflibercept versus ranibizumab: MD, 1.4 [95% CI, 1.6, 4.3]; 51 52 254 bevacizumab versus aflibercept: MD, 2.7 [95% CI, 5.2 to 0.3]; and bevacizumab versus 53 54 55 13 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 255 ranibizumab: MD, 2.0 [95% CI, 3.9 to 0.1], Table 2). 4 5 6 7 256 Treatment regimen 8 9 10 257 With respect to treatment regimen, the DRCR.net trial treated patients initially with monthly 11 12 258 injections until stable visual acuity within 6 months, followed by as needed treatment 13 14 259 (Additional file 2: Appendix 10).51 The median number of injections administered over a one 15 16 For peer review only 17 260 year period was 10 in the bevacizumab group, 9 in the aflibercept group, and 10 in the 18 19 261 ranibizumab group (Table 3).51 In the second year, the median number of injections was: 6, 5, 20 21 262 and 6 in the bevacizumab, aflibercept, and ranibizumab groups, respectively.52 Two smaller trials 22 23 24 263 both started treatment with 3 monthly intravitreal injections, followed by varying as needed 25 26 264 retreatment criteria (Table 3).14 31 27 28 29 265 Harms
30 http://bmjopen.bmj.com/ 31 32 27 33 266 After 24 months of treatment in the DRCR.net trial, mortality was reported in approximately 34 35 267 6% of bevacizumab patients, 2% of aflibercept patients and 5% of ranibizumab patients 36 37 268 (Additional file 2: Appendix 6). Serious adverse events were reported in 21% of bevacizumab
38 on September 24, 2021 by guest. Protected copyright. 39 269 patients, 27% of aflibercept patients, and 25% of ranibizumab patients. Arterial thromboembolic 40 41 42 270 events were reported in 4%, 3%, and 5%, of patients treated with bevacizumab, aflibercept, and 43 44 271 ranibizumab, respectively. Bacterial endophthalmitis and retinal detachments were reported in 45 46 272 <1% of patients treated with any of the drugs. 47 48 49 50 273 Patients with RVO-ME 51 52 53 274 Comparative effectiveness of ranibizumab, bevacizumab, and aflibercept 54 55 14 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 275 Results from 1 RCT (77 patients) showed that approximately 59% of patients attained vision 4 5 6 276 gain with bevacizumab and ranibizumab treatment, and no statistical difference was observed 7 32 8 277 between the drugs (RR: 1.0 [95% CI, 0.68 to 1.45]; Table 2 and Additional file 2: Appendix 8). 9 10 278 With respect to mean BCVA, patients treated with either drug gained an average of 16 letters 11 12 279 (MD 2.5 [95% CI, 8.0 to 5.0]). 13 14 15 280 Results from the SCORE2 trial (348 patients) showed that approximately 61% of patients treated 16 For peer review only 17 281 with bevacizumab or aflibercept attained vision gain, with no statistical difference between the 18 19 282 drugs (RR: 1.06 [95% CI, 0.91 to 1.25]; Table 2).13 With respect to mean BCVA, patients treated 20 21 22 283 with either drug gained an average of 19 letters (MD 1.52 [95% CI, 1.2 to 4.2]). 23 24 25 284 Treatment regimens 26 27 28 285 In the SCORE2 trial, patients were treated with monthly intravitreal injections for the first 6 29
30 http://bmjopen.bmj.com/ 31 286 months, with a mean number of 5.8 injections in patients treated with bevacizumab or aflibercept 32 13 33 287 (Table 3 and Additional file 2: Appendix 11). In another trial, patients were treated with one 34 35 288 initial intravitreal injection and then as needed monthly re treatment over 6 months, with a mean 36 37 289 number of 3 injections in patients treated with bevacizumab or ranibizumab.12 32
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 290 Harms 42 43 44 291 Serious adverse events were reported in 3% of bevacizumab patients and 5% of ranibizumab 45 46 292 patients (RR: 0.5 [95% CI, 0.05 to 5.26], 1 RCT, 74 patients; Additional file 2: Appendix 8).32 47 48 49 293 Serious adverse events were reported in 8% of the patients treated with bevacizumab or 50 51 294 aflibercept over 6 months (RR: 0.99 [95% CI, 0.49 to 2.00], 1 RCT, 362 patients).13 52 53 54 55 15 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 295 Patients with m-CNV 4 5 6 7 296 Comparative effectiveness of ranibizumab and bevacizumab 8 9 10 297 Results from 1 RCT (32 patients) showed that 62% of patients treated with bevacizumab and 11 12 298 56% of patients treated with ranibizumab attained vision gain (RR: 1.11 [95% CI, 0.63, 1.96], 1 13 14 299 RCT; Table 2 and Additional file 2: Appendix 11).30 With respect to mean BCVA, patients 15 16 For peer review only 17 300 treated with bevacizumab gained 12 letters and patients treated with ranibizumab gained an 18 19 301 average of 13 letters (MD: 1.3 [95% CI, 6.5 to 4.0], 2 RCTs, 80 patients).29 30 The included 20 21 302 trials did not report data on harms. 22 23 24 25 303 Treatment regimens 26 27 28 304 Both trials evaluated ranibizumab and bevacizumab with patients receiving one monthly 29
30 305 intravitreal injection and as needed monthly re treatment, with a mean number of 3.1 injections http://bmjopen.bmj.com/ 31 32 33 306 in patients treated with bevacizumab and 2.4 injections per year in patients treated with 34 29 30 35 307 ranibizumab (Table 3 and Additional file 2: Appendix 6). 36 37
38 308 DISCUSSION on September 24, 2021 by guest. Protected copyright. 39 40 41 309 This systematic review synthesized results from 19 RCTs to evaluate the comparative 42 43 44 310 effectiveness and safety of intravitreal bevacizumab, ranibizumab, and aflibercept for patients 45 46 311 with cn AMD, DME, RVO ME and m CNV. Intravitreal bevacizumab was as effective as 47 48 312 ranibizumab in patients with cn AMD, DME, RVO ME, and m CNV for the outcomes we 49 50 51 313 examined. Ranibizumab was as effective as aflibercept in patients with cn AMD. 52 53 314 In patients with DME that were treated for 2 years, vision gain was equally likely to be attained 54 55 16 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 315 with aflibercept, ranibizumab or aflibercept. In the first year of treatment, however, patients 4 5 6 316 treated with aflibercept were more likely to attain vision gain than patients treated with 7 8 317 ranibizumab or bevacizumab differential effects that were observed mainly in patients with 9 10 318 initial BCVA < 69 letter scores (equivalent to 20/50 or worse) but not observed in patients with 11 12 319 initial BCVA ≥ 69 letter scores (equivalent to 20/40 or better) based on the results from the sub 13 14 15 320 group analyses. Rates of systemic serious harms were similarly low among the anti VEGF drugs, 16 For peer review only 17 321 across the retinal conditions. In our post hoc analysis, cn AMD patients and compared to 18 19 322 monthly treatment, an as needed treatment regimen (i.e., 6 to 9 monthly injections per year) was 20 21 22 323 significantly associated with a small loss in visual acuity, but a significant increase in mortality 23 24 324 risk of 1.8% (RR: 2.0 [95% CI, 1.2, 3.5]). 25 26 325 Results from the CATT and IVAN trials showed that relative to monthly treatment, patients with 27 28 29 326 cn AMD receiving as needed treatment experienced a significant increase in risk of mortality.
30 http://bmjopen.bmj.com/ 31 327 Whether there are any biological explanations for the increased risk of mortality associated with 32 33 328 fewer monthly injections is unclear and this finding may have been attributable to chance. As 34 35 329 such, further research should be conducted to verify this result. In DME, RVO ME and m CNV 36 37
38 330 trials, patients tended to receive fewer monthly injections per year (Table 3). None of the trials in on September 24, 2021 by guest. Protected copyright. 39 40 331 DME, RVO ME and m CNV patients evaluated a monthly treatment regimen, and therefore the 41 42 332 safety risk between as needed and monthly regimens could not be evaluated. This requires 43 44 45 333 further study. 46 47 334 Additional file 2: Appendix 12 displays the mean change in BCVA over time in patients treated 48 49 335 with bevacizumab or ranibizumab. For all of the retinal conditions, patients showed 50 51 52 336 improvement in mean BCVA by 3 6 months with initial monthly injections, and maintained a 53 54 337 plateau to 24 months in the treatment of cn AMD patients (average improvement of 6 letters), 55 17 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 338 DME patients (8 letters), RVO ME patients (16 letters), and m CNV patients (11 letters). 4 5 6 339 Comparative outcomes beyond 6 months in patients with RVO ME and m CNV were lacking 7 8 340 and as such, long term comparative data of anti VEGF drugs in these patients are needed. 9 10 341 Our findings are consistent with findings from previous systematic reviews. A meta analysis of 6 11 12 342 head to head trials concluded that bevacizumab and ranibizumab had equivalent efficacy with 13 14 11 15 343 respect to visual acuity in cn AMD patients. A meta analysis of five RCTs suggested no 16 For peer review only 17 344 differences in effectiveness between ranibizumab and bevacizumab in DME patients.53 Other 18 19 345 reviews in patients with RVO ME and m CNV came to similar conclusions.9 10 54 55 Although 20 21 22 346 findings were consistent with those in these recent reviews, our review serves as an update (with 23 24 347 the inclusion of data up to 2017) while also examining the additional factor of treatment regimen. 25 26 348 There are several limitations worth noting. First, none of our sensitivity and subgroup analyses 27 28 29 349 were specified a-priori and as such, these results should be interpreted with caution. This also
30 http://bmjopen.bmj.com/ 31 350 pertains to our post hoc analysis on treatment regimen. Secondly, we limited our review to 32 33 351 English studies due to time and resources constraints. We believe, however, that the impact of 34 35 352 the restrictions is small since our findings are consistent with previous systematic reviews that 36 37
38 353 included RCTs reported in all languages, evaluating the same anti VEGF drugs for specific on September 24, 2021 by guest. Protected copyright. 39 40 354 retinal conditions,11 53 56 and results were consistent across studies, so the impact of including 41 42 355 additional studies reported in other languages, if any, would be insignificant. We only identified 43 44 45 356 a few RCTs evaluating the anti VEGF drugs in patients with DME, RVO ME and m CNV. 46 47 357 Although the rates of reported adverse events were similar across the anti VEGF drugs, the 48 49 358 assessment of harms using comparative trial data is limited. We excluded RCTs which 50 51 52 359 randomized eyes (instead of patients) since the reported analyses failed to adjust for the 53 57 54 360 correlation between the outcomes of eyes from the same individuals. Similarly, we also 55 18 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 361 excluded one quasi randomized trial,58 because we focused on randomized studies. 4 5 6 7 362 CONCLUSIONS 8 9 10 363 With few exceptions, intravitreal bevacizumab was a reasonable alternative to ranibizumab and 11 12 364 aflibercept in patients with wet cn AMD, DME, RVO ME and m CNV. The choice of anti 13 14 365 VEGF drug may depend on specific retinal conditions, baseline visual acuity, and treatment 15 16 For peer review only 17 366 regimen. 18 19 20 21 22 23 24 25 26 27 28 29
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38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 19 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 4 367 LIST OF ABBREVIATIONS 5 6 7 8 368 Adverse event (AE); Age related macular degeneration (wet AMD); Arterial thromboembolic 9 10 369 events (ATE); Best corrected visual acuity (BCVA); Bacterial endophthalmitis (BE); Confidence 11 12 370 interval (CI); Choroidal neovascularization (CNV); Diabetic macular edema (DME); Early 13 14 371 Treatment Diabetic Retinopathy Study (ETDRS); Randomized controlled trial (RCT); Risk ratio 15 16 For peer review only 17 372 (RR); Macular edema due to retinal vein occlusion (RVO ME); Standardized mean difference 18 19 373 (SMD); Vascular endothelial growth factor (VEGF); Venous thromboembolic event (VTE) 20 21 22 374 ACKNOWLEDGEMENTS 23 24 25 26 375 We thank Becky Skidmore for drafting our search strategies, Kelly Farrah for peer reviewing the 27 28 376 search strategies (PRESS), and Alissa Epworth for de duplicating search results and obtaining 29
30 377 full text articles. We thank Meghan Kenny for helping screen studies for inclusion and http://bmjopen.bmj.com/ 31 32 33 378 performing quality appraisal and Jaimie Adams for helping screen studies for inclusion. We 34 35 379 would also like to thank Michel Boucher, Sarah Berglas, Hongbo Yuan, and Sarah Jennings for 36 37 380 their valuable contribution, insights, and for facilitating the production and dissemination of the
38 on September 24, 2021 by guest. Protected copyright. 39 381 synthesized evidence. In addition we would like to thank the clinical experts and stakeholders 40 41 42 382 who provided feedback on the previous therapeutic review report. Finally, we thank Susan Le 43 44 383 and Inthuja Selvaratnam for formatting the manuscript for submission. 45 46 47 384 CONTRIBUTORS 48 49 50 51 385 BP screened titles, abstracts, and full text articles; abstracted and cleaned data, conducted quality 52 53 386 assessment; and drafted the manuscript. SMT lead the coordination of the systematic review; 54 55 20 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 387 drafted the protocol; screened titles, abstracts, and full text articles; abstracted and cleaned data; 4 5 6 388 conducted quality assessment; and helped draft and revise the manuscript. TL screened titles, 7 8 389 abstracts, and full text articles; abstracted and cleaned data; conducted quality assessment; 9 10 390 helped conduct meta analysis; and reviewed the manuscript. EL screened titles, abstracts, and 11 12 391 full text articles; abstracted and cleaned data; conducted quality assessment; and reviewed the 13 14 15 392 manuscript. JH conducted the analysis and interpretation of data; and reviewed the manuscript. 16 For peer review only 17 393 TR helped with conceptualizing the research design, drafting and revising the protocol, 18 19 394 interpretation of data; and reviewed the manuscript. GJ helped draft and revise the protocol; 20 21 22 395 screened titles, abstracts, and full text articles; abstracted data; conducted quality assessment; 23 24 396 helped interpret the data; and reviewed the manuscript. AA screened titles, abstracts, and full 25 26 397 text articles; abstracted and cleaned data; conducted quality assessment; and reviewed the 27 28 29 398 manuscript. JPS screened titles, abstracts, and full text articles; abstracted and cleaned data;
30 http://bmjopen.bmj.com/ 31 399 conducted quality assessment; and reviewed the manuscript. AS screened titles, abstracts, and 32 33 400 full text articles; abstracted and cleaned data, conducted quality assessment; and reviewed the 34 35 401 manuscript. RW screened titles, abstracts, and full text articles; abstracted and cleaned data, 36 37
38 402 conducted quality assessment; and reviewed the manuscript. RB abstracted and cleaned data, on September 24, 2021 by guest. Protected copyright. 39 40 403 conducted quality assessment; and reviewed the manuscript. EM screened titles, abstracts, and 41 42 404 full text articles; abstracted and cleaned data; and reviewed the manuscript. SES helped with 43 44 45 405 conceptualizing the research and design; interpretation of data, and reviewed the manuscript. 46 47 406 ACT conceptualized the research and design; drafted the protocol; obtained funding; assisted 48 49 407 with data acquisition and interpretation; and drafted and revised the manuscript. Authors ACT 50 51 52 408 and BP had full access to all the data in the study and takes responsibility for the integrity of the 53 54 409 data and the accuracy of the data analysis. 55 21 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 410 FUNDING 4 5 6 7 411 This work was supported by the Canadian Institutes of Health Research/Drug Safety and 8 9 412 Effectiveness Network (CIHR/DSEN). SES is funded by a Tier 1 Canada Research Chair in 10 11 413 Knowledge Translation. ACT is funded by a Tier 2 Canada Research Chair in Knowledge 12 13 414 Synthesis. The therapeutic review was commissioned by the Canadian Agency for Drugs and 14 15 16 415 Technology in HealthFor (CADTH) peer and funded review by a grant from theonly Canadian Institutes of Health 17 18 416 Research Drug Safety and Effectiveness Network. The funders had no role in design and conduct 19 20 417 of the study; collection, management, analysis, and interpretation of the data; preparation, 21 22 23 418 review, or approval of the manuscript; and decision to submit the manuscript for publication. 24 25 26 419 COMPETING INTERESTS 27 28 29 420 All authors declare no competing interests.
30 http://bmjopen.bmj.com/ 31 32 33 421 PROVENANCE AND PEER REVIEW 34 35 36 422 Not commissioned; externally peer reviewed. 37
38 on September 24, 2021 by guest. Protected copyright. 39 423 DATA SHARING STATEMENT 40 41 42 424 All datasets generated and/or analysed during the current study are available from the 43 44 45 425 corresponding author on reasonable request. 46 47 48 426 MEETING PRESENTATION 49 50 51 427 The data from the original therapeutic review was presented by ACT and SMT to the Canadian 52 53 th 54 428 Drug Expert Committee in Ottawa, Ontario, on Nov 17 , 2015. 55 22 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 429 OPEN ACCESS 4 5 6 7 430 This is an Open Access article distributed in accordance with the Creative Commons Attribution 8 9 431 Non Commercial (CC BY NC 4.0) license, which permits others to distribute, remix, adapt, 10 11 432 build upon this work non commercially, and license their derivative works on different terms, 12 13 433 provided the original work is properly cited and the use is non commercial. See: 14 15 16 434 http://creativecommons.org/licenses/by nc/4.0/For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29
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30 545 macular degeneration: 1 year outcomes of a prospective, double masked randomised clinical http://bmjopen.bmj.com/ 31 546 trial. Eye (Lond). 2010;24(11):1708 15. 32 547 43. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: 33 548 results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789 34 549 801. 35 550 44. Heier JS, Korobelnik JF, Brown DM, et al. Intravitreal Aflibercept for Diabetic Macular 36 37 551 Edema: 148 Week Results from the VISTA and VIVID Studies. Ophthalmology.
38 552 2016;123(11):2376 85. on September 24, 2021 by guest. Protected copyright. 39 553 45. The Diabetic Retinopathy Clinical Research N, Elman MJ, Aiello LP, et al. Randomized 40 554 Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt 41 555 Laser for Diabetic Macular Edema. Ophthalmology. 2010;117(6):1064 77.e35. 42 556 46. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema 43 44 557 following central retinal vein occlusion: six month primary end point results of a phase III study. 45 558 Ophthalmology. 2010;117(6):1124 33. 46 559 47. Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone 47 560 acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular 48 561 edema. Ophthalmology. 2012;119(10):2125 32. 49 562 48. Boyer D, Heier J, Brown DM, et al. Vascular endothelial growth factor Trap Eye for 50 563 macular edema secondary to central retinal vein occlusion: six month results of the phase 3 51 52 564 COPERNICUS study. Ophthalmology. 2012;119(5):1024 32. 53 565 49. Holz FG, Roider J, Ogura Y, et al. VEGF Trap Eye for macular oedema secondary to 54 566 central retinal vein occlusion: 6 month results of the phase III GALILEO study. Br J 55 26 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 567 Ophthalmol. 2013;97(3):278 84. 4 568 50. Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular 5 6 569 age related macular degeneration. N Engl J Med. 2011;364(20):1897 908. 7 570 51. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for 8 571 diabetic macular edema. N Engl J Med. 2015;372(13):1193 203. 9 572 52. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for 10 573 diabetic macular edema: two year results from a comparative effectiveness randomized clinical 11 574 trial. Ophthalmology. 2016. 12 575 53. Ford JA, Lois N, Royle P, et al. Current treatments in diabetic macular oedema: 13 14 576 systematic review and meta analysis. BMJ Open. 2013;3. 15 577 54. Ford JA, Clar C, Lois N, et al. Treatments for macular oedema following central retinal 16 578 vein occlusion: systematicFor review. peer BMJ Open review. 2014;4(2):e004120. only 17 579 55. Mitry D, Bunce C, Charteris D. Anti vascular endothelial growth factor for macular 18 580 oedema secondary to branch retinal vein occlusion. Cochrane Database Syst Rev. 19 581 2013;1:CD009510. 20 21 582 56. Solomon SD, Lindsley K, Vedula SS, et al. Anti vascular endothelial growth factor for 22 583 neovascular age related macular degeneration. Cochrane Database Syst Rev. 2014(8):Cd005139. 23 584 57. Pece A, Milani P, Monteleone C, et al. A randomized trial of intravitreal bevacizumab vs. 24 585 ranibizumab for myopic CNV. Graefes Arch Clin Exp Ophthalmol. 2015;253(11):1867 72. 25 586 58. Russo V, Barone A, Conte E, et al. Bevacizumab compared with macular laser grid 26 587 photocoagulation for cystoid macular edema in branch retinal vein occlusion. Retina. 27 588 2009;29(4):511 5. 28 29 589
30 http://bmjopen.bmj.com/ 31 32 33 34 35 36 37
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1 2 3 590 FIGURE LEGENDS 4 5 6 7 591 Figure 1. Study Flow 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29
30 http://bmjopen.bmj.com/ 31 32 33 34 35 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 28 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 30BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 4 5 TABLE 1. SUMMARY STUDY CHARACTERISTICS 6 7 8 No. of No. of No. of 9 Total No. No. of 10 studies studies studies of trials studies 11 Study Characteristic with cn- with RVO- with m- included with DME 12 AMD ME (n=2) CNV (n=2) (n=19)a (%) (n=3) (%) 13 (n=12) (%) (%) (%) 14 Year of publication 15 16 2010–2011For 5 (26.32) peer 4 (33.33)review 0 (0) only 0 (0) 1 (50) 17 2012–2013 6 (31.58) 5 (41.67) 0 (0) 0 (0) 1 (50) 18 19 2014–2015 5 (26.32) 2 (16.67) 2 (66.67) 1 (50) 0 (0) 20 2016 3 (15.79) 1 (8.33) 1 (33.33) 1 (50) 0 (0) 21 Geographic region 22 23 Europe 8 (42.11) 6 (50) 0 (0) 0 (0) 2 (100) 24 North America 5 (26.32) 3 (25) 1 (33.33) 1 (50) 0 (0) 25 26 Asia 4 (21.05) 2 (16.67) 1 (33.33) 1 (50) 0 (0) 27 Africa 1 (5.26) 0 (0) 1 0 (0) 0 (0) 28 Multi continent 1 (5.26) 1 (8.33) 1 (33.33) 0 (0) 0 (0) 29
Setting http://bmjopen.bmj.com/ 30 31 Single Centre 6 (31.58) 2 (16.67) 1 (33.33) 1 (50) 2 (100) 32 12 (63.16) 10 (83.33) 1 (33.33) 1 (50) 0 (0) 33 Multi Centre 34 NR 1 (5.26) 0 (0) 1 (33.33) 0 (0) 0 (0) 35 Follow-up duration 36 37 6 12 months 14 (73.68) 9 (75) 2 (66.67) 2 (100) 1 (50)
38 13 19 months 4 (21.05) 2 (16.67) 1 (33.33) 0 1 (50) on September 24, 2021 by guest. Protected copyright. 39 ≥20 months 1 (5.26) 1 (8.33) 0 0 0 (0) 40 Footnotes: 41 a 42 Total number of randomized controlled trials, n=19, from 18 publications 43 44 Abbreviations: cn AMD, choroidal neovascular age related macular degeneration; DME, 45 diabetic macular edema; m CNV, myopic choroidal neovascularization; NR, not reported; RVO 46 ME, macular edema due to retinal vein occlusion. 47 48 49 50 51 52 53 54 55 29 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
c 2 0% 0% I 66% 66% 0% 0% 0% 0% NA NA NA NA NA NA NA NA 1.06 (0.73, 1.22) 1.22) 1.06 (0.73, NA 0.94 (0.72, 1.23) 1.23) 0.94 (0.72, NA 1.11 (0.63, 1.96) 1.96) 1.11 (0.63, NA 1.06 (0.80, 1.38) 1.38) 1.06 (0.80, NA 1.06 (0.91, 1.25) 1.25) 1.06 (0.91, NA 1.00 (0.68, 1.45) 1.45) 1.00 (0.68, NA -2.0 (-3.9, -0.1) -2.0 (-3.9, -0.1) 1.4 ( 1.6, 4.3) 4.3) 1.4( 1.6, 27% Risk Ratio orRisk (95% Estimate CI) -2.7 (-5.2, -0.3) -2.7 (-5.2, -0.3) 0% 0% 0.63 (0.15, 2.61) 2.61) 0.63 (0.15, NA 2.08 (0.52, 8.33) 8.33) 2.08 (0.52, NA 0.48 (0.12, 1.91) 1.91) 0.48 (0.12, NA -0.05 (-2.5, 2.4) -0.052.4) (-2.5, 1.350) 1.350) -0.03 (-1.08, 1.02) 1.02) -0.03 (-1.08, 1.5 (-1.2, 4.2) 4.2) 1.5 (-1.2, -2.5 (-8.0, 5.0) 5.0) -2.5 (-8.0, Mean Difference Mean Difference
b 37% 37% 37% 37% 39% 39% 61% 61% 56% 56% 59% 59% 18.1 18.1 18.9 18.9 14.0 (12.3 to 15.7) 14.015.7) to (12.3 Comparator effect Mean (Range) 0% 0% 2% 2% 3% 3% 2% 2%
b Effect Effect http://bmjopen.bmj.com/ 30 30 39% 39% 35% 35% 35% 35% 15.6 15.6 10.0 (SD: 11.8) 10.011.8) (SD: 12.4) 12.8 (SD: 19.6) 19.6) 8.8 (8.3, 9.4) 9.4) 8.8(8.3, 8.8 (8.19.4) to 5% 5% (5 5) to 6% (5 6) to 0.90 to (0.60 7.2 (4.1, 15.2) 15.2) 7.2(4.1, 11.4) 5.9(0.6, 6% (0 to 11) 6% (0 11) to 14) 7% (4 to 0.911.19) (0.7, 4% 32% (30 to 34) 32% 34) (30 to 32% 34) (31 to 0.991.22) to (0.81 52% 22% (12 to 33) 22% 33) (12 to 23% 29) (14 to 1.07) 0.95 (0.84, 0% 2% 2% Treatment 2% 2% 3% 3% Mean Mean (Range) BMJ Open ~Snellen b 20/80 20/80 20/80 20/80 20/80 20/63 20/63 20/80 20/80 20/80 Baseline ETDRS ETDRS Baseline letters equivalent on September 24, 2021 by guest. Protected copyright. # of RCTs # RCTs of (# of patients) patients) For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
a Vision loss Vision loss 1 (32) 30~ 20/250 0% BCVA change BCVA 1 (348) 50~ 20/100 18.6 BCVA change BCVA 1 (77) 56~ 20/80 BCVA change BCVA 2 (462) 20/80 56 65) ~ (47, 16.2 to (12.8 Vision loss Vision loss 1 (392) 65~ 20/50 Vision gain Vision gain 1 (392) 65~ 20/50 BCVA change BCVA 1 (386) 65~ 20/50 Vision loss Vision loss 1 (376) 65~ 20/50 BCVA change BCVA 2 (456) 20/63 59 65) ~ (54, 10.5) 10.3 (10.0, 12.112.3) to (11.9 Vision loss Vision loss 1 (376) 65~ 20/50 Vision gain Vision gain 1 (376) 65~ 20/50 BCVA change change BCVA 2 (1793) 55) ~ 54to (53 Vision loss Vision loss 2 (1815) 55) ~ 54to (53 BCVA change change BCVA 8 (3064) 61) ~ 56to (35 Vision loss Vision loss 10 (3302) 61) ~ 60to (35 Vision gain Vision gain 9 (3245) 61) ~ 57to (35 Vision gain Vision gain 2 (1815) 55) ~ 54to (53 Vision gain Vision gain 1 (358) 50~ 20/100 65% Vision gain Vision gain 1 (386) 65~ 20/50 Vision gain Vision gain 1 (32) 30~ 20/250 62% Vision gain Vision gain 1 (74) 56~ 20/80 59% Outcome
vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. vs. omparator Aflibercept Aflibercept Aflibercept Aflibercept Aflibercept Aflibercept Aflibercept Aflibercept Ranibizumab Ranibizumab Ranibizumab Ranibizumab Ranibizumab Ranibizumab Ranibizumab Ranibizumab Ranibizumab Ranibizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Treatment vs. C DME m CNV m CNV cn AMD cn AMD RVO ME RVO ME RESULTS EFFECTIVENESS TABLE COMPARATIVE 2. Condition 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 31 of 88 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 32 of 88 0% 0% -1.3 (-6.5, -4.0) -1.3 (-6.5, -4.0) http://bmjopen.bmj.com/ 31 31 BMJ Open on September 24, 2021 by guest. Protected copyright.
For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BCVA change BCVA 2 (80) 20/160 42 55) ~ (30, 15.9) to 12.2 (8.5 17.3) to 13.4 (9.5 BCVA, best corrected visual acuity; CI, confidence interval; cn AMD, choroidal neovascular age related macular degeneration; degeneration; macular age related neovascular choroidal cn AMD, interval; confidence CI, acuity; visual best corrected BCVA, vs. vs.
Ranibizumab Ranibizumab <75 was interpreted as low evidence of substantial variation across included RCTs. RCTs. included across variation of substantial evidence low as interpreted was <75 2 Mean (range) were derived across control groups of the included RCTs. RCTs. included the of groups control across derived were (range) Mean In terms of outcomes, vision gain was defined as a gain in BCVA of ≥15 EDTRS letters, vision loss of ≥15 EDTRS letters, and visual acuity was was acuity visual and letters, EDTRS ≥15 of loss vision letters, EDTRS ≥15 of BCVA in asgain a defined was gain vision of outcomes, terms In I expressed using ETDRS letters (with conversion, if necessary). The main analysis was conducted with outcomes at the longest follow up duration duration follow up longest at the outcomes with conducted was analysis The main ifnecessary). conversion, (with letters ETDRS using expressed RCT. for each Footnotes: a c
Abbreviations: DME, diabetic macular edema; ETDRS, early treatment diabetic retinopathy study; m CNV, myopic choroidal neovascularization; NA, not not NA, neovascularization; choroidal myopic m CNV, study; retinopathy diabetic treatment early ETDRS, edema; macular diabetic DME, occlusion. vein retinal to due edema macular trials; RVO ME, controlled randomized RCT, applicable; b 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
a
7.1)
b
b
c c 10 10 5.1 6.5 5.6 6.0 6.9 11.4 7.7 6.9 8.7 8.7 8.5 8.5 5.7 (4.4 5.7 (4.6 7.9) 6.3 8.9 8.9 8.0 8.0 11.5 (11.0 11.9) 11.5 11.3 (10.9 11.7) 11.3 Mean monthly Mean monthly per injections (range) year
1 1 1 1 1 2 2 1 1 1 1 6 5 1 1 3 5 # of# RCT s
http://bmjopen.bmj.com/ 32 32 BMJ Open
needed treatment (every month) with ranibizumab with month) treatmentneeded (every on September 24, 2021 by guest. Protected copyright.
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only
As needed treatment till stable visual acuity (up to 6 months) + as needed treatment treatment as needed to + (up months) 6 acuity till visual stable treatment As needed 1 As needed treatment till stable visual acuity (up to 6 months) + as needed treatment treatment as needed to + (up months) 6 acuity till visual stable treatment As needed month) ranibizumabwith (every 3 initial monthly treatments + as needed treatment (every month for 3 months) 3 + for month treatment(every treatments as needed + initial3 monthly bevacizumab with month) (every treatment as needed 3 initial monthly treatments + as needed treatment (every month for 3 months) 3 + for month treatment(every treatments as needed + initial3 monthly ranibizumab with month) (every treatment as needed 3 initial monthly treatments + as needed treatment (every month) with aflibercept with month) treatment(every treatments as needed + initial3 monthly 3 initial monthly treatments + as needed treatment (every month) with ranibizumab with month) treatment(every treatments as needed + initial3 monthly 3 initial monthly treatment and as needed treatment (every 2 months) with with months) 2 treatment (every treatment as needed and initial3 monthly aflibercept Monthly treatment with aflibercept with treatment Monthly As needed monthly treatment with bevacizumab treatmentbevacizumab with monthly As needed As needed monthly treatment with ranibizumab treatment ranibizumab with monthly As needed 3 initial monthly treatments and as needed treatment (every 3 months) with with months) 3 (every treatment treatments as needed and initial3 monthly 3 initial monthly treatments and as needed treatment (every 3 months) with with months) 3 (every treatment treatments as needed and initial3 monthly ranibizumab 3 initial monthly treatments as + initial3 monthly with month) treatment(every treatments as needed + initial3 monthly Treat and and bevacizumab with extend Treat Treat and and ranibizumab with extend Treat Monthly treatment with with bevacizumab treatment Monthly Monthly treatment with ranibizumab with treatment Monthly Treatment regimen Treatment bevacizumab bevacizumab
DME
cn AMD TABLE 3. SUMMARY OF TREATMENT REGIMENS REGIMENS TREATMENT OF TABLE SUMMARY 3. Condition 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 33 of 88 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 34 of 88
c 3.1 (1.9 4.3) 3.1 2.4 (1.7 3.1) 2.4 11.5 11.6 6.0 6.4 9
2 2 1 1 1 1 1
http://bmjopen.bmj.com/ 33 33 BMJ Open
on September 24, 2021 by guest. Protected copyright.
For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml cn AMD, choroidal neovascular age related macular degeneration; DME, diabetic macular edema; m CNV, myopic choroidal choroidal myopic m CNV, edema; macular diabetic DME, degeneration; macular age related neovascular choroidal cn AMD, 1 initial monthly treatment + as needed treatment (every month) month) bevacizumab with treatment (every treatment as needed + initial1 monthly 1 initial monthly treatment + as needed treatment (every month) month) ranibizumabwith treatment (every treatment as needed + initial1 monthly Monthly treatment with with bevacizumab treatment Monthly Monthly treatment with aflibercept with treatment Monthly 1 initial monthly treatment + as needed treatment (every month) month) bevacizumab with treatment (every treatment as needed + initial1 monthly 1 initial monthly treatment + as needed treatment (every month) month) ranibizumabwith treatment (every treatment as needed + initial1 monthly As needed treatment till stable visual acuity (up to 6 months) + as needed treatment treatment as needed to + (up months) 6 acuity till visual stable treatment As needed month) aflibercept with (every (every month) month) bevacizumab with (every
Value was reported once for both trials in Heier et al. 2012. al. et in Heier trials both for once reported was Value Mean and ranges were derived from trial specific means. Cases, in which a single RCT reported on a regimen, do not have an associated range. range. associated an have not do regimen, a on reported RCT a single which in Cases, means. trial specific from derived were ranges and Mean 2015) et al. (Wells values median Reported neovascularization; RCT, randomized controlled trial; RVO ME, macular edema due to retinal vein occlusion. vein retinal to due edema macular RVO ME, trial; controlled randomized RCT, neovascularization; c Footnotes: a b
m CNV
RVO ME Abbreviations:
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
c 2 I Mean Mean 0.73 (0.55, 0.95) 0.95) 0.73 (0.55, 0% Risk Ratio orRisk Estimate (95% CI) Estimate Difference Difference
b 32.8) 32.8) Monthly Regimen Regimen Monthly Mean (Range)
b http://bmjopen.bmj.com/ 34 34 BMJ Open 4.6% (2.6 to 6.6) 6.6) to4.6% (2.6 3.3) to 2.3% (1.4 3.45) 2.00 (1.15, 12% As needed regimen As needed Mean (Range) on September 24, 2021 by guest. Protected copyright. and Snellen b Baseline ETDRS ETDRS Baseline letters equivalent For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml , a For peer review only RCTs 2/1622 2/1622 20/63 63) ~ 62to (61 6.4) 4.9(3.5, 8.3) 6.9(5.5, 1.9 ( 0.5, 3.3) 0% # of patients patients
Mortality Mortality 2/1795 NA BCVA BCVA change Vision gain Vision gain 2/1622 20/63 63) ~ 62to (61 26.4) to 20.8% (15.1 to 28.9% (25.1 CI, confidence interval; ETDRS, early treatment diabetic retinopathy study; NA, not applicable; RCT, randomized controlled controlled randomized RCT, not applicable; NA, study; retinopathy diabetic treatment early ETDRS, interval; confidence CI,
<75 was interpreted as low evidence of substantial variation across included RCTs. For each treatment regimen, patients were randomized tobe randomized were patients regimen, treatment each For RCTs. included across variation of substantial evidence low as interpreted was <75 2 Mean (range) were derived across control groups of the included RCTs. RCTs. included the of groups control across derived were (range) Mean CATT and IVAN trials.(Martin, 2011; Chakravarthy 2013) 2013) Chakravarthy 2011; trials.(Martin, IVAN and CATT I As Needed Rx Rx As Needed vs. Monthly Rx Rx Monthly vs. treated with bevacizumab or ranibizumab. or ranibizumab. bevacizumab with treated Abbreviations: trials; Rx, treatment. trials; Rx,
Footnotes: a b c TABLE 4. COMPARISON OF MONTHLY VERSUS AS NEEDED ANTI-VEGF TREATMENT REGIMENS IN CN-AMD CN-AMD IN TREATMENT REGIMENS VERSUS ANTI-VEGF NEEDED AS MONTHLY OF TABLE COMPARISON 4. PATIENTS Comparison Outcome # of Page 35 of 88 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 36BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 4 1 ADDITIONAL FILES 5 6 7 8 2 Additional File 1: PRISMA Checklist 9 10 3 Additional File 2: Supplementary Online Content 11 12 4 Appendix 1: Detailed methods 13 14 5 Appendix 2: Detailed study characteristics 15 16 For peer review only 17 6 Appendix 3: Detailed patient characteristics 18 19 7 Appendix 4: Cochrane risk of bias results for individual studies 20 21 8 Appendix 5: Risk of bias results 22 23 24 9 Appendix 6: Treatment effect estimates 25 26 10 Appendix 7: Forest plots for primary outcome in choroidal neovascular age related macular 27 28 11 degeneration (cn AMD) population 29
30 http://bmjopen.bmj.com/ 31 12 Appendix 8: Summary data used in risk of bias results 32 33 13 Appendix 9: Sensitivity analysis estimates 34 35 14 Appendix 10: Summary of anti VEGF treatment protocols 36 37 15 Appendix 11: Summary of results from the DRCR.net trial (Wells 2015a and Wells 2016b)
38 on September 24, 2021 by guest. Protected copyright. 39 40 16 Appendix 12: Mean change in best corrected visual acuity letter scores over time in patients 41 42 17 treated with bevacizumab or ranibizumab 43 44 45 46 47 48 49 50 51 52 53 54 55 35 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 FIGURE 1: STUDY FLOW 3 4
5 Database search and Grey literature 6 previous reviews (n = 3104) (n = 72) 7 8 9 10 11 Identification 12 13
14 Record
15 16 For peer review only 17 18 Citations screened
19 (n = 3176) 20 21 22 Citations excluded 23 (n = 2736) 24 • Not a population of interest n=423 25 • Not an RCT n=1941
26 1 Level screening • Not an intervention of interest n=182 27 • Not a relevant comparator n=190 28 29
30 http://bmjopen.bmj.com/ 31 Full-text assessed 32
for eligibility 33 (n = 440) 34 35 Full-text articles excluded 36 (n = 418) 37 • Not a population of interest n=14
38 on September 24, 2021 by guest. Protected copyright. • Not an RCT n=107 39 • Not an intervention of interest n=112 Level 2 Level screening 40 • Not a relevant comparator n=54 41 • No full text n=119 42 • Not relevant outcome n=8 43 • Duplicate n=4 44
45 46 18 articles* + 4 47 companion reports 48 49 Included 50
51 52 53 *18 articles describing 19 randomized controlled trials 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 Supplementary Online Content 4 5 6 7 8 Appendix 1: Detailed methods ...... 2 9 10 Protocol ...... 2 11 Literature Search Strategy ...... 2 12 13 Keywords ...... 2 14 15 Eligibility Criteria ...... 2 16 Study selection ...... For peer review only 4 17 18 Data abstraction ...... 4 19 Risk of bias assessment ...... 4 20 21 Data Analysis in CADTH report ...... 5 22 23 Data analysis in manuscript ...... 5 24 Excluded RCT’S ...... 5 25 26 Medline Literature Search ...... 5 27 Appendix 2: Detailed study characteristics ...... 13 28 29 Appendix 3: Detailed patient characteristics ...... 16
30 http://bmjopen.bmj.com/ Appendix 4: Cochrane risk of bias results for individual studies ...... 18 31 32 Appendix 5: Risk of bias results ...... 20 33 34 Appendix 6: Treatment effect estimates ...... 21 35 Appendix 7: Forest plots for primary outcome in choroidal neovascular age related macular degeneration (cn- 36 AMD) population ...... 30 37
38 A: Vision gain in cn-AMD population ...... 30 on September 24, 2021 by guest. Protected copyright. 39 40 B: Sensitivity analyses for vision gain in cn-AMD population ...... 31 41 Sensitivity Analysis: 1 Year Follow-Up ...... 31 42 43 Sensitivity Analysis: Low Risk of Selection Bias ...... 31 44 Sensitivity Analysis: De Novo Patients ...... 32 45 46 Appendix 8: Summary data used in risk of bias results ...... 33 47 Appendix 9: Sensitivity analysis estimates ...... 35 48 49 Appendix 10: Summary of anti-VEGF treatment protocols ...... 37
50 a b 51 Appendix 11: Summary of results from the DRCR.net trial (Wells 2015 and Wells 2016 ) ...... 43 52 Appendix 12: Mean change in best-corrected visual acuity letter scores over time in patients treated with 53 bevacizumab or ranibizumab ...... 46 54 55 References ...... 47 56 57 58 1 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 Appendix 1: Detailed methods 4 5 6 We conducted a systematic review using methods from the Cochrane Handbook for Systematic Reviews and 7 reported the results using the PRISMA statement.1 The SR was commissioned by CADTH and funded by a grant 8 9 from the Canadian Institutes of Health Research Drug Safety and Effectiveness Network. The methods are outlined 2 10 briefly below, as they are outlined in full in the CADTH report. 11 12 Protocol 13 14 We drafted a protocol with input from clinical experts, patient advocacy groups, industry stakeholders and CADTH. 15 We posted the draft on the CADTH website to obtain feedback from additional stakeholders, revised the protocol as 16 necessary, and registeredFor the final versionpeer with PROSPERO review (CRD 42015022041). only 17 18 Literature Search Strategy 19 20 The following bibliographic databases were searched from inception until August 17th 2017, 2015: MEDLINE 21 (1946 ) with in process records & daily updates via Ovid; Embase (1974 ) via Ovid; Cochrane Central Register of 22 Controlled Trials via Ovid, and PubMed. Grey literature (i.e., studies that are not widely available or commercially 23 published) was identified by searching relevant websites according to the “Clinical Trials” section of the CADTH 24 Grey Matters checklist.3 We used Google and other Internet search engines to search for additional web based 25 materials, including conference abstracts. We obtained additional studies by reviewing the references of all included 26 27 studies and feedback from clinical experts, patient advocacy groups, and industry stakeholders. In addition, we 28 contacted the three manufacturers of the anti VEGF drugs to identify further potentially relevant trials. 29 An experienced information specialist developed the literature search strategy. It was peer reviewed by another 30 information specialist using the PRESS statement.4 The final search strategy can be found in Appendix A and the http://bmjopen.bmj.com/ 31 others are available upon request of the corresponding author. 32 33 The literature search consisted of both controlled vocabulary, such as the National Library of Medicine’s MeSH 34 (Medical Subject Headings), and keywords (see below). The main search concepts were anti VEGF drugs and the 35 relevant retinal conditions. Validated methodological filters were applied to limit retrieval to RCTs.5 Where 36 possible, retrieval was limited to humans. Retrieval was not limited by publication year or by language, but non 37 English language articles were excluded during screening, to increase feasibility of the study.
38 on September 24, 2021 by guest. Protected copyright. 39 Keywords 40 41 (intravitreal OR intra vitreal or implant or implanted or implants or inject or injected or injects or injection or 42 injections or Anti VEGF or antiVEGF or VEGF inhibitor or VEGF antagonist or visudyne or verteporfin or PDT or 43 44 PDTV or VPDT) 45 AND 46 47 (retinal degeneration OR wet macular degeneration OR wAMD OR neovascular macular degeneration OR exudative 48 macular degeneration or diabetic retinopathy or DRE or Macular Edema or Retinal Vein Occlusion or Choroidal 49 Neovascularization or BRVO or CRVO) 50 51 Eligibility Criteria 52 53 The inclusion criteria were specified as follows according to the Population, Intervention, Comparator, Outcome, 54 Study design and Time framework (Cochrane Handbook).5 55 56 57 58 2 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 • Populations: patients ≥ 18 years of age and with retinal conditions including wet AMD, DME, ME/RVO 4 and myopic CNV. 5 6 • Interventions: anti VEGF drugs in use in Canada, namely ranibizumab, intravitreal bevacizumab and 7 aflibercept 8 Comparators: placebo, ranibizumab, intravitreal bevacizumab or aflibercept 9 • 10 • Outcomes: 14 outcomes were selected a-priori at the protocol stage according to feedback from the 11 research team, clinical experts, patient advocacy groups, industry stakeholders and CADTH, including five 12 efficacy outcomes and nine safety outcomes (outlined below). 13 14 • Study design: parallel and cluster RCTs. 15 • Time: RCTs published at any time; all reports pertaining to an RCT were located to obtain data at the 16 For peer review only 17 longest follow up duration. 18 We excluded studies reporting only results for pediatric patients (<18 years of age), studies evaluating the anti 19 VEGF drug pegaptanib, as it is no longer licensed for use in Canada, studies that compared an anti VEGF drug with 20 other comparators (such as intravitreal corticosteroids, grid laser photocoagulation or cataract removal surgery), and 21 studies reported in languages other than English. Studies fulfilling the last two exclusion criteria were excluded to 22 allow for the project timelines to be met, as outlined in the Limitations and Research Implications sections below. 23 24 We included the following efficacy outcomes: 25 26 1. Vision gain, defined as a gain in Best Corrected Visual Acuity (BCVA) of ≥15 letters on the Early 27 Treatment Diabetic Retinopathy Study (ETDRS) chart, 28 2. Vision loss, defined as a loss in BCVA of ≥15 ETDRS letters, 29 3. Change from baseline in BCVA letters, 30 http://bmjopen.bmj.com/ 31 4. Legal blindness, 32 33 5. Vision related function. 34 We included the following safety outcomes: 35 36 1. All cause mortality, 37 2. Arterial venous thromboembolism (VT),
38 on September 24, 2021 by guest. Protected copyright. 39 3. Venous VT, 40 4. Bacterial endophthalmitis (BE), 41 42 5. Increased intraocular pressure, 43 6. Retinal detachment, 44 45 7. Adverse events (AEs) 46 8. Serious AEs, 47 48 9. Withdrawals due to AEs 49 We considered BCVA data derived from Snellen or ETDRS letter charts or the logarithm of the Minimum Angle of 50 Resolution (logMAR) chart for assessing efficacy outcomes 1 3.6 The Snellen chart is the current standard for 51 6 8 52 measurement of visual acuity in clinical practice. The ETDRS chart is the ‘gold standard’ for measuring visual 6 53 acuity in clinical trials. The Snellen chart has letters of different sizes arranged from largest at the top to smallest at 54 the bottom, which are read, one eye at a time, at a distance of 6 metres (20 feet). The test retest variability of the 55 Snellen chart ranges from ±5 to 16.5 letters in normal patients.9 10 The test retest variability of the ETDRS charts 56 ranges from ±3.5 to 10 letters.11 A change of at least 10 letters (or two lines) is required to capture a true clinical 57 58 3 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 41 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 change in visual acuity.6 12 With respect to vision related function, we abstracted data from the 25 item National 4 Eye Institute Visual Function Questionnaire (NEI VFQ 25), which is a self reported survey questionnaire that 5 assesses the influence of visual impairment on health related quality of life.13 Changes in the NEI VFQ overall 6 scores of 10 points or more are associated with clinically relevant changes in vision.14 7 8 Study selection 9 10 Citations from the literature search were imported into an online systematic review software.15 Also imported were 11 12 the inclusion criteria, which were used for level 1 screening of citations (titles/abstracts) and level 2 screening of 13 potentially relevant full text articles. The 14 members of the review team underwent two training exercises; each 14 involved a random sample of 50 citations, which were screened independently by all team members. Level 1 15 screening proceeded after 80% agreement had been achieved among the reviewers on the second training exercise.16 16 17 Paired reviewers conductedFor the level 1peer screening review of each citation, independently. only The estimated frequency of 17 disagreement was 8%, which was resolved by a third reviewer. We retrieved the full text articles of potentially 18 relevant citations identified by at least one reviewer for level 2 screening. The team underwent a training exercise 19 using a random sample of 20 full text articles, which resulted in 70% agreement. Paired reviewers independently 20 screened each full text article. The estimated frequency of disagreement was 14%, which was resolved by a third 21 reviewer. This reviewer also verified all eligible studies. 22 23 Data abstraction 24 25 We developed a data abstraction form with inputs from two physicians. We piloted and refined the form two times, 26 27 each time using five randomly selected studies. Subsequently, paired reviewers conducted the abstraction, 18 28 independently. Numerical data available only in figures were extracted using WebPlotDigitizer. A third reviewer 29 conducted a quality check on all data, and resolved any remaining discrepancies.
30 We abstracted data pertaining to study characteristics, patient populations, interventions, and outcomes. Multiple http://bmjopen.bmj.com/ 31 reports of the same trial (hereafter companion reports) were identified using the trial registration identifier, trial 32 19 33 name, or a juxtaposition of the author names, treatment comparisons, sample sizes and outcomes, if necessary. We 34 abstracted data from all companion reports, identified differences, and reconciled the differences through discussion. 35 For each set of companion reports, we considered one as the major publication and others as companion reports. We 36 abstracted outcome data from all trial reports and used the data corresponding to the longest duration of follow up in 37 the meta analysis.5
38 on September 24, 2021 by guest. Protected copyright. 39 Risk of bias assessment 40 41 The risk of bias in the included trials was appraised using the Cochrane risk of bias tool, including selection bias, 42 performance bias, detection bias, attrition bias, reporting bias, and other biases such as funding sources.20 For 43 selection bias, we assessed the reporting of random sequence generation and allocation concealment. For 44 performance bias, we assessed the reporting of blinding of patients and trial personnel, and for detection bias, the 45 reporting of the blinding of outcome assessors. In the assessment of performance and detection biases, we 46 considered the objectivity of the primary outcome of individual trials in assessing performance and detection biases. 47 48 For RCTs that had been registered, the primary outcome was identified from the trial protocol, which was vision 49 gain or change in mean BCVA in the majority of the included RCTs. Otherwise, we identified the primary outcome 50 using an a-priori defined algorithm.21 22 In brief, we selected from the trial report the outcome that was listed in the 51 title or objectives, the most serious clinical outcome among all the trial outcomes, or the first reported outcome in 52 the results section. 53 54 Paired reviewers conducted the risk of bias assessment, independently. Discrepancies were resolved by discussion or 55 the involvement of a third reviewer. 56 57 58 4 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 42BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 Data Analysis in CADTH report 4 5 We derived treatment effect estimates using the odds ratio (OR) for binary outcomes such as vision gain, vision loss 6 or the presence or absence of a harmful event. The standardized mean difference (SMD) was used for treatment 7 comparisons involving BCVA data from different visual acuity charts, such as ETDRS or Snellen charts. The SMD 8 expresses the difference in the treatment means in terms of the standard deviations of the measurements. The mean 9 10 difference (MD) was used for comparison involving BCVA data that were consistently reported using the same 11 measurement scale, either the ETDRS or Snellen chart. This was also the case for vision related function 12 measurements from the NEI VFQ questionnaire. 13 The results from multiple arms of the same anti VEGF drugs at different dosages were combined according to the 14 guidance in the Cochrane handbook.5 When an RCT did not provide standard deviations for a continuous outcome 15 23 16 measure, missing data wereFor imputed peer from available review data from other RCTs only using established methods. This was 17 necessary in meta analyses involving BCVA measures and vision related functions. 18 We conducted meta analyses of pairwise comparisons of all comparators, including the anti VEGF drugs and 19 placebo. This was done separately for each of the four retinal conditions. The variation across RCTs in any outcome 20 2 2 5 measures was assessed using the I statistic, with values of I >75% indicating substantial statistical heterogeneity. 21 Pooled treatment effect estimates and 95% confidence intervals (CIs) were derived using the meta analytical random 22 23 24 23 effects model. The meta analyses were conducted using the "metafor” package in R (version 3.1.1). 24 Data analysis in manuscript 25 26 27 Study results were synthesized with respect to benefits and harms, trends in BCVA improvement over time, and 28 treatment regimens (e.g., monthly and as needed regimens). To facilitate the synthesis of results, BCVA values 25 29 reported in logMAR and decimal measures were converted to approximate ETDRS letter scores, with approximate 26
30 standard deviations. Pairwise comparisons of drugs were assessed at the longest treatment duration, allowing for http://bmjopen.bmj.com/ 31 the inclusion of trials in the meta analysis that reported outcome data at different time points. Subgroup analyses 32 were conducted at 12 months and 24 months, as these were the most frequently reported time points. For DME 33 patients, treatment effect estimates were obtained for all patients as well as pre specified subgroups based upon 34 baseline BCVA, as reported in the DCRC.net trial.27 The meta analysis was conducted using a random effects 35 model, given the assumption of varying treatment effects across trials. A sensitivity analysis was conducted by 36 37 restricting to trials determined to be at low risk of selection bias. Between study heterogeneity was assessed using the I² statistic, with values above 75% indicating substantial heterogeneity.5 38 on September 24, 2021 by guest. Protected copyright. 39 40 41 Excluded RCT’S 42 43 The RCT by Rajagopal et al. 201528 (n=98 participants) was excluded because the investigators reported in the 44 results section that an additional nine patients were included in the study but were not randomized to treatment due 45 to financial hardship and were instead assigned to the bevacizumab group. The study by Pece et al. 201429 was 46 excluded because the investigators randomized 78 eyes from 80 patients with myopic CNV to treatment with 47 48 bevacizumab or ranibizumab, and reported eye based analyses. For this review we were only interested in patient 49 based analyses. 50 51 Medline Literature Search 52 53 Interface: Ovid 54 Databases: 55 56 Embase <1974 to 2015 May 26> 57 58 5 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 43 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 MEDLINE Daily and MEDLINE 1946 to present 4 5 MEDLINE In Process & Other Non Indexed Citations 6 Cochrane Central Register of Controlled Trials
38 on September 24, 2021 by guest. Protected copyright. 39 11 Macular Edema/ 40 12 ((macula* or retina*) adj3 (edema$1 or oedema$1)).tw,kw. 41 42 13 (Irvine Gass adj3 (edema$1 or oedema$1 or syndrome$1)).tw,kw. 43 14 (cystoid macula* adj dystroph*).tw,kw. 44 45 15 Retinal Vein Occlusion/ 46 16 (retinal vein adj3 (occlu* or obstruct* or clos* or stricture* or steno* or block* or embolism*)).tw,kw. 47 48 17 (BRVO or CRVO).tw,kw. 49 18 Choroidal Neovascularization/ 50 51 19 ((choroid* or subretinal or sub retinal) adj1 neovasculari#ation*).tw,kw. 52 20 CNV.tw,kw. 53 54 21 or/2 20 [CONDITIONS – MEDLINE] 55 22 Vascular Endothelial Growth Factor A/ai 56 57 58 6 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 44BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 23 (anti adj2 VEGF$1).tw,kw. 4 5 24 antiVEGF$1.tw,kw. 6 25 (antivascular endothelial growth factor$1 or anti vascular endothelial growth factor$1).tw,kw. 7 8 26 Antibodies, Monoclonal, Humanized/ 9 27 (monoclonal antibod* and humani#ed).tw,kw. 10 11 28 (antibod* adj2 humani#ed).tw,kw. 12 29 Angiogenesis Inhibitors/ 13 14 30 (angiogen* adj3 (inhibitor* or antagonist*)).tw,kw. 15 31 (anti angiogen* or antiangiogen*).tw,kw. 16 For peer review only 17 32 aflibercept.tw,kw. 18 33 ("AVE 0005" or AVE0005 or "AVE 005" or AVE005 or "Bay 86 5321" or "Bay86 5321" or Eylea or "UNII 19 15C2VL427D" or Zaltrap or ZIV aflibercept).tw,kw. 20 21 34 ((vasculotropin or vascular endothelial growth factor or VEGF) adj trap*).tw,kw. 22 35 aflibercept.rn. 23 24 36 Bevacizumab.tw,kw. 25 37 (Altuzan or Avastin or "nsc 704865" or nsc704865 or "rhuMAb VEGF" or "UNII 2S9ZZM9Q9V").tw,kw. 26 27 38 IVB injection$1.tw,kw. 28 39 Bevacizumab.rn. 29
30 40 Pegaptanib.tw,kw. http://bmjopen.bmj.com/ 31 32 41 ("EYE 001" or EYE001 or Macugen or "NX 1838" or NX1838 or "UNII 3HP012Q0FH").tw,kw. 33 42 Pegaptanib.rn. 34 35 43 Ranibizumab.tw,kw. 36 44 (Lucentis or "rhuFab V2" or "UNII ZL1R02VT79").tw,kw. 37 45 IVR injection$1.tw,kw. 38 on September 24, 2021 by guest. Protected copyright. 39 46 Ranibizumab.rn. 40 41 47 or/22 46 [ANTI VEGF AGENTS – MEDLINE] 42 48 21 and 47 [ANTI VEGF AGENTS & CONDITIONS – MEDLINE] 43 44 49 exp Photochemotherapy/ 45 50 Photosensitizing Agents/ 46 47 51 (photochemo* or photo chemo* or photodynamic* or photo dynamic* or photosensiti* or photo 48 sensiti*).tw,kw. 49 52 PDT.tw,kw. 50 51 53 or/49 52 52 54 verteporfin.tw,kw. 53 54 55 (verteporphin or "BPD MA" or "CL 318,952" or "CL 318952" or "UNII 0X9PA28K43" or Visudyne).tw,kw. 55 56 verteporfin.rn. 56 57 58 7 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 45 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 57 or/54 56 4 5 58 53 and 57 6 59 (PDTV or "PDT V" or VPDT or "V PDT").tw,kw. 7 8 60 58 or 59 [VISUDYNE PDT – MEDLINE] 9 61 21 and 60 [VISUDYNE PDT & CONDITIONS – MEDLINE] 10 11 62 Triamcinolone Acetonide/ 12 63 ((Triamcinol* adj acet*) or Aristocort or Aristospan or Asmacort or Azmacort or "BRN 0060069" or "CCRIS 13 5231" or Cinonide or Clinacort or "EINECS 200 948 7" or Kenacort or Kenalog* or Kenlog or "NSC 21916" or 14 Triamcot or Triam Forte or Triam Injekt or Triamonide or Tricort* or Triesense or Tristoject or "UNII 15 F446C597KA" or Volon).tw,kw. 16 For peer review only 17 64 triamcinolone acetonide.rn. 18 19 65 Glucocorticoids/ 20 66 (glucocorticoid* or glucorticoid*).tw,kw. 21 22 67 (anecortave or "AL 3789" or "AL 3789" or "EINECS 231 812 5" or "NSC 15475" or "NSC 24345" or Retaane 23 or "UNII Y0PC411K4T").tw,kw. 24 68 anecortave acetate.rn. 25 26 69 Pregnadienediols/ 27 70 (dihydroxypregnadiene* or di hydroxypregnadiene* or pregnadienediol*).tw,kw. 28 29 71 exp Dexamethasone/
30 72 (Dexamethasone or Decaject* or Decameth or Dexasone or Dexpak or Hexadecadrol or Hexadrol or Maxidex http://bmjopen.bmj.com/ 31 or Millicorten or Oradexon or Ozurdex).tw,kw. 32 33 73 dexamethasone.rn. 34 74 (intravitreal adj3 (corticoid* or corticosteroid* or steroid*)).tw,kw. 35 36 75 or/62 74 37 76 exp Injections/
38 on September 24, 2021 by guest. Protected copyright. 39 77 (depot or implant* or infus* or inject* or intravitreal* or intra vitreal* or microsphere* or micro sphere* or 40 suspension*).tw,kw. 41 42 78 or/76 77 43 79 75 and 78 [CORTICOSTEROID/INTRAVITREAL INJECTIONS MEDLINE] 44 45 80 21 and 79 (3513) [CORTICOSTEROID/INTRAVITREAL INJECTIONS & CONDITIONS MEDLINE 46 81 (controlled clinical trial or randomized controlled trial).pt. 47 48 82 clinical trials as topic.sh. 49 83 (randomi#ed or randomly or RCT$1 or placebo*).tw. 50 51 84 ((singl* or doubl* or trebl* or tripl*) adj (mask* or blind* or dumm*)).tw. 52 85 trial.ti. 53 54 86 or/81 85 55 87 (48 or 61 or 80) and 86 56 57 58 8 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 46BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 88 exp Animals/ not (exp Animals/ and Humans/) 4 5 89 87 not 88 6 90 (comment or editorial or interview or news).pt. 7 8 91 (letter not (letter and randomized controlled trial)).pt. 9 92 89 not (90 or 91) 10 11 93 92 use prmz [MEDLINE RCTS] 12 94 macular degeneration/ 13 14 95 age related macular degeneration/ 15 96 wet macular degeneration/ 16 For peer review only 17 97 ((exudative or neovascular or wet) adj3 ((macula* adj2 degeneration) or (macula* adj2 deterioration) or 18 maculopath* or (macula* adj2 dystroph*))).tw,kw. 19 98 ((exudative or neovascular or wet) adj2 (AMD or ARMD)).tw,kw. 20 21 99 (wAMD or wARMD).tw,kw. 22 100 diabetic retinopathy/ 23 24 101 ((diabet* or DM) adj3 retinopath*).tw,kw. 25 102 diabetic macular edema/ 26 27 103 (PDR or DME or DMO).tw,kw. 28 104 exp macular edema/ 29
30 105 ((macula* or retina*) adj3 (edema$1 or oedema$1)).tw,kw. http://bmjopen.bmj.com/ 31 32 106 (Irvine Gass adj3 (edema$1 or oedema$1 or syndrome$1)).tw,kw. 33 107 (cystoid macula* adj dystroph*).tw,kw. 34 35 108 exp retina vein occlusion/ 36 109 (retinal vein adj3 (occlu* or obstruct* or clos* or stricture* or steno* or block* or embolism*)).tw,kw. 37 110 (BRVO or CRVO).tw,kw. 38 on September 24, 2021 by guest. Protected copyright. 39 111 subretinal neovascularization/ 40 41 112 ((choroid* or subretinal or sub retinal) adj1 neovasculari#ation*).tw,kw. 42 113 CNV.tw,kw. 43 44 114 or/94 113 [CONDITIONS – EMBASE] 45 115 vasculotropin inhibitor/ 46 47 116 (anti adj2 VEGF$1).tw,kw. 48 117 antiVEGF$1.tw,kw. 49 50 118 (antivascular endothelial growth factor$1 or anti vascular endothelial growth factor$1).tw,kw. 51 119 monoclonal antibody/ 52 53 120 (monoclonal antibod* and humani#ed).tw,kw. 54 121 (antibod* adj2 humani#ed).tw,kw. 55 56 122 angiogenesis inhibitor/ 57 58 9 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 47 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 123 (angiogen* adj3 (inhibitor* or antagonist*)).tw,kw. 4 5 124 (anti angiogen* or antiangiogen*).tw,kw. 6 125 aflibercept/ 7 8 126 (aflibercept or "AVE 0005" or AVE0005 or "AVE 005" or AVE005 or "Bay 86 5321" or "Bay86 5321" or 9 Eylea or "UNII 15C2VL427D" or Zaltrap or ZIV aflibercept).tw,kw. 10 127 ((vasculotropin or vascular endothelial growth factor or VEGF) adj trap*).tw,kw. 11 12 128 aflibercept.rn. 13 129 bevacizumab/ 14 15 130 (bevacizumab or Altuzan or Avastin or "nsc 704865" or nsc704865 or "rhuMAb VEGF" or "UNII 16 2S9ZZM9Q9V").tw,kw.For peer review only 17 131 IVB injection$1.tw,kw. 18 19 132 Bevacizumab.rn. 20 133 pegaptanib/ 21 22 134 (Pegaptanib or "EYE 001" or EYE001 or Macugen or "NX 1838" or NX1838 or "UNII 23 3HP012Q0FH").tw,kw. 24 25 135 Pegaptanib.rn. 26 136 ranibizumab/ 27 28 137 (Ranibizumab or Lucentis or "rhuFab V2" or "UNII ZL1R02VT79").tw,kw. 29 138 IVR injection$1.tw,kw.
30 http://bmjopen.bmj.com/ 31 139 Ranibizumab.rn. 32 140 or/115 139 [ANTI VEGF AGENTS – EMBASE] 33 34 141 114 and 140 [ANTI VEGF AGENTS & CONDITIONS – EMBASE] 35 142 photodynamic therapy/ 36 37 143 photosensitizing agent/
38 144 (photochemo* or photo chemo* or photodynamic* or photo dynamic* or photosensiti* or photo on September 24, 2021 by guest. Protected copyright. 39 sensiti*).tw,kw. 40 41 145 PDT.tw,kw. 42 146 or/142 145 43 44 147 verteporfin/ 45 148 (verteporphin or "BPD MA" or "CL 318,952" or "CL 318952" or "UNII 0X9PA28K43" or Visudyne).tw,kw. 46 47 149 verteporfin.rn. 48 150 or/147 149 49 50 151 146 and 150 51 52 152 (PDTV or "PDT V" or VPDT or "V PDT").tw,kw. 53 153 151 or 152 [VISUDYNE PDT – EMBASE] 54 55 154 114 and 153 [VISUDYNE PDT & CONDITIONS – EMBASE] 56 155 triamcinolone/ 57 58 10 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 48BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 156 triamcinolone acetonide/ 4 5 157 ((Triamcinol* adj acet*) or Aristocort or Aristospan or Asmacort or Azmacort or "BRN 0060069" or "CCRIS 6 5231" or Cinonide or Clinacort or "EINECS 200 948 7" or Kenacort or Kenalog* or Kenlog or "NSC 21916" or 7 Triamcot or Triam Forte or Triam Injekt or Triamonide or Tricort* or Triesense or Tristoject or "UNII 8 F446C597KA" or Volon).tw,kw. 9 158 triamcinolone.rn. 10 11 159 triamcinolone acetonide.rn. 12 160 exp glucocorticoid/ 13 14 161 (glucocorticoid* or glucorticoid*).tw,kw. 15 162 anecortave/ 16 For peer review only 17 163 (anecortave or "AL 3789" or "AL 3789" or "EINECS 231 812 5" or "NSC 15475" or "NSC 24345" or 18 Retaane or "UNII Y0PC411K4T").tw,kw. 19 20 164 anecortave.rn. 21 165 pregnane derivative/ 22 23 166 (dihydroxypregnadiene* or di hydroxypregnadiene* or pregnadienediol*).tw,kw. 24 167 dexamethasone/ 25 26 168 dexamethasone isonicotinate/ 27 169 (Dexamethasone or Decaject* or Decameth or Dexasone or Dexpak or Hexadecadrol or Hexadrol or Maxidex 28 or Millicorten or Oradexon or Ozurdex).tw,kw. 29
30 170 dexamethasone.rn. http://bmjopen.bmj.com/ 31 171 dexamethasone isonicotinate.rn. 32 33 172 (intravitreal adj3 (corticoid* or corticosteroid* or steroid*)).tw,kw. 34 173 or/155 172 35 36 174 exp injection/ 37 175 intravitreal drug administration/
38 on September 24, 2021 by guest. Protected copyright. 39 176 vi.fs. [EMBASE FLOATING SUBJECT HEADING FOR INTRAVITREAL DRUG ADMIN] 40 177 (depot or implant* or infus* or inject* or intravitreal* or intra vitreal* or microsphere* or micro sphere* or 41 42 suspension*).tw,kw. 43 178 or/174 177 44 45 179 173 and 178 [CORTICOSTEROID/INTRAVITREAL INJECTIONS EMBASE] 46 180 114 and 179 [CORTICOSTEROID/INTRAVITREAL INJECTIONS & CONDITIONS EMBASE] 47 48 181 randomized controlled trial/ or controlled clinical trial/ 49 182 exp "clinical trial (topic)"/ 50 51 183 (randomi#ed or randomly or RCT$1 or placebo*).tw. 52 184 ((singl* or doubl* or trebl* or tripl*) adj (mask* or blind* or dumm*)).tw. 53 54 185 trial.ti. 55 186 or/181 185 56 57 58 11 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 49 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 187 (141 or 154 or 180) and 186 4 5 188 exp animal experimentation/ or exp models animal/ or exp animal experiment/ or nonhuman/ or exp 6 vertebrate/ 7 189 exp humans/ or exp human experimentation/ or exp human experiment/ 8 9 190 188 not 189 10 191 187 not 190 11 12 192 editorial.pt. 13 193 letter.pt. not (letter.pt. and randomized controlled trial/) 14 15 194 191 not (192 or 193) 16 195 194 use emczd [EMBASEFor RCTS]peer review only 17 18 196 93 or 195 [MEDLINE / EMBASE RCTS] 19 197 remove duplicates from 196 [TOTAL UNIQUE HITS] 20 21 198 197 use prmz [UNIQUE MEDLINE] 22 199 197 use emczd [UNIQUE EMBASE] 23 24 25 *************************** 26 27 28
29
30 http://bmjopen.bmj.com/ 31 32 33 34 35 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 12 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 50 of 88 Study duration (months) mple mple size Overall sa
Multi 321 12 Multi 501 12 Multi 332 12 Multi 1217 12 Multi 1240 12 Setting (multi/si ngle centre) Multi 610 24 Multi 441 12 Single 55 12 2008 2008 2011 2009 2009 2012 Jan 2009 2009 Jan Dec2011 Sep Sep 2010 Sep 2010Sep Study period Mar 27, Mar 2008 Oct 2010 15, Mar 2009 Mar 2012 Jul 2008 2008 2011 Aug 2007 Aug Apr 2008 2008 Apr
Parallel Parallel RCT Parallel Parallel RCT Parallel Parallel RCT Parallel Parallel RCT Parallel Parallel RCT Study design Parallel Parallel RCT Parallel Parallel RCT Parallel Parallel RCT 12)
= 13 http://bmjopen.bmj.com/
BMJ Open US, US, Canada Netherla nds , , Belgium, Brazil, Colombia Czech , Republic, France, Germany , UK Argentina Australia, Austria, Austria AMD (n AMD cn on September 24, 2021 by guest. Protected copyright. Netherlands TrialRegister: NTR1704 Trialidentifier Country ISRCTN921665 60 EK 07 192 1007 EudraCT / Nr. 2007 005157 33 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
Trial name For peer review only ar of ar e 2013 MANTA NCT00710229 Austria 2015 LUCAS NCT01127360 Norway 2012 VIEW 2 NCT00637377 2012 VIEW 1 NCT00509795 2014 NR public ation Y 2016 BRAMD 30 2013 IVAN 33 2013 GEFAL NCT01170767 France
34 32
35 36 36 31 First author First Heier Heier Krebs Kodjikian Chakravarthy Scholler Berg Schauwvlieghe Appendix 2: Detailed study characteristics characteristics study 2: Detailed Appendix
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Study duration (months) mple mple a size Overall s
Multi 1208 12 Single 28 12 Multi 60 18 Setting (multi/si ngle centre) 2008 2008 2010 NR NR Single 42 15 NA Multi 120 18 2007 2007 2009 2007 2007 2009 Study period Parallel Parallel RCT Parallel Parallel RCT Parallel Parallel RCT Parallel Parallel RCT Parallel Parallel RCT Study design
14 http://bmjopen.bmj.com/ BMJ Open Hungary, Hungary, India, Israel, Italy, Japan, Republic ofKorea, Latvia, Mexico, Netherla nds, Poland, Portugal, Singapor e, Slovakia, Spain, Sweden, Switzerla nd, United Kingdom US Egypt India India DME3) (n = on September 24, 2021 by guest. Protected copyright. Trialidentifier Country ISRCTN733598 06 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
Trial name For peer review only 2011 CATT NCT00593450 US 2011b NR NR 2011a NR NR 2017 NR NR 2015 NR NCT01627249 US Parallel 2012 Aug Multi 660 12 public ation Year of Year 2010 NR 40
38 37 41 39 27 Wells Fouda Subramanian Martin Biswas Biswas First author First
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MULTI 362 6 Single 32 6 NR NR 100 12 Single 55 18 Setting (multi/si ngle centre) Single 75 6 Sep 2014 Sep Dec 2016 Feb 2008 Feb Dec 2008 2011 2011 2014 Jul 2007 Jul Study period Jan 2012 2012 Jan 2013 Feb Apr 2006 2006 Apr
Parallel Parallel RCT Parallel Parallel RCT RCT Oct 2014 Parallel Parallel RCT Parallel Parallel RCT Study design Parallel Parallel RCT
15 http://bmjopen.bmj.com/ BMJ Open ME2) (n = Italy India Italy Turkey CNV (n = CNV 2) m RVO on September 24, 2021 by guest. Protected copyright. ISRCTN498032 72 Trialidentifier Country CTRI/2012/01/0 03120 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
Trial name For peer review only 2012 NR NR 2014 NR NR 2017 SCORE2 NCT01969708 US public ation Year of Year cn AMD – choroidal neovascularage related macular degeneration; DME diabetic macular– oedema; m CNV myopic – choroidal 2015 MARVEL 44 2010 NR 46
45 42 43 Gharbiya Iacono Narayanan Scott Ekinci First author First neovascularization;– NR not reported; RCTrandomized – controlled trials; RVO ME macular – edema due toretinal vein occlusion Abbreviations:
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
patients patients Lens status of of status Lens
40 % pse udo pha kic
hypertension hypertension
% of patients with with patients of %
A1C >8.5% >8.5% A1C
% of patients with with patients of %
Mean A1C value value A1C Mean
diabetes diabetes
% of patients with with patients of %
% female female %
var value value var
TX 4 mean age age mean 4 TX
TX 4 mean age age mean 4 TX
var value value var
TX 3 mean age age mean 3 TX TX 3 mean age age mean 3 TX
var value value var TX 2 mean age age mean 2 TX 16 http://bmjopen.bmj.com/
ME2) ( n= TX 2 mean age age mean 2 TX BMJ Open AMD (n = 12) AMD DME3) (n =
RVO cn
var value value var
TX 1 mean age age mean 1 TX TX 1 mean age age mean 1 TX
on September 24, 2021 by guest. Protected copyright.
variance value value variance
Overall mean age age mean Overall
variance type type variance Overall mean age age mean Overall For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
Overall mean age age mean ForOverall peer review only
NR NR NR NR 79.2 7.4 80.1 7.3 78.4 7.8 79.3 7.6 62 NR NR NR NR NR NR NR SD NR 73 9 74.1 8.5 74.7 8.6 73.8 8.6 55.5 NR NR NR NR NR NR NR SD NR 78.2 7.6 77.7 7.9 78.4 8.1 77.9 8.4 58.8 NR NR NR NR NR # of eyes eyes of #
120 8 332 78 SD 7 79 7 78 7 NR NR NR NR 56 NR NR NR NR 120 2 121 0 First author & year year & author First 28 78.6 SD NR 78 NR 80 NR NR NR NR NR 4.6 NR NR NR NR NR NR 77.7 SD 7.4 77.8 7.6 77.7 7.3 NR NR NR NR 60 NR NR NR NR NR 40 33 501 NR NR NR 79.6 6.9 78.7 7.3 NR NR NR NR 66 NR NR NR 57 NR 104 NR NR NR 63.5 NR 64.4 NR NR NR NR NR 52 NR NR NR NR NR 60 60 NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR 55 NR SD NR 79.5 6.8 80.8 6.6 NR NR NR NR 70.9 NR NR NR NR NR 34 38 37 32 70 NR SD NR 55.1 4.7 56.6 5.8 NA NA NA NA NR 100 NR NR NR NR
100 NR NR NR 68 9 65 14 NR NR NR NR 68 100 NR 0 NR NR 317 NR SD NR 76.7 7.8 77.6 8.1 NR NR NR NR 63.7 0 NR NR NR NR 660 61 SD 10 60 10 62 10 60 11 NR NR 47 100 NR NR NR NR NR NR SD NR 78.7 7.6 78 8.2 NR NR NR NR NR NR NR NR NR NR 41 39 42 35 27 31
30
36 36 Appendix 3: Detailed patient characteristics characteristics patient 3: Detailed Appendix Ekinci2014 Wells2015 Fouda Fouda 2017 Subramanian2010 Martin 2011 Martin Biswas 2011b Biswas Biswas 2011a Biswas Heier Heier – 2012 VIEW 2 Heier Heier – 2012 VIEW 1 Krebs 2013 Krebs Kodjikian Kodjikian 2013 Chakravarthy2013 Scholler Scholler 2014 Berg Berg 2015 Schauwvlieghe 2016
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patients patients Lens status of of status Lens
83.1 % cata ract
hypertension hypertension
% of patients with with patients of %
A1C >8.5% >8.5% A1C
% of patients with with patients of %
Mean A1C value value A1C Mean
diabetes diabetes
% of patients with with patients of %
% female female %
var value value var
TX 4 mean age age mean 4 TX
TX 4 mean age age mean 4 TX
var value value var
TX 3 mean age age mean 3 TX TX 3 mean age age mean 3 TX
var value value var TX 2 mean age age mean 2 TX
17 http://bmjopen.bmj.com/ TX 2 mean age age mean 2 TX CNV (n = CNV 2) BMJ Open
m
var value value var
TX 1 mean age age mean 1 TX TX 1 mean age age mean 1 TX
on September 24, 2021 by guest. Protected copyright.
variance value value variance
Overall mean age age mean Overall
variance type type variance Overall mean age age mean Overall For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
Overall mean age age mean Overall For peer review only
# of eyes eyes of # First author & year year & author First 75 NR NR NR 53 NR 50 NR NR NR NR NR 45.3 17 NR NR 50 NR 44 32 NR SD NR 60.6 10.5 59.1 11.4 NR NR NR NR 68.8 NR NR NR NR NR cn AMD – choroidal neovascularage related macular degeneration;DME diabetic macular– oedema; m CNV myopic – choroidal 46 55 NR SD NR 65 12 61 11 NR NR NR NR 76.4 NR NR NR NR NR 362 69 SD 12 69 11 69 13 NA NA NA NA 43.4 31.5 NR NR 76.8 45 43 occlusion;SDstandard – deviation; TX treatment – neovascularization;NAnot applicable;– NR reported;– not RCT randomized – controlled trials; RVO ME – macularedema retinal to due vein Abbreviations: Gharbiya Gharbiya 2010 Iacono Iacono 2012 Narayanan2015 Scott 2017 Scott
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1 2 3 Appendix 4: Cochrane risk of bias results for individual studies 4 5 6 Cochrane ROB item 7 STUDY 8 1 2 3 4 5 6 7 9 cn AMD (n = 12) 10 Schauwvlieghe 11 30 Low risk Low risk Low risk Low risk Low risk Low risk Low risk 12 2016 13 Berg 201531 Low risk Low risk Low risk Low risk Low risk Low risk Low risk 14 32 Unclear Unclear Scholler 2014 Low risk Low risk Low risk Low risk Low risk 15 risk risk 16 Chakravarthy 201333 For Low riskpeer Low risk review Low risk Low only risk Low risk Low risk Low risk 17 34 Unclear Unclear 18 Kodjikian 2013 Low risk Low risk Low risk Low risk Low risk risk risk 19 35 Unclear 20 Krebs 2013 Low risk Low risk Low risk Low risk Low risk Low risk risk 21 Heier 2012 – VIEW Unclear 22 36 Low risk Low risk Low risk Low risk Low risk High risk 1 risk 23 Heier 2012 – VIEW Unclear 24 36 Low risk Low risk Low risk Low risk Low risk High risk 2 risk 25 37 Unclear Unclear Unclear Unclear Unclear Biswas 2011a Low risk Low risk 26 risk risk risk risk risk 27 38 Unclear Unclear Unclear Biswas 2011b Low risk Low risk Low risk Low risk 28 risk risk risk 29 39 Unclear
Martin 2011 Low risk Low risk Low risk Low risk Low risk Low risk http://bmjopen.bmj.com/ 30 risk 31 40 Unclear Unclear Unclear Subramanian 2010 Low risk Low risk Low risk Low risk 32 risk risk risk 33 DME (n = 3) 34 41 Unclear Unclear Unclear Unclear Unclear Unclear Low risk 35 Fouda 2017 36 risk risk risk risk risk risk 27 Unclear 37 Wells 2015 Low risk Low risk Low risk Low risk Low risk Low risk risk 38 on September 24, 2021 by guest. Protected copyright. 42 Unclear Unclear Unclear Unclear 39 Ekinci 2014 Low risk Low risk Low risk 40 risk risk risk risk 41 RVO ME (n = 2) 42 Scott 201743 Low risk Low risk Low risk Low risk Low risk Low risk High risk 43 44 Unclear Unclear Unclear 44 Narayanan 2015 Low risk Low risk Low risk Low risk 45 risk risk risk 46 m CNV (n = 2)
47 45 Unclear Unclear Iacono 2012 Low risk Low risk Low risk Low risk Low risk 48 risk risk 49 46 Unclear Unclear Gharbiya 2010 Low risk Low risk Low risk Low risk Low risk 50 risk risk 51 52 Note: The legend for the ROB table is as follows: 53 1: Random sequence generation 54 2: Allocation concealment 55 3: Blinding of patients & personnel 56 4: Blinding of outcome assessment 57 58 18 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 56BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 5: Incomplete outcome data 4 6: Selective reporting 5 7: Other bias 6 7 Abbreviations: cn AMD – choroidal neovascular age related macular degeneration; DME – diabetic 8 macular oedema; m CNV – myopic choroidal neovascularization; RVO ME – macular edema due to 9 retinal vein occlusion 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29
30 http://bmjopen.bmj.com/ 31 32 33 34 35 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 19 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from 20 http://bmjopen.bmj.com/ BMJ Open on September 24, 2021 by guest. Protected copyright.
For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Appendix 5: Risk of bias results results 5: bias of Risk Appendix
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b
2 I NR NR NR NR NR NR NR NR NR NR NR NR (95% CI) (95% Risk Difference Risk NR NR NR NR NR NR NR NR 0.05 (-2.36, 2.46) 2.46) (-2.36, 0.05 66% 0.03 (-1.02, 1.08) 1.08) (-1.02, 0.03 0% NR NR NR NR -2.23 (-5.07, 0.61) 0.61) (-5.07, -2.23 73% CI) Risk Ratio Risk (95% NR NR NR NR NR NR NR NR NR NR NR NR [Range] effectestimate Mean comparator NR NR NR NR NR NR NR NR NR NR NR NR 21 http://bmjopen.bmj.com/
b BMJ Open [Range] Mean treatment effectestimate on September 24, 2021 by guest. Protected copyright.
Total patients
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml a For peer review only Treatment Effects in choroidal neovascular Age-related Macular Degeneration Degeneration Macular Age-related neovascular in choroidal Effects Treatment No. ofNo. RCTs vs Ctrl x R Comparison Comparison Aflibercept vs. Aflibercept vs. Bevacizumb 3 1823 0.12] [0, 0.04 0.06] [0, 0.02 (0.32-12.5) 2.04 0.47) (-0.25, 0.11 0% Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab 2 1632 14.46 ± 5.32 14.40 ± 5.60 NA Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 8 3064 15.2] [4.1, 7.24 11.43] [0.6, 5.85 NA Ranibizumab Ranibizumab 2 1793 9.41] [8.25, 8.83 9.4] [8.1, 8.75 NA Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 10 3302 0.11] [0, 0.06 0.14] [0.04, 0.07 1.1 (0.84-1.43) 2.23) (-1.46, 0.39 4% Ranibizumab Ranibizumab 2 1815 0.05] [0.05, 0.05 0.06] [0.05, 0.06 0.9 (0.6-1.35) 1.72) (-2.75, -0.51 0% Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 9 3245 0.33] [0.12, 0.22 0.29] [0.14, 0.23 (0.84-1.08) 0.95 1.62) (-4.86, -1.62 0% Ranibizumab Ranibizumab 2 1815 0.34] [0.3, 0.32 0.34] [0.31, 0.32 (0.81-1.22) 0.99 6.4) (-6.82, -0.21 52% in # in Mean Mean Vision Vision letters letters letters letters gain in in gain Vision- letters) letters) related related BCVA of BCVA function function Appendix 6: Treatment effect estimates estimates effect 6: Treatment Appendix
Blindness Blindness change in in change Outcome Vision loss loss Vision BCVA (MD (MD BCVA in BCVA of BCVA in ≥15 EDTRS EDTRS ≥15 ≥15 EDTRS EDTRS ≥15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
2 I NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR (95% CI) (95% Risk Difference Risk NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR CI) Risk Ratio Risk (95% NR NR NR NR NR NR NR NR NR NR 1.75 (0.44-6.67) (0.44-6.67) 1.75 0.77) (-0.40, 0.18 0% NR NR NR NR NR NR 0.25 (0.01-7.69) (0.01-7.69) 0.25 0.44) (-0.93, -0.25 NA [Range] effectestimate Mean comparator NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR 0 0 22 http://bmjopen.bmj.com/
b BMJ Open [Range] Mean treatment effectestimate on September 24, 2021 by guest. Protected copyright.
Total patients
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml a For peer review only No. ofNo. RCTs
Rx vs Ctrl Rx Comparison Comparison Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 3 2011 0.01] 0 [0, 0] 0 [0, Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 3 2135 0.01] 0 [0, 0.01] 0 [0, (0.42-5.88) 1.59 0.79) (-0.43, 0.18 0% Ranibizumab Ranibizumab 1 913 0.0033 Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 4 2033 0.05] [0, 0.03 0.08] [0, 0.04 (0.51-1.47) 0.86 0.9) (-0.97, -0.03 0% Ranibizumab Ranibizumab 2 1818 0.02] [0.01, 0.02 0.02] [0.02, 0.02 (0.45-2.04) 0.96 1.18) (-1.32, -0.07 0% Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 5 3026 0.28] [0.12, 0.19 0.28] [0.09, 0.18 (0.93-1.27) 1.09 0.05) (-0.01, 0.02 12% Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 6 2941 0.12] [0.01, 0.04 0.06] [0.01, 0.03 (0.72-1.79) 1.14 0.36) (-0.74, 0.31 0% Ranibizumab Ranibizumab NR NR NR Ranibizumab vs. Bevacizumb Aflibercept NR NR NR almitis almitis events events events events events events mbolic mbolic mbolic mbolic Serious Serious Venous Venous Arterial Arterial adverse adverse Bacterial Bacterial
Mortality Mortality Outcome endophth thromboe thromboe Page 59 of 88 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 60 of 88
2 I NR NR NR NR NR NR NR NR NR NR NA NA 11.73, 11.73, - (95% CI) (95% Risk Difference Risk 2.05 ( 2.05 NR NR NR NR 1.36 (-1.59, 4.31) 4.31) (-1.59, 1.36 27% -2.7 (-0.3, -5.2) -5.2) -2.7 (-0.3, NA -2.0 (-3.90, -0.09) -0.09) -2.0 (-3.90, 0% - 7.62) 7.62) NR NR NR NR NR NR CI) Risk Ratio Risk (95% NR NR NR NR 0.48 (0.12, 1.91) 1.91) (0.12, 0.48 1.43) (-4.78, -1.67 NA 0.94 (0.72, 1.24) 1.24) (0.72, 0.94 NA NA NR NR NR NR NR NR 2.08 (0.52-8.33) (0.52-8.33) 2.08 4.78) (-1.43, 1.67 NA 1.59 (0.38-6.67) (0.38-6.67) 1.59 3.7) (-1.87, 0.92 NA 0.94 (0.72-1.23) (0.72-1.23) 0.94 11.73) (-7.62, 2.05 NA 1.06 (0.82-1.37) (0.82-1.37) 1.06 11.75) (-7.44, 2.16 NA
[Range] effectestimate Mean comparator NR NR NR NR 0.03 0.03 0.37 0.37 NR NR NR NR NR NR 0.02 0.02 0.02 0.02 0.37 0.37 0.37 0.37 23 http://bmjopen.bmj.com/
b BMJ Open [Range] Mean treatment effectestimate on September 24, 2021 by guest. Protected copyright.
Treatment Effects in Diabetic Macular Edema Edema Macular in Diabetic Effects Treatment Total patients
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml a For peer review only No. ofNo. RCTs Rx vs Ctrl Rx Comparison Comparison Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept 1 386 11.8 ± 10.0 12.4 ± 12.8 NA Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 2 456 10.54) 10.27 (10.0, 12.3) 12.08 (11.87, NA Ranibizumab Ranibizumab 2 462 19.64) 16.22 (12.8, 15.65) 13.97 (12.3, Bevacizumb vs. vs. Bevacizumb Aflibercept 1 376 0.02 Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 1 376 0.03 Ranibizumab Ranibizumab 1 392 0.02 Bevacizumb vs. vs. Bevacizumb Aflibercept 1 386 0.35 Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 1 376 0.35 Ranibizumab Ranibizumab 1 392 0.39 Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 2 1526 0.01] [0.01, 0.01 0.01] 0 [0, (0.31-16.67) 2.33 0.96) (-0.2, 0.38 0% Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR nt nt BCVA BCVA Mean Mean Vision Vision letters letters letters letters letters letters gain in in gain Vision- Retinal Retinal related related BCVA of BCVA function function
change in in change Outcome detachme Vision loss loss Vision in BCVA of BCVA in ≥15 EDTRS EDTRS ≥15 ≥15 EDTRS EDTRS ≥15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
2 I NR NR NR NR NR NR NR NR NR NR NR NR NR NR NA NA 12.04, 12.04, - (95% CI) (95% Risk Difference Risk 4.13 ( 4.13 NR NR NR NR NR NR - 3.78) 3.78) NR NR NR NR NR NR NR NR CI) Risk Ratio Risk (95% NR NR NR NR NR NR 1.11 (0.46, 2.68) 2.68) (0.46, 1.11 4.29) (-3.37, 0.46 NA 1.2 (0.85, 1.69) 1.69) 1.2 (0.85, 12.04) (-3.78, 4.13 NA 0.85 (0.39, 1.85) 1.85) (0.39, 0.85 3.36) (-5.2, -0.92 NA NR NR NR NR NR NR NR NR 0.9 (0.37-2.17) 0.9 (0.37-2.17) 3.37) (-4.29, -0.46 NA 0.6 (0.22-1.61) 0.6 (0.22-1.61) 1.69) (-5.36, -1.83 NA 0.83 (0.59-1.18) (0.59-1.18) 0.83 1.18 (0.54-2.56) (0.54-2.56) 1.18 5.2) (-3.36, 0.92 NA [Range] effectestimate Mean comparator NR NR NR NR NR NR 0.04 0.04 0.21 0.21 0.06 0.06 NR NR NR NR NR NR NR NR 0.04 0.04 0.03 0.03 0.25 0.25 0.05 0.05 24 http://bmjopen.bmj.com/
b BMJ Open [Range] Mean treatment effectestimate on September 24, 2021 by guest. Protected copyright.
Total patients
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml a For peer review only No. ofNo. RCTs Rx vs Ctrl Rx Comparison Comparison Bevacizumb vs. vs. Bevacizumb NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept 1 436 0.05 Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 1 436 0.05 Ranibizumab Ranibizumab 1 436 0.05 Bevacizumb vs. vs. Bevacizumb Aflibercept 1 436 0.25 Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 1 436 0.21 Ranibizumab Ranibizumab 2 507 0.27) , (0.01 0.14 0.25) (0.01, 0.13 (0.78-1.47) 1.08 5.13) , (-4.00 0.56 0% Bevacizumb vs. vs. Bevacizumb Aflibercept 1 436 0.05 Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 1 436 0.06 Ranibizumab Ranibizumab 2 513 0.02) (0.01, 0.02 0.05) (0.01, 0.03 (0.17-1.28) 0.47 0.94) (-4.95, -2.00 NA Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR events events events events events events mbolic mbolic mbolic mbolic Serious Serious Venous Venous Arterial Arterial adverse adverse
Mortality Mortality Blindness Blindness Outcome thromboe thromboe 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 61 of 88 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 62 of 88
2 I NR NR NR NR NR NR NR NR NR NR NA NA NE NE (95% CI) (95% Risk Difference Risk NR NR -1.5 (-4.2, 1.2) 1.2) -1.5 (-4.2, NA NR NR NR NR NR NR NR NR -2.5 (-8.0, 5.0) 5.0) -2.5 (-8.0, NA NE NE CI) Risk Ratio Risk (95% NR NR 0.5 (0.05, 5.47) 5.47) 0.5 (0.05, 1.09) (-2.01, -0.46 NA 0.33 (0.01, 8.14) 8.14) (0.01, 0.33 0.81) (-1.72, -0.46 NA 1.06 (0.91, 1.25) 1.25) (0.91, 1.06 14) , ( -6.25 3.87 NR NA NA NR NR NR NR NR NR NR NR 2 (0.18-20) 2 (0.18-20) NR 1.61 (0.21-12.5) (0.21-12.5) 1.61 1.87) 0.4 (-1.06, 0% NE NE 3.03 (0.12-100) (0.12-100) 3.03 1.72) (-0.81, 0.46 NA NA NA 1 (0.68-1.45) 1 (0.68-1.45) 22.37) 0 (-22.37, NA [Range] effectestimate Mean comparator NR NR 0.0092 0.0092 0 0 0.61 0.61 18.9 18.9 NR NR NR NR NR NR NR NR 0.0046 0.0046 0 0 0 0 18.1 18.1 0.59 0.59 25 http://bmjopen.bmj.com/
b BMJ Open [Range] Mean treatment effectestimate on September 24, 2021 by guest. Protected copyright.
Total patients Treatment Effects in Retinal Vein Occlusion – Macular Edema Edema Macular – Occlusion Vein in Retinal Effects Treatment
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml a For peer review only No. ofNo. RCTs
Rx vs Ctrl Rx Comparison Comparison Bevacizumb vs. vs. Bevacizumb 1 362 18.6 Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 1 77 15.6 Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept 1 358 0.65 Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 1 74 0.59 Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept 1 436 0.0046 Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 1 436 0.0092 Ranibizumab Ranibizumab 2 512 0.01) 0.004 (0, 0 Bevacizumb vs. vs. Bevacizumb Aflibercept 1 436 0.01 Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 1 436 0.01 Aflibercept Ranibizumab 2 512 0 nt nt in # in Mean Mean Vision Vision letters letters letters letters gain in in gain almitis almitis Retinal Retinal letters) letters) BCVA of BCVA Bacterial Bacterial
change in in change Outcome endophth detachme Vision loss loss Vision BCVA (MD (MD BCVA in BCVA of BCVA in ≥15 EDTRS EDTRS ≥15 ≥15 EDTRS EDTRS ≥15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
2 I NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR (95% CI) (95% Risk Difference Risk NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR CI) Risk Ratio Risk (95% NR NR NR NR 1.01 (0.06, 16.04) 16.04) (0.06, 1.01 1.53) , (-1.52 0.01 NR 0.51 (0.05, 5.53 ) ) 5.53 (0.05, 0.51 1.32) (-2.41, -0.54 NR 1.01 (0.5, 2.06) 2.06) (0.5, 1.01 5.59) (-5.42, 0.09 NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR 0.5 (0.05-5.26) 0.5 (0.05-5.26) 6.26) -2.7 (-11.67, NA [Range] effectestimate Mean comparator NR NR NR NR 0.011 0.011 0.0055 0.0055 0.0769 0.0769 NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR 0.05 0.05 26 http://bmjopen.bmj.com/
b BMJ Open [Range] Mean treatment effectestimate on September 24, 2021 by guest. Protected copyright.
Total patients
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml a For peer review only No. ofNo. RCTs vs. vs.
Rx vs Ctrl Rx Comparison Comparison Bevacizumb vs. vs. Bevacizumb Aflibercept 1 362 0.0056 Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept 1 362 0.079 Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 1 74 0.03 Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept 1 362 0.0056 Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept Bevacizumb Ranibizumab NR NR NR Aflibercept Ranibizumab NR NR NR events events events events mbolic mbolic Vision- related related Serious Serious Arterial Arterial adverse adverse function function
Mortality Mortality Blindness Blindness Outcome thromboe Page 63 of 88 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 64 of 88
2 I NR NR NR NR NR NR NA NA NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NA NA NA NA 27.71, 27.71, - (95% CI) (95% Risk Difference Risk NR NR NR NR NR NR NE NE 6.25 ( 6.25 40.21) 40.21) NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NA NA CI) Risk Ratio Risk (95% NR NR NR NR NR NR 0.34 (0.01, 8.22) 8.22) (0.01, 0.34 ) 0.97 (-2.06, -0.54 NR NE NE NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NA NA 1.11 (0.63-1.96) (0.63-1.96) 1.11 [Range] effectestimate Mean comparator NR NR NR NR NR NR 0 0 0.006 0.006 NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR 0 0 0.56 0.56 27 http://bmjopen.bmj.com/
b BMJ Open [Range] Mean treatment effectestimate on September 24, 2021 by guest. Protected copyright.
Total Treatment Effects in Myopic Choroidal Neovascularization Neovascularization Choroidal in Myopic Effects Treatment patients
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml a For peer review only No. ofNo. RCTs Rx vs Ctrl Rx Comparison Comparison Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 1 32 0 Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 1 32 0.62 Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept 1 362 0 Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept 1 362 0 Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR nt nt Vision Vision letters letters letters letters gain in in gain almitis almitis events events mbolic mbolic Retinal Retinal Venous Venous BCVA of BCVA Bacterial Bacterial
Outcome endophth thromboe detachme Vision loss loss Vision in BCVA of BCVA in ≥15 EDTRS EDTRS ≥15 ≥15 EDTRS EDTRS ≥15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
2 I NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR (95% CI) (95% Risk Difference Risk NR NR NR NR NR NR NR NR NR NR NR NR -1.26 (-6.52, 4.00) 4.00) (-6.52, -1.26 0% NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR CI) Risk Ratio Risk (95% NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR [Range] effectestimate Mean comparator NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR 28 http://bmjopen.bmj.com/
b BMJ Open [Range] Mean treatment effectestimate on September 24, 2021 by guest. Protected copyright.
Total patients
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml a For peer review only No. ofNo. RCTs Rx vs Ctrl Rx Comparison Comparison Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab 2 80 15.87) 12.18 (8.5, 17.31) (9.5, 13.4 NA Ranibizumab Ranibizumab NR NR NR Aflibercept vs. Aflibercept NR NR NR NR NR in # in Mean Mean events events Vision- letters) letters) related related Serious Serious Arterial Arterial adverse adverse function function
Mortality Mortality Blindness Blindness change in in change Outcome BCVA (MD (MD BCVA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 65 of 88 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 66 of 88
2 I NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR (95% CI) (95% Risk Difference Risk NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR
CI) Risk Ratio Risk (95% NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR [Range] effectestimate Mean comparator NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR 29 http://bmjopen.bmj.com/
b BMJ Open [Range] Mean treatment effectestimate on September 24, 2021 by guest. Protected copyright.
Total patients
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml a For peer review only No. ofNo. RCTs
Rx vs Ctrl Rx BCVA best corrected visual acuity; confidenceCI interval; Ctrl control; Treatment ETDRS Early Retinopathy Diabetic Comparison Comparison Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Aflibercept vs. Aflibercept vs. Bevacizumb Ranibizumab NR NR NR Ranibizumab Ranibizumab NR NR NR Bevacizumb vs. vs. Bevacizumb Aflibercept NR NR NR Ranibizumab vs. Bevacizumb Ranibizumab NR NR NR
nt nt almitis almitis events events events events mbolic mbolic mbolic mbolic Retinal Retinal Venous Venous Thesummarystatistics derived bytaking were the mean range and across estimates fromstudies. included Bacterial Bacterial Meta analysis not conducted was for comparisons RCT; 1 with point estimate the and 95% confidence interval calculated were using datafrom
Outcome endophth thromboe thromboe detachme a single single a trial. Abbreviations: Study; meanStudy; MD difference; NA not applicable; NE not NRestimable; not reported;RCT controlled randomized trials; Rx treatment; Footnotes: a b SMD standardized SMD mean difference 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 67 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 Appendix 7: Forest plots for primary outcome in choroidal neovascular age 4 5 6 related macular degeneration (cn AMD) population 7 8 9 A: Vision gain in cn-AMD population 10 11 Bevacizumab Ranibizumab 12 13 Author(s) and Year Gain Total Gain Total Relative Risk [95% CI] 14 15 Berg 2015 50 167 50 172 1.03 [0.74, 1.43] 16 For peer review only 17 Kodjikian 2013 39 191 39 183 0.96 [0.65, 1.42] 18 Subramanian 2010 5 15 1 7 2.33 [0.33, 16.41] 19 Biswas 2011a 3 25 7 27 0.46 [0.13, 1.60] 20 21 Krebs 2013 35 154 34 163 1.09 [0.72, 1.65] 22 Martin 2011 159 586 168 599 0.97 [0.80, 1.16] 23 Chakravarthy 2013 41 254 63 271 0.69 [0.49, 0.99] 24 25 Biswas 2011 6 50 14 54 0.46 [0.19, 1.11] 26 Schauwvlieghe 2016 39 161 32 166 1.26 [0.83, 1.90] 27 28 29 RE Model 0.95 [0.84, 1.07]
30 http://bmjopen.bmj.com/ 31 32 0.05 0.25 1 4 33 Risk Ratio (log scale) 34 Aflibercept Ranibizumab 35 36 37 Author(s) and Year Gain Total Gain Total Relative Risk [95% CI]
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 Heier 2012 VIEW 1 206 605 94 304 1.10 [0.90, 1.35] 43
44 Heier 2012 VIEW 2 187 615 99 291 0.89 [0.73, 1.09] 45 46 47 48
49 RE Model 0.99 [0.81, 1.22] 50 51
52 0.05 0.25 1 4 53 Risk Ratio (log scale) 54 55 56 57 58 30 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 68BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 4 B: Sensitivity analyses for vision gain in cn-AMD population 5 6 Sensitivity Analysis: 1 Year Follow-Up 7 Bevacizumab Ranibizumab 8 9 Author(s) and Year Gain Total Gain Total Relative Risk [95% CI] 10 11 12 Berg 2015 47 184 50 187 0.96 [0.68, 1.35]
13 Kodjikian 2013 39 191 39 183 0.96 [0.65, 1.42] 14 15 Subramanian 2010 5 15 1 7 2.33 [0.33, 16.41] 16 Krebs 2013 For 35peer154 review34 163 only 1.09 [0.72, 1.65] 17 18 Martin 2011 159 586 168 599 0.97 [0.80, 1.16] 19 Chakravarthy 2012 83 288 97 275 0.82 [0.64, 1.04] 20 21 Schauwvlieghe 2016 39 161 32 166 1.26 [0.83, 1.90] 22 23 24 RE Model 0.96 [0.85, 1.08] 25 26 0.05 0.25 1 4 27 Risk Ratio (log scale) 28 29 Sensitivity Analysis: Low Risk of Selection Bias 30 http://bmjopen.bmj.com/
31 Bevacizumab Ranibizumab 32 33 34 Author(s) and Year Gain Total Gain Total Relative Risk [95% CI] 35 36 37
38 Berg 2015 50 167 50 172 1.03 [0.74, 1.43] on September 24, 2021 by guest. Protected copyright. 39 40 Chakravarthy 2013 41 254 63 271 0.69 [0.49, 0.99] 41 42 43 Schauwvlieghe 2016 39 161 32 166 1.26 [0.83, 1.90] 44 45 46
47 RE Model 0.96 [0.68, 1.33] 48 49 50 51 0.05 0.25 1 4 52 Risk Ratio (log scale) 53
54 55 56 57 58 31 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 69 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 Sensitivity Analysis: De Novo Patients 4 5 Bevacizumab Ranibizumab 6 7 Author(s) and Year Gain Total Gain Total Relative Risk [95% CI] 8 9 10 11 12 Subramanian 2010 5 15 1 7 2.33 [0.33, 16.41] 13
14 Krebs 2013 35 154 34 163 1.09 [0.72, 1.65] 15 16 Martin 2011 For 159peer586 review168 599 only 0.97 [0.80, 1.16] 17 18 19 20 21 RE Model 0.99 [0.84, 1.17] 22 23 24 0.05 0.25 1 4 25 26 Risk Ratio (log scale) 27 28 29
30 http://bmjopen.bmj.com/ 31 32 33 34 35 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 32 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 70 of 88
0 0 1 2 24 24 NA NA NA NA
1 0 0 0 18 18 NA NA NA NA
1 0 2 8 12 12 NA NA NA NA
0 0 1 0 8 DME
2 1 0 4 6 m CNV m CNV cn AMD cn AMD RVO ME RVO ME Length of follow up (months) (months) follow upLength of 33 http://bmjopen.bmj.com/
s BMJ Open
0 0 1 0 4
on September 24, 2021 by guest. Protected copyright. 2 1 0 4 3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 1 For peer review only
# of RCTs # of RCTs 0 # of RCTs # of RCTs 0 # of RCTs # of RCTs 1 # of RCTs # of RCTs 0 Ranibizumab Ranibizumab NA 11.09 (30.00) NA 12.38 (32.00) NA 27.00 (34.00) 27.00 (36.00) NA Ranibizumab Ranibizumab NA 15.91 (0.42) NA 18.10 (0.42) NA Ranibizumab Ranibizumab 4.46 (0.24) NA 9.05 (0.24) NA 10.44 (0.36) 11.37 (0.58) NA 12.30 (0.52) Ranibizumab Ranibizumab NA 5.19 (0.43) NA 6.02 (0.38) NA 6.23 (0.8) NA 6.10 (1.30)
Bevacizumab Bevacizumab NA 10.28 (31.00) NA 10.42 (33.00) NA 28.00 (35.00) 28.00 (37.00) NA Bevacizumab Bevacizumab NA 13.23 (0.35) NA 15.60 (0.35) NA Bevacizumab Bevacizumab 4.48 (0.19) NA 7.90 (0.45) NA 9.30 (0.59) 10.06 (0.60) NA 10.00 (0.75) Bevacizumab Bevacizumab NA 5.14 (0.45) NA 5.66 (0.45) NA 6.35 (0.52) NA 5.84 (1.85) Mean (SEM) (SEM) in BCVA in BCVA letter score letter score improvement
Appendix 8: Summary data biasused in of risk result 8: Summary Appendix
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from 34 http://bmjopen.bmj.com/ BMJ Open on September 24, 2021 by guest. Protected copyright.
For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BCVA best corrected cn AMD visual acuity; choroidal – neovascularage related macular degeneration; DME– diabeticmacular Abbreviations: oedema;m CNV myopic – choroidal neovascularization;NAnot applicable;– RCT controlled randomized – trial; macularRVO ME – edema due to retinal veinto occlusion; SEM standard error– of the mean Page 71 of 88 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 72 of 88
2 I 59% 6.34) Ranibizumab (95% CI) (95% Proportion vs. 1.42 (6.34, 1.42 3.5, Difference(%) / Mean Difference 0.67 ( 3.72, 2.38,) 0.67 0% 1.62 ( 4.86, 1.62,) 1.62 0% ) Bevacizumab 1.08,) (95% CI) (95% 0.95 (0.84, 0.95 Risk Ratio Risk 0.96 (0.85, 0.96 1.08 degeneration(cn AMD)
a in choroidal neovascular choroidal in age relatedmacular Mean [Range] comparator Sensitivity of Analyses effectestimate 35 http://bmjopen.bmj.com/ ] treatment effect BMJ Open Mean estimate[Range
Total patients on September 24, 2021 by guest. Protected copyright.
. of . 8 8 3064 7.24 [4.1,15.2] 5.85 [0.6,11.43] NA ( 1.02, 0.03 1.08) 0% 3 3 1191 0.11] 0.09 [0.08, 0.1] 0.08 [0.05, (0.78, 1.14 1.67) ( 1.79, 4.59) 1.4 NA 3 3 1191 0.11] 0.09 [0.08, 0.1] 0.08 [0.05, (0.65, 1.18 2.13) 8 8 3214 0.06 [0, 0.11] 0.14] 0.07 [0.03, (0.86, 1.18 1.54) ( 0.98, 0.57 (2.11) 2% 3 3 1191 0.3] 0.23 [0.16, 0.29] 0.24 [0.19, (0.77, 0.94 1.16) ( 6.58, 2.85,) 1.87 NA 3 3 1191 0.3] 0.23 [0.16, 0.29] 0.24 [0.19, (0.68, 0.95 1.33) ( 8.42,6.49,) 0.97 61% 7 7 3159 0.26 [0.2,0.33] 0.35] 0.24 [0.14, 9 9 3245 0.33] 0.22 [0.12, 0.29] 0.23 [0.14, 10 3302 0.06 [0, 0.11] 0.14] 0.07 [0.04, (0.84, 1.10 1.43) ( 1.46, 0.39 2.23,) 4% o RCTs N
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml months For peermonths review only duration duration duration effectsmodel) effectsmodel) effectsmodel) effectsmodel) Analysis selection bias selection (fixed selection bias selection (fixed SA Follow up SA for 12 SA Follow up SA for 12 selection bias selection (random selection bias selection (random Main follow upLongest Main Main follow upLongest Main Main follow upLongest Main SA Trials SA with lowrisk of SA Trials SA with lowrisk of SA Trials SA with lowrisk of SA Trials SA with lowrisk of
Appendix 9: Sensitivity analysis estimates estimates analysis 9: Sensitivity Appendix Outcome Mean in change BCVA loss in loss of BCVA ≥15 EDTRS letters gain ingain of BCVA ≥15 EDTRS letters
Vision Vision Vision Vision 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
2 I 2% 2% 0.70) (95% CI) (95% Proportion Difference(%) / Mean Difference 0.30 (0.70, 1.29, 0.30
(95% CI) (95% Risk Ratio Risk
a Mean [Range] comparator effectestimate 36 http://bmjopen.bmj.com/ ] treatment effect BMJ Open Mean estimate[Range
Total patients on September 24, 2021 by guest. Protected copyright. 3 3 1191 5.95 [4.1,7.8] 6.36 [4.9,7.5] NA ( 2.14, 0.52 1.10) NA 3 3 1191 5.95 [4.1,7.8] 6.36 [4.9,7.5] NA ( 2.14, 0.52 1.10) 0% 8 8 3134 7.33 [4.7,15.2] 6.12 [0.6,11.43] NA RCTs No. ofNo.
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
months For peer review only effectsmodel) effectsmodel) selection bias selection (fixed SA Follow up SA for 12 selection bias selection (random BCVA best corrected visual acuity; confidenceCI interval; ETDRS Treatment Early Retinopathy Diabetic Study;NA not SA Trials SA with lowrisk of SA Trials SA with lowrisk of The summarystatistics derived bytaking were the mean range and across estimates fromstudies. included Abbreviations: applicable;RCT randomized controlled trials;SA sensitivity analysis Footnote: a
Outcome Analysis Page 73 of 88 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 74 of 88 Reconstitutionof bevacizumabfor intravitreal injectionreported (Yes/No) No Yes Yes dedtreatment criteria loss of VA lossof ofVA ≥5letters withOCT of evidence the macula; fluid in increasein OCT central thickness retinal ofleast 100 um;at area new ofnew nAMD; macular haemorrhage; fluid persistent OCT on at month least1 after previous the intravitrealinjection. Sign of Sign recurrence None As nee As
s 37 http://bmjopen.bmj.com/ BMJ Open cn AMD (n cn AMD = 12) on September 24, 2021 by guest. Protected copyright. 3 monthly monthly 3 injections.Repeated injectionsasneeded treatment Follow up criteria. duration for 9 months. Treat and extend protocol: injections Monthly signs till no of AMD active found. were Subsequently, injection intervals be can extended by 2 wksmax to 12 wks, shortenedbyor 2 wks depending on AMDactivities. for Follow up 12 months. injections Initial andrepeated injectionsasneeded (treat and extend) Monthly injections Monthly for months. 12 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
For peer review only
TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml
31
32 30 Scholler Scholler 2014 Author, Author, year Treatmentarms Treatmentprotocol Berg Berg 2015 Schauwvlieghe 2016 Appendix 10: Summary of anti VEGF treatment protocol of treatment anti VEGF 10:Summary Appendix
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Reconstitutionof bevacizumabfor intravitreal injectionreported (Yes/No) Yes Yes Yes visual visual acuity lossofleast at letters 5 OCT with fluorescein or angiographicevidenceof fluid the macula; in an increase inOCT central thickness retinal ofleast 100 um;at new macularhaemorrhage; of new area classic CNV; evidenceor fluidof on persistent OCT month least 1 at after the previous injection. lossof ≥5letters from previous visit the with obvious no atrophy subretinalor fibrosis and fluid OCT; with on and/or active exudation on OCT;increased CNV and/or area or persistence ofon leakage angiography since previous the and/or visit; new persistentor subretinalintraretinalor macular hemorrhage. Prespecifiedclinical and OCT for criteria disease active met. were As needed As treatment criteria 38 http://bmjopen.bmj.com/ BMJ Open on September 24, 2021 by guest. Protected copyright. 3 monthly monthly 3 injections.Repeated injectionsasneeded treatment Follow up criteria. for months. 12 3 monthly monthly 3 injections.Repeated injectionsasneeded treatment Follow up criteria. for months. 9 TX 1 & TX TX& monthly1 3 injections2: monthly + injections for 24 months. TX TX& monthly3 3 injections4: repeated monthly 3 + injectionsas treatment needed criteria. For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml TXranibizumab 3: mg/0.05 ml 0.5 TXbevacizumab 4: mg/0.05 1.25 ml
35
34 33 Krebs 2013 Krebs Kodjikian Kodjikian 2013 Chakravarthy 2013 Author, Author, year Treatmentarms Treatmentprotocol
Page 75 of 88 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 76 of 88 Reconstitutionof bevacizumabfor intravitreal injectionreported (Yes/No) NA NA No No None None an increase an CMT in morethanof100 um a or in BCVA fall bymore ETDRS than 5 letters an increase an CMT in morethanof100 um a or in BCVA fall bymore ETDRS than 5 letters As needed As treatment criteria 39 http://bmjopen.bmj.com/ BMJ Open on September 24, 2021 by guest. Protected copyright. TX 1, 2, & 3: TX3: 2, 1, Approximately& injections monthly for months. 12 monthly TX3 injections4: and bimonthly every injections for 12 months. TX 1, 2, & 3: TX3: 2, 1, Approximately& injections monthly for months. 12 monthly TX3 injections4: and bimonthly every injections for 12 months. 3 monthly monthly 3 injections.Repeated injectionsasneeded treatment Follow up criteria. for months. 18 3 monthly monthly 3 injections.Repeated injectionsasneeded treatment Follow up criteria. for months. 18 For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml TXranibizumab 1: mg/0.05 ml 0.5 TXaflibercept 2: mg/0.05 ml 0.5 TXaflibercept 3: mg/0.05 2 ml TXaflibercept 4: mg/0.05 2 ml TXranibizumab 1: mg/0.05 ml 0.5 TXaflibercept 2: mg/0.05 ml 0.5 TXaflibercept 3: mg/0.05 2 ml TXaflibercept 4: mg/0.05 2 ml TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml
36 36 38 37 Biswas Biswas 2011b Biswas Biswas 2011a Heier Heier – 2012 VIEW2 Heier Heier – 2012 VIEW1 Author, Author, year Treatmentarms Treatmentprotocol
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Reconstitutionof bevacizumabfor intravitreal injectionreported (Yes/No) Yes None Yes
Fluid on Fluid OCT, or new persistenthemorrhage, decreased visual acuity as comparedthe with previous examination,dyeor leakage or sizeincreased lesion on fluorescein angiography. Re injection Re injection macularif edema or persisted worsenedand visual acuity worsened in comparisonthe with preceding The visit. treatment was withheld ifthere was change no ofmacular thickness visualor for acuity successive two visitsbut was once reinstated vision macularor edema worsenedagain. Improvement or worsening macularof edema wasdefined 10% asa changeof comparisonCMT in with last visit 0.1 change while of visual in acuity comparison with last visit wasconsidereda significantchange. Patients returned Patients monthly to undergo visual measurements acuity chart, (ETDRS OCT clinical and exam)patients If showed a qualitative increasefluid in intraretinal or subretinalfluid byOCT As needed As treatment criteria 40 http://bmjopen.bmj.com/ BMJ Open DME3) (n = on September 24, 2021 by guest. Protected copyright. TX 1 & TX TX& 1 monthly 2: injections formonths. 12 TX TX& 3 monthly 4: injectionsas treatment needed criteria. The drugs injectedintowere the study eyesat baselineand then month 1 every the until 3rd month (loadingdose of three injections). theDuring follow up period, the re injection drug considered was monthly on basis 3 monthly monthly 3 injections.Repeated injectionsasneeded treatment Follow up criteria. for months. 12 For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml TXranibizumab 3: mg/0.05 ml 0.5 TXbevacizumab 4: mg/0.05 1.25 ml TXranibizumab 1: mg/0.05 ml 0.5 Tx2 aflibercept 2: mg/0.05ml TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml
41 39
40 Fouda Fouda 2017 Subramanian 2010 Martin 2011 Martin Author, Author, year Treatmentarms Treatmentprotocol
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 77 of 88 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 78 of 88 Reconstitutionof bevacizumabfor intravitreal injectionreported (Yes/No) No Yes No Central macular Central thickness was>275 umifor there wasan increase inBCVA ofleast 3 at letterscompared with baseline Patients Patients were baseline injected at and then month every unless visual acuity or was 20/20 centralbetter subfieldwitha thickness below eligibility thresholdthe and there wasno improvement worsening responseor toin the two past injections. months, 6 Startingat irrespective acuity ofvisual central and subfield thickness,injection an was if withheld there wasno improvement worsening or after consecutive two injections, treatment but was reinitiated if the visual acuity letterscore or central subfield the thickness worsened. As needed As treatment criteria 41 http://bmjopen.bmj.com/ BMJ Open RVO ME2) (n = on September 24, 2021 by guest. Protected copyright. Monthly injections Monthly for months 6 applicable Not Start monthlyStart with3 injections. Subsequently, additional 3 injections monthly asneeded. injections till stableused were visual acuity wasobtained. for Follow up 12 months. Monthly injections Monthly until stable visual acuity months.within 6 Subsequently, irrespective of andvisual central acuity subfield thickness, injection an was if withheld there was no improvement worsening or after consecutive two injections, but treatmentwasreinitiated ifthe visual acuityletterscore or the subfield central thickness worsened. Laser PCTwas or initiated at after the 24 week for visit persistent DME.Follow up formonths. 12 After 6 injections,After 6 additional For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml TX aflibercept 2 1: mg/0.05ml TXbevacizumab 2: mg/0.05 1.25 ml TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml TXaflibercept 3: mg/0.05 2 ml
42 27 43 Scott 2017 Scott Ekinci2014 Wells2015 Author, Author, year Treatmentarms Treatmentprotocol
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Reconstitutionof bevacizumabfor intravitreal injectionreported (Yes/No) Yes Yes No subretinal/intraretinalfluid on OCT, leakage FA appearanceon or of a newhemorrhage. Monthly additional Monthly injections performed were absence until offluorescein from leakage the and CNV absencecollections of fluid any on OCTobtained. were >50um in CRTincrease compared the with previous thinnest measurement; or new cystoid persistent retinal changes sub or fluid retinal OCT; on lossof >5 letters from the previous best measurementVA conjunction in increase with any CRT; in increase in ofVA >5 lettersbetween the currentand most visits. recent As needed As treatment criteria 42 http://bmjopen.bmj.com/ BMJ Open m CNV (n m CNV = 2) on September 24, 2021 by guest. Protected copyright. Initial injection. Initial Repeated monthly injectionsaccording to asneeded treatmentfor criteria 18 months. Initial injection. Initial Repeated monthly injectionsaccording to asneeded treatmentfor months. criteria 6 Initial injection. Initial Repeated monthly injectionsaccording to asneeded treatmentfor months. criteria 6 Maculargrid laser photocoagulation wasallowed concurrently with injections after 3 months. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
For peer review only TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml TXranibizumab 1: mg/0.05 ml 0.5 TXbevacizumab 2: mg/0.05 1.25 ml BCVA – Best correctedvisual acuity; – cn AMD choroidal neovascular age related macular degeneration; CRTcentral retinal–
45
46 44 Gharbiya Gharbiya 2010 Iacono Iacono 2012 Narayanan 2015 Author, Author, year Treatmentarms Treatmentprotocol Abbreviations:
thickness;– diabetic DME macularoedema; ETDRS– Treatment Early Diabetic Retinopathy m CNV Study; myopic– choroidal neovascularization;NAnot applicable;– NR reported;– not OCT optical – coherence tomography; RCT randomized– controlled trials;RVO ME – macularedema retinal to due occlusion; vein SDstandard – TXdeviation; treatment; – – visualacuityVA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 79 of 88 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 80 of 88
2 I NA NA NA NA NA 12.72) 30.53) 16.86) 11.75) (95% CI) (95% Proportion 17.16 (3.79, 17.16 2.69 ( 7.34, 2.69 2.16 ( 7.44, 2.16 2.84 ( 11.17, 2.84 0.7 ( 1.3, 0.7 2.8) NA 2.3 ( 1.1, 2.3 5.6) NA Difference(%) / Mean Difference
) ) b ) NA NA (95% CI) (95% Risk Ratio Risk 1.06 (0.82, 1.06 1.37 1.30 (1.01, 1.30 1.69) (1.00, 10.1 19.00) 1.35 (1.06, 1.35 1.72) and Wells 2016 and Wells 0.2 (0.63, 1.10 1.92) ( 9.14, 1.83 12.8) NA a 0.18 (0.64, 1.18 2.17) 0.67 0.58 (0.82, 1.05 1.35) 0.01 (0.20, 0.99 4.76) ( 2.00, 0 2.02) NA 0.42 0.39 Mean effect [Range] estimateb estimateb comparator 43 http://bmjopen.bmj.com/ al (Wells 2015 al (Wells i BMJ Open [Range] effectestimate Meantreatment
Afliberceptvs. Ranibizumab Total patients on September 24, 2021 by guest. Protected copyright.
a . of . 1 1 192 ± 16.1 12.1 ± 18.1 13.8 1 1 211 0.15 1 1 203 0.50 1 1 200 0.19 1 1 192 0.55 No RCTs
For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BCVA ≥ 69 BCVA letters BCVA ≥ 69 BCVA letters BCVA 69 BCVA letters < BCVA 69 BCVA letters < BCVA 69 BCVA letters < Participants with baseline Participants with baseline Participants with baseline Participants with baseline Participants with baseline Follow up for Follow up 12 months 1 414 0.01 Follow up for Follow up 24 months 1 392 ± 12.3 10.5 ± 12.8 12.4 Follow up for Follow up 12 months 1 414 0.32 Follow up for Follow up 24 months 1 392 0.02 0.02 (0.38, 1.59 6.67) ( 1.87, 0.92 3.7) NA Follow up for Follow up 24 months 1 392 0.37 Subgroup of Treatment Analysis Anti VEGF EffectsDiabetic in Macular Edema (DME) to the DRCR.net According RCT Outcome vsComparison Ctrl Rx Appendix 11: Summary of results from the DRCR.net tr DRCR.net of resultsthe from 11:Summary Appendix Mean in change BCVA (SMD) loss in loss of BCVA ≥15 EDTRS letters gain ingain of BCVA ≥15 EDTRS letters
Vision Vision Vision Vision 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from NA NA NA NA NA NA NA NA NA 4.04) 8.61) 7.74) 8.14) 12.26) 2.1 (0.1, 4.2) 2.1 4.7 (1.4, 8.0) 4.7 1.58 ( 11.77, 1.58 3.18 ( 14.11, 3.18 5.99 ( 20.12, 5.99 2.7 ( 5.2, 0.3) ( 5.2, 2.7 4.7 ( 8.8, 0.5) ( 8.8, 4.7 14.0 ( 23.00, 14.0 25.49 ( 38.72, 25.49 4.21 ( 13.82, 4.21 5.4) NA
NA ( 3.4, 1.1 1.1) NA NA ( 2.3, 0.4 1.5) NA NA ( 2.9, 0.7 1.5) NA NA NA NA NA 0.68 (0.52, 0.68 0.89) 0.62 (0.47, 0.62 0.81) 0.2 (0.47, 0.84 1.52) 0.18 (0.5, 0.91 1.65) 0.67 0.58 (0.69, 0.9 1.16) 0.42 0.39 (0.69, 0.89 1.16) 44 http://bmjopen.bmj.com/ BMJ Open Bevacizumabvs Aflibercept on September 24, 2021 by guest. Protected copyright. 1 1 412 0.01 0.01 (0.2, 1 4.9) ( 2.02, 0 2.00) NA 1 1 196 ± 8.8 6.8 ± 8.4 7.8 1 1 190 ± 13.3 13.4 ± 18.1 13.8 1 1 210 0.16 1 1 204 0.41 1 1 196 0.17 1 1 190 0.52 1 1 211 ± 6.8 8.3 ± 7.6 8.0 1 1 203 ± 14.2 10.6 ± 18.9 11.5 1 1 200 ± 7.0 8.6 ± 8.4 7.8
For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BCVA ≥ 69 BCVA letters BCVA ≥ 69 BCVA letters BCVA ≥ 69 BCVA letters BCVA ≥ 69 BCVA letters BCVA ≥ 69 BCVA letters BCVA 69 BCVA letters < BCVA 69 BCVA letters < BCVA 69 BCVA letters < BCVA 69 BCVA letters < Participants with baseline Participants with baseline Participants with baseline Participants with baseline Participants with baseline Participants with baseline Participants with baseline Participants with baseline Participants with baseline SA Follow up SA for 12 months Follow up for Follow up 24 months 1 386 ± 10.0 11.8 ± 12.8 12.4 Follow up for Follow up 12 months 1 414 0.29 Follow up for Follow up 24 months 1 386 0.03 0.02 (0.4, 4.2) 1.3 ( 2.58, 0.76 4.1) NA Follow up for Follow up 12 months 1 414 ± 11.2 9.4 ± 13.3 11.1 Follow up for Follow up 24 months 1 386 0.35 Mean in change BCVA (SMD) loss in loss of BCVA ≥15 EDTRS letters gain ingain of BCVA ≥15 EDTRS letters
Vision Vision Vision Vision Page 81 of 88 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 82 of 88 NA NA 3.5 ( 1.4, 5.7) ( 1.4, 3.5 6.5 ( 10.1, 6.5 2.9) NA ( 2.7, 0.7 1.3) NA NA NA
45 http://bmjopen.bmj.com/ BMJ Open on September 24, 2021 by guest. Protected copyright. 1 1 210 ± 7.4 7.5 ± 7.6 8.0 1 1 204 ± 11.8 12.0 ± 18.9 11.5
For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BCVA ≥ 69 BCVA letters BCVA 69 BCVA letters < BCVA best corrected visual acuity; confidenceCI interval; ETDRS Treatment Early Retinopathy Diabetic Study;NA not Participants with baseline Participants with baseline Follow up for Follow up 12 months 1 414 ± 10.1 9.7 ± 13.3 11.1 Bolded estimates Bolded statistical indicate significance. Wells Glassman JA, AR, AR,Ayala et al.Aflibercept, bevacizumab, ranibizumabor for diabetic macular J edema. Med. Engl N Wells Glassman JA, AR, AR,Ayala et al.Aflibercept, Bevacizumab, Ranibizumabor forMacular Diabetic Edema: Results Two Year from a 2015;372(13):1193 1203. ComparativeEffectiveness RandomizedClinical Trial. Ophthalmology.2016;123(6):1351 1359. Abbreviations: applicable;RCT randomized controlled trials;Rx treatment; sensitivity SA analysis; SMD standardized meandifference Footnote: a b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
46 http://bmjopen.bmj.com/ uity letter scores over time in patients treated with patients treated time in letter scores over uity c BMJ Open on September 24, 2021 by guest. Protected copyright.
For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BCVA – Best correctedvisual acuity; – cn AMD choroidal neovascular age related macular degeneration;DME diabetic – breviations: b controlledtrials; RVO ME –macular to edema retinal due vein occlusion macularoedema; ETDRS– Treatment Early Diabetic Retinopathy m CNV Study; myopic – choroidal neovascularization; RCT randomized – Appendix 12: Mean change in best corrected visual a visual 12:in best corrected change Appendix Mean A bevacizumab or ranibizumab ranibizumab or bevacizumab
Page 83 of 88 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 84BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
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30 28. Rajagopal R, Shah GK, Blinder KJ et al. Bevacizumab versus ranibizumab in the http://bmjopen.bmj.com/ 31 treatment of macular edema due to retinal vein occlusion: 6 month results of the 32 CRAVE study. Ophthalmic Surg Lasers Imaging Retina. 2015;46(8):844 850. 33 29. Pece A, Milani P, Monteleone C et al. A randomized trial of intravitreal 34 bevacizumab vs. ranibizumab for myopic CNV. Graefes Arch Clin Exp 35 Ophthalmol. 2015;253(11):1867 1872. 36 37 30. Schauwvlieghe AME, Dijkman G, Hooymans JM et al. Comparing the
38 Effectiveness of Bevacizumab to Ranibizumab in Patients with Exudative Age on September 24, 2021 by guest. Protected copyright. 39 Related Macular Degeneration. The BRAMD Study. PLoS One. 40 2016;11(5):e0153052. 41 31. Berg K, Pedersen TR, Sandvik L et al. Comparison of ranibizumab and 42 bevacizumab for neovascular age related macular degeneration according to 43 44 LUCAS treat and extend protocol. Ophthalmology. 2015;122(1):146 152. 45 32. Scholler A, Richter Mueksch S, Weingessel B et al. Differences of frequency in 46 administration of ranibizumab and bevacizumab in patients with neovascular 47 AMD. Wiener Klinische Wochenschrift. 2014;126(11 12):355 359. 48 33. Chakravarthy U, Harding SP, Rogers CA et al. Alternative treatments to inhibit 49 VEGF in age related choroidal neovascularisation: 2 year findings of the IVAN 50 randomised controlled trial. Lancet. 2013;382(9900):1258 1267. 51 52 34. Kodjikian L, Souied EH, Mimoun G et al. Ranibizumab versus bevacizumab for 53 neovascular age related macular degeneration: results from the GEFAL 54 noninferiority randomized trial. Ophthalmology. 2013;120(11):2300 2309. 55 56 57 58 48 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 86BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 88
1 2 3 35. Krebs I, Schmetterer L, Boltz A et al. A randomised double masked trial 4 comparing the visual outcome after treatment with ranibizumab or bevacizumab 5 6 in patients with neovascular age related macular degeneration. Br J Ophthalmol. 7 2013;97(3):266 271. 8 36. Heier JS, Brown DM, Chong V et al. Intravitreal aflibercept (VEGF trap eye) in 9 wet age related macular degeneration. Ophthalmology. 2012;119(12):2537 2548. 10 37. Biswas P, Sengupta S, Choudhary R et al. Comparing ranibizumab with 11 bevacizumab. Ophthalmology. 2011;118(3):600 600. 12 38. Biswas P, Sengupta S, Choudhary R et al. Comparative role of intravitreal 13 14 ranibizumab versus bevacizumab in choroidal neovascular membrane in age 15 related macular degeneration. Indian J Ophthalmol. 2011;59(3):191 196. 16 39. Martin DF, ForMaguire peerMG, Ying GS review et al. Ranibizumab only and bevacizumab for 17 neovascular age related macular degeneration. N Engl J Med. 18 2011;364(20):1897 1908. 19 40. Subramanian ML, Abedi G, Ness S et al. Bevacizumab vs ranibizumab for age 20 21 related macular degeneration: 1 year outcomes of a prospective, double masked 22 randomised clinical trial. Eye (Lond). 2010;24(11):1708 1715. 23 41. Fouda SM, Bahgat AM. Intravitreal aflibercept versus intravitreal ranibizumab for 24 the treatment of diabetic macular edema. Clin Ophthalmol. 2017;11:567 571. 25 42. Ekinci M, Ceylan E, Cakici O et al. Treatment of macular edema in diabetic 26 retinopathy: comparison of the efficacy of intravitreal bevacizumab and 27 ranibizumab injections. Expert Rev Ophthalmol. 2014;9(2):139 143. 28 29 43. Scott IU, VanVeldhuisen PC, Ip MS et al. Effect of Bevacizumab vs Aflibercept
30 on Visual Acuity Among Patients With Macular Edema Due to Central Retinal http://bmjopen.bmj.com/ 31 Vein Occlusion: The SCORE2 Randomized Clinical Trial. JAMA. 32 2017;317(20):2072 2087. 33 44. Narayanan R, Panchal B, Das T et al. A randomised, double masked, controlled 34 study of the efficacy and safety of intravitreal bevacizumab versus ranibizumab in 35 the treatment of macular oedema due to branch retinal vein occlusion: MARVEL 36 37 Report No. 1. Br J Ophthalmol. 2015;99(7):954 959.
38 45. Iacono P, Parodi MB, Papayannis A et al. Intravitreal ranibizumab versus on September 24, 2021 by guest. Protected copyright. 39 bevacizumab for treatment of myopic choroidal neovascularization. Retina. 40 2012;32(8):1539 1546. 41 46. Gharbiya M, Giustolisi R, Allievi F et al. Choroidal neovascularization in 42 pathologic myopia: intravitreal ranibizumab versus bevacizumab a randomized 43 44 controlled trial. Am J Ophthalmol. 2010;149(3):458 464. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 49 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 1 7-8; 7-8; 7; Appendix 7; 1 6; Appendix 6; 1 6 6 3-4 3-4 page # # page Reported onReported 8; Appendix 8; 1 7-8; 7-8; 6 6 Appendix1 Appendix1 Appendix1 http://bmjopen.bmj.com/ BMJ Open on September 24, 2021 by guest. Protected copyright.
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Describe method Describe of dataextraction from reports(e.g., forms, piloted inindependently, duplicate) processesand any for confirming obtaining and from data investigators. State the State process for studies selecting (i.e., screening, eligibility, includedin systematic review, and, ifapplicable, included the meta-analysis). in Present full electronicPresent search strategyfor least one at database, including limits any used, such could that repeated. it be Describe all Describe information sources databases (e.g., of with dates coverage, contact study with authorsidentify additionalto studies) in the search and searched. date last Specify study Specify characteristics PICOS, (e.g., length of follow-up) characteristics and report (e.g., considered, years language, publication status) used for ascriteria eligibility, giving rationale. Indicate Indicate review if a protocolexists, if canand it where Webaccessed (e.g.,be address), and, if available, provideregistration information registrationincluding number. Provide anProvide statement explicit of questions being addressedwithreference to participants, interventions,comparisons, outcomes, study and design(PICOS). Describe the Describe rationale for review inthe the context of what already is known. Provide a structured a Provide summary including, asapplicable: background; objectives;datasources; criteria, study eligibility participants, andinterventions; study appraisaland synthesis methods; limitations; results; conclusions and implications ofkey findings; systematic review registration number. Identify the Identify report systematic asa meta-analysis, review, both.or Checklistitem For peer review only
1 # 4 8 9 3 6
Data collection Data process 10 Study selection Study Search Search Information sourcesInformation 7 Eligibility criteria Eligibility Protocol and registrationProtocol 5 METHODS Objectives Objectives Rationale Rationale INTRODUCTION Structuredsummary 2 ABSTRACT Title Title TITLE Section/topic Section/topic PRISMA Checklist Checklist PRISMA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 87 of 88 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from Page 88 of
10; 10; Appendix 10-16, 10-16, 4-5 4-5 10-16 9-16, 9-16, 10; 10; Appendix 4-5 10; 10; Appendix 2-3 8-9; 8-9; 8; Appendix 8; 1 8; Appendix 8; 1 7-8, 7-8, 8-9; 8-9; 9; Fig. 1 9; 8-9; 8-9; Appendix9 Appendix7 Appendix1 Appendix1 Appendix1 Appendix1 http://bmjopen.bmj.com/ BMJ Open )for meta-analysis. each 2 on September 24, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Give results ofresults Give additional analyses, if (e.g.,done sensitivity subgroupor analyses, meta- [see regression Item 16]). Present results Present of any assessmentof risk across of (see Itembias studies 15). Present results Present of each meta-analysis done, including confidence intervalsand measures of consistency. For all outcomes Forall considered(benefits harms),or for study: each present, (a) simple summary for eachdata intervention group (b) effect estimates confidence intervals, and ideally with a forest plot. Present Present dataon risk of ofstudy and, each bias ifavailable, outcome any assessmentlevel (see item 12). For each study, Foreach present characteristics for which data extracted were (e.g., study PICOS,size, follow-upperiod) and providethe citations. Give numbersGive screened,of studies assessed for eligibility, and includedin the review, with reasonsfor exclusions each at stage, ideally flow with a diagram. Describe methods Describe of additional analyses (e.g., sensitivity subgroupor analyses, meta- regression), ifindicating done, pre-specified.which were Specify Specify assessment any riskofthat may bias cumulative affectof evidence(e.g., the publication selective bias, reporting studies). within Describe the Describe methods of handling dataand combining ofresults studies, if done, including measures(e.g., I consistency of State the State principal summarymeasures (e.g., risk ratio,means). difference in Describe methods Describe used for assessing risk studies of of bias individual (including specification of whetherthis done the at was studyoutcome or this level), and how information is be used to in datasynthesis. any List and define List variables all for data which sought were (e.g., PICOS,fundingsources) any and assumptionsand simplifications made. For peer review only
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DISCUSSION Riskacross of bias studies Synthesisof results 21 Results of Results individual studies Risk within of bias studies Study characteristics Study 18 Study selection Study RESULTS Riskacross of bias studies Synthesisof results 14 Summarymeasures 13 Riskindividual in of bias studies Data Data items Additional Additional analysis 23 Additional Additional analyses 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
22 19 18-19 16-19 http://bmjopen.bmj.com/ BMJ Open on September 24, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Describe sources Describe of funding for systematic the review support and (e.g., other supply of data); of funders role for systematic the review. Provide a a Provide general interpretationof the results thecontext in of other evidence, and implications forfuture research. Discussstudy limitations at and outcome(e.g., level risk review-level ofand at bias), (e.g., retrieval incomplete of identifiedresearch, reporting bias). Summarizethe main findings the strengthincluding ofevidencefor main each outcome; consider relevance their key to groups (e.g., healthcareproviders, policy makers).users, and For peer review only
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Moher D, A, Liberati Tetzlaff J, Altman DG, The Group PRISMA (2009). Items Preferred Reporting for and The Systematic Reviews Statement. PRISMA Meta-Analyses: PLoS From: Funding Funding FUNDING Conclusions Limitations Summaryof evidence 24 Med 6(7): e1000097. doi:10.1371/journal.pmed1000097 doi:10.1371/journal.pmed1000097 e1000097. 6(7): Med 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 89 of 88 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
Anti–Vascular Endothelial Growth Factor Treatment for Retinal Conditions: A Systematic Review and Meta-analysis
Journal: BMJ Open ManuscriptFor ID peerbmjopen-2018-022031.R1 review only Article Type: Research
Date Submitted by the 27-Nov-2018 Author:
Complete List of Authors: Pham, Ba; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program Thomas, Sonia; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program Lillie, Erin; Li Ka Shing Knowledge Institute, St Michael's Hospital, Knowledge Translation Program Lee, Taehoon; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program Hamid, Jemila; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program; McMaster University, Department of
Clinical Epidemiology and Biostatistics http://bmjopen.bmj.com/ Richter, Trevor; Canadian Agency for Drugs and Technologies in Health, Janoudi, Ghayath; Canadian Agency for Drugs and Technologies in Health Agarwal, Arnav; McMaster University, Department of Clinical Epidemiology and Biostatistics; University of Toronto, Faculty of Medicine Sharpe, Jane ; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program Scott, Alistair; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program on September 24, 2021 by guest. Protected copyright. Warren, Rachel; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program Brahmbhatt, Ronak; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program Macdonald, Erin; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program; University of Toronto, Institute of Health Policy, Management and Evaluation Straus, Sharon; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Knowledge Translation Program; University of Toronto, Department of Geriatric Medicine Tricco, Andrea; Li Ka Shing Knowledge Institute, St Michael's Hospital; University of Toronto, Epidemiology Division, Dalla Lana School of Public Health
Primary Subject Ophthalmology Heading:
Secondary Subject Heading: Pharmacology and therapeutics
ranibizumab, bevacizumab, aflibercept, anti-vascular endothelial growth Keywords: factor, age-related macular degeneration, diabetic macular edema
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29
30 http://bmjopen.bmj.com/ 31 32 33 34 35 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 1 Anti–Vascular Endothelial Growth Factor Treatment for Retinal Conditions: A Systematic 4 5 6 2 Review and Meta-analysis 7 8 9 10 3 Ba’ Pham PhD, MSc1 Email: [email protected] 11 12 4 Sonia M. Thomas MSc1 Email: [email protected] 13 14 5 Erin Lillie MSc1 Email: [email protected] 15 16 For1 peer review only 17 6 Taehoon Lee MD, MPH Email: [email protected] 18 19 7 Jemila S. Hamid PhD, MSc1,2 Email: [email protected] 20 21 8 Trevor Richter PhD, MSc3 Email: [email protected] 22 23 3 24 9 Ghayath Janoudi MD, MSc Email: [email protected] 25 26 10 Arnav Agarwal HBSc2,4 Email: [email protected] 27 28 11 Jane P. Sharpe BSc1 Email: [email protected] 29
30 1 http://bmjopen.bmj.com/ 31 12 Alistair Scott BSc Email: [email protected] 32 33 13 Rachel Warren MA1 Email: [email protected] 34 35 14 Ronak Brahmbhatt MBBS, MPH1 Email: [email protected] 36 37 15 Erin Macdonald MSc, HBSc1,5 Email: [email protected] 38 on September 24, 2021 by guest. Protected copyright. 39 40 16 Sharon E. Straus MD, MSc1,6 Email: [email protected] 41 42 17 Andrea C. Tricco PhD, MSc1,7,* Email: [email protected] 43 44 45 46 18 1 Li Ka Shing Knowledge Institute, St. Michael’s Hospital, 209 Victoria Street, East Building, 47 48
49 19 Toronto, Ontario, M5B 1W8, Canada 50 51 20 2 Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main 52 53 21 Street West, Hamilton, Ontario, L8S 4K1, Canada 54 55 56 1 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 22 3 Canadian Agency for Drugs and Technologies in Health (CADTH), 865 Carling Avenue, 4 5 6 23 Ottawa, Ontario, K1S 5S8, Canada 7 8 24 4 Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 9 10 25 1A8, Canada 11 12 26 5 Institute of Health Policy, Management and Evaluation, University of Toronto, 6th floor, 155 13 14 15 27 College Street, Toronto, Ontario, M5T 3M7, Canada 16 For peer review only 17 28 6 Department of Geriatric Medicine, University of Toronto, 27 King’s College Circle, Toronto, 18 19 29 Ontario, M5S 1A1, Canada 20 21 7 22 30 Epidemiology Division, Dalla Lana School of Public Health, University of Toronto, 6th Floor, 23 24 31 155 College Street, Toronto, Ontario, M5T 3M7, Canada 25 26 27 28 32 * Corresponding Author 29
30 http://bmjopen.bmj.com/ 31 33 Dr. Andrea C. Tricco 32 33 34 Scientist, Knowledge Translation program 34 35 35 Li Ka Shing Knowledge Institute, St. Michael’s Hospital 36 37 36 209 Victoria Street, East Building, Toronto, Ontario, M5B 1W8, Canada 38 on September 24, 2021 by guest. Protected copyright. 39 40 37 Phone: 416-864-6060 ext. 77521, e-mail: [email protected] 41 42 43 44 38 Word count: 300/300 (Abstract), 3955/4000 (Main text), 1 figure, 4 tables, 2 supplementary 45 46 39 files 47 48 49 50 51 52 53 54 55 56 2 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 4 40 ABSTRACT 5 6 7 8 41 Objectives: To evaluate the comparative effectiveness and safety of intravitreal bevacizumab, 9 10 42 ranibizumab, and aflibercept for patients with choroidal neovascular age-related macular 11 12 43 degeneration (cn-AMD), diabetic macular edema (DME), macular edema due to retinal vein 13 14 44 occlusion (RVO-ME) and myopic choroidal neovascularization (m-CNV). 15 16 For peer review only 17 45 Design: Systematic review and random-effects meta-analysis. 18 19 46 Methods: Multiple databases were searched from inception to August 17th, 2017. Eligible head- 20 21 47 to-head randomized controlled trials (RCTs) comparing the anti-VEGF drugs in adult patients 22 23 24 48 aged ≥18 years with the retinal conditions of interest. Two reviewers independently screened 25 26 49 studies, extracted data and assessed risk of bias. 27 28 50 Results: Nineteen RCTs involving 7459 patients with cn-AMD (n=12), DME (n=3), RVO-ME 29
30 http://bmjopen.bmj.com/ 31 51 (n=2), and m-CNV (n=2) were included. Vision gain was not significantly different in patients 32 33 52 with cn-AMD, DME, RVO-ME, and m-CNV treated with bevacizumab versus ranibizumab. 34 35 53 Similarly, vision gain was not significantly different between cn-AMD patients treated with 36 37 54 aflibercept versus ranibizumab. Patients with DME treated with aflibercept experienced 38 on September 24, 2021 by guest. Protected copyright. 39 40 55 significantly higher vision gain at 12 months than patients receiving ranibizumab or 41 42 56 bevacizumab, however this difference was not significant at 24 months. Rates of systemic 43 44 57 serious harms were similar across anti-VEGF agents. Post-hoc analyses revealed that an as- 45 46 47 58 needed treatment regimen (6-9 injections per year) was associated with a mortality increase of 48 49 59 1.8% (RR: 2.0, [1.2, 3.5], 2 RCTs, 1795 patients) compared to monthly treatment in cn-AMD 50 51 60 patients. 52 53 54 55 56 3 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 61 Conclusions: Intravitreal bevacizumab was a reasonable alternative to ranibizumab and 4 5 6 62 aflibercept in patients with cn-AMD, DME, RVO-ME and m-CNV. The only exception was for 7 8 63 patients with DME and low visual acuity (<69 ETDRS letters), where treatment with aflibercept 9 10 64 was associated with significantly higher vision gain (≥15 ETDRS letters) than bevacizumab or 11 12 65 ranibizumab at 12 months; but the significant effects were not maintained at 24 months. The 13 14 15 66 choice of anti-VEGF drugs may depend on the specific retinal condition, baseline visual acuity, 16 For peer review only 17 67 and treatment regimen. 18 19 68 Trial registration: PROSPERO CRD 42015022041 20 21 22 69 23 24 70 Keywords: ranibizumab, bevacizumab, aflibercept, anti-vascular endothelial growth factor, age- 25 26 71 related macular degeneration, diabetic macular edema, retinal vein occlusion, myopic choroidal 27 28 29 72 neovascularization
30 http://bmjopen.bmj.com/ 31 32 33 34 35 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 4 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 4 73 STRENGTHS AND LIMITATIONS OF THIS STUDY 5 6 7 8 74 We consolidated the evidence for treatment choice of all common retinal conditions, 9 10 75 allowing the interpretation of the strength of the evidence of benefits and harms of the anti- 11 12 76 VEGF drugs across conditions. 13 14 15 77 We summarized information regarding treatment regimens (e.g., 3 initial monthly intravitreal 16 For peer review only 17 78 injections and as-needed monthly retreatment, treat and extend), as-needed retreatment 18 19 79 criteria, and the reconstitution of bevacizumab, and examined the influence of the choice of 20 21 22 80 treatment regimens on the benefits and harms of the anti-VEGF drugs for specific retinal 23 24 81 conditions. 25 26 82 We limited our review to English studies, and found that very few RCTs evaluated the anti- 27 28 29 83 VEGF drugs in patients with RVO-ME and m-CNV.
30 http://bmjopen.bmj.com/ 31 84 Our sensitivity and subgroup analyses were not specified a-priori and should be interpreted 32 33 85 with caution. 34 35 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 5 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 86 BACKGROUND 4 5 6 7 87 Retinal conditions due to neovascular abnormality are common in older adults. Choroidal 8 9 88 neovascular age-related macular degeneration (cn-AMD) is the leading cause of irreversible 10 11 89 blindness in individuals aged 50 years or older in high-income countries.1, 2 If left untreated, 12 13 90 potentially irreversible visual impairment can also be caused by diabetic macular edema (DME) 14 15 16 91 and macular edema Fordue to retinal peer vein occlusion review (RVO-ME). 3-5only Choroidal neovascularization 17 18 92 secondary to pathologic myopia (myopic CNV) is another major cause of blindness and visual 19 20 93 impairment worldwide.6, 7 Together, these retinal diseases cause substantial reduction in quality 21 22 8 23 94 of life, and are a significant burden on healthcare systems. 24 25 26 95 Ranibizumab, off-label use of repackaged bevacizumab, and aflibercept are widely used anti- 27 28 96 vascular endothelial growth factor (anti-VEGF) drugs for intravitreal treatment of retinal 29
30 http://bmjopen.bmj.com/ 31 97 conditions. Multiple systematic reviews have evaluated the comparative effectiveness of anti- 32 33 98 VEGF drugs in patients with cn-AMD, DME, RVO-ME, and m-CNV;9-12 but given the 34 35 99 publication of new trials in patients with RVO-ME13 and DME,14 and long-term follow-up data 36 37 100 for patients with cn-AMD,15 an update is necessary. We aimed to conduct a systematic review to 38 on September 24, 2021 by guest. Protected copyright. 39 40 101 evaluate the comparative effectiveness and safety of bevacizumab, ranibizumab, and aflibercept 41 42 102 for patients with cn-AMD, DME, RVO-ME, and m-CNV. 43 44 45 103 METHODS 46 47 48 49 104 A systematic review regarding the comparative efficacy and safety of the anti- VEGF drugs was 50 51 105 planned in response to a query from the Canadian Drug Safety and Effectiveness Network 52 53 106 (PROSPERO CRD 42015022041), for which a preliminary report was prepared to inform listing 54 55 56 6 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 107 recommendations.16, 17 The report included a meta-analysis of pairwise comparisons of the anti- 4 5 6 108 VEGF drugs for individual retinal conditions, as well as a network meta-analysis to evaluate the 7 8 109 anti-VEGF drugs in cn-AMD patients. This paper summarizes results of the meta-analysis; a 9 10 110 separate paper is underway for the network meta-analysis results. 11 12 111 The current review was conducted using the Cochrane Handbook for Systematic Reviews and 13 14 15 112 reported using the PRISMA statement18 (Additional file 1). The methods are outlined briefly 16 For peer review only 17 113 below, as they are described in greater detail in Additional file 2: Appendix 1 and a related 18 19 114 therapeutic review report.17 20 21 22 23 115 Data Sources and Searches: 24 25 116 MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched. Studies 26 27 28 117 that are not widely available or commercially published (i.e., grey literature), were identified 29
30 118 using an established approach.19 Additional studies were identified by searching reference lists of http://bmjopen.bmj.com/ 31 32 119 included studies, and email correspondence with expert clinicians and anti-VEGF drug 33 34 35 120 manufacturers. 36 37
38 121 An information specialist developed the search strategy, which was peer-reviewed by another on September 24, 2021 by guest. Protected copyright. 39 40 122 information specialist using the PRESS statement.20 The MEDLINE strategy can be found in 41 42 th 43 123 Additional file 2: Appendix 1. The search was conducted on May 27 , 2015 and updated on 44 45 124 August 17th, 2017. 46 47 48 125 Study Selection and Outcome Definitions: 49 50 51 126 Eligible studies were randomized controlled trials (RCTs) that directly compared intravitreal 52 53 127 bevacizumab, ranibizumab, and/or aflibercept for the treatment of patients (aged ≥18 years) with 54 55 56 7 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 128 cn-AMD, DME, RVO-ME or m-CNV. We excluded RCTs comparing anti-VEGF drugs with 4 5 6 129 other comparators, such as photodynamic therapy, intravitreal corticosteroids, and grid laser 7 8 130 photocoagulation (Appendix 1). Due to time and resource constraints, we only included studies 9 10 131 published in English. 11 12 13 132 Eligible RCTs reported one of the following benefits and harms outcomes: vision gain, defined 14 15 16 133 as a gain in Best-CorrectedFor Visual peer Acuity (BCVA)review letter score only of ≥15 on the Early Treatment 17 18 134 Diabetic Retinopathy Study (ETDRS) chart;21 vision loss, defined as a loss in BCVA letter score 19 20 135 of ≥15; mean change in BCVA from baseline; legal blindness (BCVA of 20/200 or worse 21 22 23 136 measured on a standard Snellen chart, or worse than 20/100 visual acuity measured on ETDRS 24 25 137 chart); vision-related function according to the 25-item National Eye Institute Visual Function 26 27 138 Questionnaire (NEI-VFQ-25);22 serious adverse events; all-cause mortality; arterial 28 29 139 thromboembolic events (TEs); venous TEs; bacterial endophthalmitis; and retinal detachment. 30 http://bmjopen.bmj.com/ 31 32 140 All titles/abstracts and potentially relevant full-text articles were screened by two reviewers, 33 34 141 independently. Discrepancies were discussed and if necessary, resolved with input from a third 35 36 142 reviewer. When multiple reports of the same trial were identified, the main report was included, 37
38 on September 24, 2021 by guest. Protected copyright. 39 143 and the others were treated as companion reports.23 40 41 42 144 Data Extraction and Quality Assessment: 43 44 45 145 Data extraction forms were developed with input from three clinicians, pilot-tested, and refined 46 47 146 twice. Data extraction was conducted by two reviewers, independently. Discrepancies were 48 49 147 discussed and if necessary, resolved with input from a third reviewer. A similar approach was 50 51 52 148 followed for quality assessment using the Cochrane risk-of-bias tool for RCTs.24 53 54 149 Patient and Public Involvement 55 56 8 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 150 There was no patient or public involvement in the conduct of this study. 4 5 6 7 151 Synthesis of study results 8 9 152 Study results were synthesized with respect to benefits and harms of treatment, treatment 10 11 12 153 regimen (e.g., monthly and as-needed regimens), and trends in BCVA improvement over time. 13 14 154 With respect to visual acuity improvement, meta-analyses were conducted with studies reporting 15 16 155 BCVA letter score asFor measured peer on the ETDRS review chart. For studies only reporting visual acuity in 17 18 25 19 156 logMAR and decimal values, the values were converted to approximate ETDRS letter scores, 20 21 157 with approximate standard deviations.26 Pairwise comparisons of drugs were assessed at the 22 23 158 longest treatment duration, allowing for the inclusion of trials in the meta-analysis that reported 24 25 159 outcome data at different time points. Subgroup analyses were conducted at 12 months and 24 26 27 28 160 months, as these were the most frequently reported time points. A post hoc analysis was 29
30 161 conducted to compare different treatment regimens across the drugs. For DME patients, http://bmjopen.bmj.com/ 31 32 162 treatment effect estimates were obtained for all patients as well as subgroups based upon baseline 33 34 27 35 163 BCVA, which were pre-specified in the DRCR.net trial. The meta-analysis was conducted 36 37 164 using a random-effects model, as we assumed treatment effects varied across trials. A sensitivity
38 on September 24, 2021 by guest. Protected copyright. 39 165 analysis was conducted by restricting results to trials determined to be at low risk of selection 40 41 42 166 bias. Between-study heterogeneity was assessed using the I² statistic, with values above 75% 43 44 167 indicating substantial heterogeneity.28 45 46 47 168 RESULTS 48 49 50 169 Literature search 51 52 53 170 After screening 3176 titles/abstracts and 440 full-text articles, 19 head-to-head RCTs of the anti- 54 55 56 9 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 171 VEGF drugs were included, with 7459 patients, including 12 RCTs for cn-AMD, 3 RCTs for 4 5 6 172 DME, 2 RCTs for RVO-ME, and 2 RCTs for m-CNV (Figure 1, Additional file 2: Appendix 7 8 173 1).27, 29-42 Given our inclusion criteria, we excluded RCTs that compared anti-VEGF drugs with 9 10 174 placebo or laser photocoagulation.43-49 11 12 13 175 Study and patient characteristics 14 15 16 176 Studies were completedFor between peer 2010 and review 2017 with an average only sample size of 393 patients per 17 18 19 177 trial (range: 28, 1240) (Table 1, Additional file 2: Appendix 2-3). The mean age ranged from 20 21 178 approximately 60 to 80 years, and females accounted for 5% to 76% of the patients. The average 22 23 179 follow-up duration was 13 months (range: 6-24 months). RCTs were conducted in Europe (n=8), 24 25 180 North America (n=5), Asia (n=4), Africa (n=1) and across multiple continents (n=1); most were 26 27 28 181 multi-centre RCTs (n=13), in addition to 6 single-centre RCTs. 29
30 http://bmjopen.bmj.com/ 31 182 Risk of bias assessment 32 33 34 183 Random sequence generation and allocation concealment were unclear for 12/19 (63.2%) and 35 36 184 9/19 (47.4%) of the included RCTs, respectively, suggesting the potential for selection bias 37 38 185 (Additional file 2: Appendix 4-5). The RCTs were at low risk with respect to blinding of on September 24, 2021 by guest. Protected copyright. 39 40 41 186 participants and trial personnel 18/19 (94.7%), blinding of outcome assessment 18/19 (94.7%), 42 43 187 incomplete outcome data 13/19 (68.4%), and selective reporting 13/19 (68.4%). Two of the 19 44 45 188 RCTs (10.5%) were industry-funded.38 46 47 48 49 189 Patients with cn-AMD 50 51 52 190 Comparative effectiveness of bevacizumab and ranibizumab 53 54 55 56 10 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 191 Results from 10 RCTs (3302 patients) showed that approximately 22% of patients attained vision 4 5 6 192 gain of ≥15 BCVA letter scores with treatment, and patients treated with bevacizumab were as 7 8 193 likely to attain vision gain as those treated with ranibizumab (Risk Ratio (RR): 1.05; [95% 9 10 194 confidence interval (CI), 0.93, 1.19], Table 2, Additional file 2: Appendix 6-7). Over an average 11 12 195 treatment duration of 16 months, approximately 94% of patients maintained their vision, with no 13 14 15 196 statistical difference between patients treated with bevacizumab or ranibizumab (RR of vision 16 For peer review only 17 197 loss: 0.91 [95% CI, 0.70, 1.19]). Patients treated with bevacizumab or ranibizumab gained an 18 19 198 average of 7 letters in terms of mean BCVA with no statistical difference between the drugs 20 21 22 199 (mean difference [MD] 0.03 letters [95% CI, -1.02, 1.08]). Approximately 2-4% patients treated 23 24 200 with bevacizumab or ranibizumab became legally blind (RR: 2.04 [95% CI, 0.32 to 12.50], 3 25 26 201 trials, 1823 patients). Overall, the results were consistent across the 10 trials and did not change 27 28 29 202 with the sensitivity analyses restricted to trials determined to be at low risk of selection bias and
30 http://bmjopen.bmj.com/ 31 203 with different follow-up lengths (Additional file 2: Appendix 6, 8-9). 32 33 34 204 Comparative effectiveness of aflibercept and ranibizumab 35 36 37 205 Results from 2 RCTs (1815 patients; Table 2, and Additional file 2: Appendix 6) showed that 38 on September 24, 2021 by guest. Protected copyright. 39 40 206 approximately 32% of patients attained vision gain with treatment, and patients treated with 41 42 207 aflibercept were as likely to attain vision gain as patients treated with ranibizumab (RR: 0.99 43 44 208 [95% CI, 0.81 to 1.22]). Over an average assessment and treatment duration of 12 months, 45 46 47 209 approximately 95% of patients maintained their vision, and aflibercept patients were as likely to 48 49 210 maintain vision as ranibizumab patients (RR of vision loss: 0.90 [95% CI, 0.60 to 1.35]). With 50 51 211 respect to mean BCVA, patients gained on average 9 letters (MD: -0.05 [95% CI, -2.5, 2.4]). 52 53 54 212 Compared to baseline, patients gained some visual-related function, with an average of 5 points 55 56 11 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 213 on the NEI-VFQ-25 questionnaire (MD: 2.2 [95% CI, -0.6, 5.1]). 4 5 6 7 214 Comparative effectiveness of bevacizumab and aflibercept 8 9 10 215 There were no RCTs that directly compared bevacizumab and aflibercept (Table 2, and 11 12 216 Additional file 2: Appendix 6).Regarding BCVA change, the mean difference between 13 14 217 bevacizumab and ranibizumab was -0.03 (95% CI: -1.08, 1.02) whereas the mean difference 15 16 For peer review only 17 218 between aflibercept and ranibizumab was -0.05 (95% CI: -2.5, 2.4), suggesting a mean 18 19 219 difference between bevacizumab and aflibercept of 0.02 (95% CI: -2.60, 2.64)50. For vision gain, 20 21 220 the corresponding risk ratio estimate was 0.95 (95% CI: 0.84, 1.07) for bevacizumab versus 22 23 24 221 ranibizumab and 0.99 (95% CI: 0.81, 1.22) for bevacizumab versus ranibizumab, suggesting a 25 26 222 risk ratio estimate of 0.96 (95% CI: 0.75, 1.22) between bevacizumab and aflibercept. 27 28 29 223 Treatment regimens
30 http://bmjopen.bmj.com/ 31 32 33 224 Additional file 2: Appendix 10 provides detailed information regarding the treatment regimens in 34 35 225 the included trials, the as-needed re-treatment criteria and the reconstitution of bevacizumab for 36 37 226 intravitreal injections. The treatment regimens varied widely, and are summarized in Table 3
38 on September 24, 2021 by guest. Protected copyright. 39 227 along with the mean number of injections per year for each treatment regimen. The number of 40 41 42 228 reported treatment regimens varied by condition (cn-AMD (n=6), DME (n=3), RVO-ME (n=2), 43 44 229 and m-CNV (n=1)). In cn-AMD patients, the two most commonly reported regimens for 45 46 230 bevacizumab and ranibizumab included monthly injections (~11 injections/year) and 3 monthly 47 48 49 231 injections followed by as-needed treatment (~6 injections/year). Aflibercept was most commonly 50 51 232 administered using a monthly regimen (~11 injections/year). 52 53 54 233 Results of our posthoc analysis comparing as-needed versus monthly treatment in cn-AMD 55 56 12 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 234 patients are summarized in Table 4. The as-needed treatment regimen with ranibizumab or 4 5 6 235 bevacizumab was less effective than the monthly regimen in improving mean BCVA (MD: -1.9 7 8 236 letters [95% CI, -3.3 to -0.5 letters], 2 RCTs, 1622 patients) and vision gain (RR: 0.73 [95% CI, 9 10 237 0.55 to 0.95]). When the regimens were assessed for non-inferiority at 1 year with an inferiority 11 12 238 margin of 5 points, monthly bevacizumab was equivalent to monthly ranibizumab (MD: -0.5 13 14 15 239 [95% CI, -3.9, 2.9]), as-needed bevacizumab was equivalent to as-needed ranibizumab (MD: -0.8 16 For peer review only 17 240 [95% CI, -4.1, 2.5]), as-needed ranibizumab was equivalent to monthly ranibizumab (MD: -1.7 18 19 241 [95% CI, -4.7, 1.3]) but monthly bevacizumab was not equivalent to as-needed bevacizumab 20 21 51 22 242 (MD: -2.1 [95% CI, -5.7, 1.6]). Compared to the monthly regimen, the as-needed regimen was 23 24 243 associated with a significant increase in mortality of 1.8% (95% CI, 0.1% to 3.4%, meta-analysis 25 26 244 of mortality data reported in 2 RCTs, 1795 patients) [RR, 2.0; 95% CI, 1.2 to 3.5].35, 51 27 28 29 245 Harms 30 http://bmjopen.bmj.com/ 31 32 33 246 Over an average of 14 months (range: 12-24 months), mortality was reported in 4% and 3% of 34 35 247 patients treated with bevacizumab or ranibizumab, respectively (RR: 1.14 [95% CI, 0.72 to 36 37 248 1.79], 6 RCTs, 2941 patients, Additional file 2: Appendix 6). Serious adverse events were 38 on September 24, 2021 by guest. Protected copyright. 39 40 249 reported in 19% and 18% of patients treated with bevacizumab or ranibizumab, respectively 41 42 250 (RR: 1.09 [95% CI, 0.93 to 1.27], 5 RCTs, 3026 patients). Arterial thromboembolic events were 43 44 251 reported in 4% and 3%of patients treated with bevacizumab or ranibizumab, respectively (RR: 45 46 47 252 0.86 [95% CI, 0.51, 1.47], 4 RCTs, 2033 patients). Venous thromboembolic events, bacterial 48 49 253 endophthalmitis and retinal detachment were reported in <1% of patients treated with either 50 51 254 drug. In the trials evaluating aflibercept and ranibizumab, arterial thromboembolic events were 52 53 54 255 reported in 2% of patients treated with aflibercept or ranibizumab (RR: 0.96 [95% CI, 0.45, 55 56 13 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 256 2.04], 2 RCTs, 1818 patients), and venous thromboembolic events were reported in <1% of 4 5 6 257 patients treated with either drug. Data on other harms were not available. 7 8 9 258 Patients with DME 10 11 12 259 Comparative effectiveness of ranibizumab, bevacizumab and aflibercept 13 14 15 260 Results from the trial by the Diabetic Retinopathy Clinical Research Network (DRCR.net trial, 16 For peer review only 17 18 261 620 patients) showed that over 2 years of treatment, patients were as likely to attain vision gain 19 20 262 with ranibizumab (37%), bevacizumab (35%), or aflibercept (39%) - bevacizumab versus 21 22 263 ranibizumab: RR: 0.94 [95% CI, 0.72, 1.23]; aflibercept versus bevacizumab: RR: 1.06 [95% CI, 23 24 25 264 0.80, 1.38]; and aflibercept versus ranibizumab: RR: 1.06 [95% CI, 0.82, 1.37]; Table 2). Over 2 26 27 265 years of treatment, approximately 98% of patients maintained their vision with all 3 drugs. 28 29 266 Besides the DRCR.net RCT, two small single-centered RCTs reported BCVA data, one
30 http://bmjopen.bmj.com/ 31 14 32 267 comparing aflibercept with ranibizumab , and another comparing bevacizumab and 33 34 268 ranibizumab31. Patients’ mean BCVA improved by approximately 13 letters with aflibercept, 10 35 36 269 letters with bevacizumab and 12 letters with ranibizumab (aflibercept versus ranibizumab: MD, 37 38 270 1.4 [95% CI, -1.6, 4.3]; bevacizumab versus aflibercept: MD, -2.7 [95% CI, -5.2 to -0.3]; and on September 24, 2021 by guest. Protected copyright. 39 40 41 271 bevacizumab versus ranibizumab: MD, -2.0 [95% CI, -3.9 to -0.1], Table 2). 42 43 44 272 The DRCR.net trial reported results stratified by baseline visual acuity at 12 and 24 months 45 46 273 (Appendix 11). In patients with high baseline visual acuity (BCVA ≥ 69 letters), approximately 47 48 49 274 16% of patients treated with bevacizumab, 15% of patients treated with ranibizumab and 18% of 50 51 275 patients treated with aflibercept attained vision gain at 12 months (RR of bevacizumab versus 52 53 276 aflibercept: 0.91 [95% CI: 0.50, 1.65]; RR of aflibercept versus ranibizumab: 1.18 [95% CI: 54 55 56 14 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 277 0.64, 2.17]). Vision gain at 24 months was 17% with bevacizumab, 19% with ranibizumab and 4 5 6 278 20% with aflibercept (RR of bevacizumab versus aflibercept: 0.84 [95% CI: 0.47, 1.52]; RR of 7 8 279 aflibercept versus ranibizumab: 1.10 [95% CI: 0.63, 1.92]). In patients with low baseline visual 9 10 280 acuity (BCVA < 69 letters), approximately 41% of patients treated with bevacizumab, 50% of 11 12 281 patients treated with ranibizumab and 67% of patients treated with aflibercept attained vision 13 14 15 282 gain at 12 months (RR of bevacizumab versus aflibercept: 0.62 [95% CI: 0.47, 0.81]; RR of 16 For peer review only 17 283 aflibercept versus ranibizumab: 1.35 [95% CI: 1.06, 1.72]). At 24 months, vision gain was 52% 18 19 284 with bevacizumab, 55% with ranibizumab and 58% with aflibercept (RR of bevacizumab versus 20 21 22 285 aflibercept: 0.90 [95% CI: 0.69, 1.16]; RR of aflibercept versus ranibizumab: 1.05 [95% CI: 23 24 286 0.82, 1.35]). 25 26 27 287 Treatment regimen 28 29
30 http://bmjopen.bmj.com/ 31 288 With respect to treatment regimen, the DRCR.net trial treated patients initially with monthly 32 33 289 injections until stable visual acuity within 6 months, followed by as-needed treatment 34 35 290 (Additional file 2: Appendix 10).52 The median number of injections administered over a one- 36 37 291 year period was 10 in the bevacizumab group, 9 in the aflibercept group, and 10 in the 38 on September 24, 2021 by guest. Protected copyright. 39 40 292 ranibizumab group (Table 3).52 In the second year, the median number of injections was: 6, 5, 41 42 293 and 6 in the bevacizumab, aflibercept, and ranibizumab groups, respectively.53 Two smaller trials 43 44 294 both started treatment with 3 monthly intravitreal injections, followed by monthly re-treatment 45 46 47 295 with persistence of macular edema, thickening of central macular or worsening of visual acuity 48 49 296 (Table 3 and Appendix 10 – Summary of treatment protocols).14, 31 50 51 52 297 Harms 53 54 55 56 15 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 298 After 24 months of treatment in the DRCR.net trial,27 mortality was reported in approximately 4 5 6 299 6% of bevacizumab patients, 2% of aflibercept patients and 5% of ranibizumab patients 7 8 300 (Additional file 2: Appendix 6). Serious adverse events were reported in 21% of bevacizumab 9 10 301 patients, 27% of aflibercept patients, and 25% of ranibizumab patients. Arterial thromboembolic 11 12 302 events were reported in 4%, 3%, and 5%, of patients treated with bevacizumab, aflibercept, and 13 14 15 303 ranibizumab, respectively. Bacterial endophthalmitis and retinal detachments were reported in 16 For peer review only 17 304 <1% of patients treated with any of the drugs. 18 19 20 305 Patients with RVO-ME 21 22 23 24 306 Comparative effectiveness of ranibizumab, bevacizumab, and aflibercept 25 26 27 307 Results from one randomized, double-blind, controlled and non-inferiority trial conducted in 28 29 308 India (including 77 patients with ME due to branch RVO) showed that approximately 59% of
30 http://bmjopen.bmj.com/ 31 32 309 patients attained vision gain with bevacizumab and ranibizumab treatment, and no statistical 33 34 310 difference was observed between the drugs (RR: 1.0 [95% CI, 0.68 to 1.45]; Table 2 and 35 36 311 Additional file 2: Appendix 8).32 With respect to mean BCVA, patients treated with either drug 37 38 312 gained an average of 16 letters (MD -2.5 [95% CI, -8.0 to 5.0]). on September 24, 2021 by guest. Protected copyright. 39 40 41 313 Results from the SCORE2 randomized non-inferiority trial conducted in 66 centers in the United 42 43 314 States (348 patients with ME due to central RVO) showed that approximately 61% of patients 44 45 315 treated with bevacizumab or aflibercept attained vision gain, with no statistical difference 46 47 13 48 316 between the drugs (RR: 1.06 [95% CI, 0.91 to 1.25]; Table 2). With respect to mean BCVA, 49 50 317 patients treated with either drug gained an average of 19 letters (MD 1.52 [95% CI, -1.2 to 4.2]). 51 52 53 318 Treatment regimens 54 55 56 16 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 319 In the SCORE2 trial, patients were treated with monthly intravitreal injections for 6 months, with 4 5 6 320 a mean number of 5.8 injections in patients treated with bevacizumab or aflibercept (Table 3 and 7 8 321 Additional file 2: Appendix 11).13 In the other trial, patients were treated with one initial 9 10 322 intravitreal injection and then as-needed monthly re-treatment over 6 months, with a mean 11 12 323 number of 3 injections in patients treated with bevacizumab or ranibizumab.13, 32 13 14 15 16 324 Harms For peer review only 17 18 19 325 Serious adverse events were reported in 3% of bevacizumab patients and 5% of ranibizumab 20 21 326 patients (RR: 0.5 [95% CI, 0.05 to 5.26], 1 RCT, 74 patients; Additional file 2: Appendix 8).32 22 23 24 327 Serious adverse events were reported in 8% of the patients treated with bevacizumab or 25 26 328 aflibercept over 6 months (RR: 0.99 [95% CI, 0.49 to 2.00], 1 RCT, 362 patients).13 27 28 29 329 Patients with m-CNV
30 http://bmjopen.bmj.com/ 31 32 33 330 Comparative effectiveness of ranibizumab and bevacizumab 34 35 36 331 Two small RCTs both conducted in Italy evaluated ranibizumab and bevacizumab for patients 37
38 332 with m-CNV. Results from one RCT (32 patients) showed that 62% of patients treated with on September 24, 2021 by guest. Protected copyright. 39 40 333 bevacizumab and 56% of patients treated with ranibizumab attained vision gain (RR: 1.11 [95% 41 42 43 334 CI, 0.63, 1.96], 1 RCT; Table 2 and Additional file 2: Appendix 11).30 The other RCT (55 44 45 335 patients) only report BCVA results.29 With respect to mean BCVA, patients treated with 46 47 336 bevacizumab gained 12 letters and patients treated with ranibizumab gained 13 letters (MD: -1.3 48 49 29, 30 50 337 [95% CI, -6.5 to 4.0], 2 RCTs, 80 patients). The included trials did not report data on harms. 51 52 53 338 Treatment regimens 54 55 56 17 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 339 Both trials evaluated ranibizumab and bevacizumab with patients receiving one monthly 4 5 6 340 intravitreal injection and as-needed monthly re-treatment for 18 and 6 months, respectively, with 7 8 341 a mean number of 3.1 injections per year in patients treated with bevacizumab and 2.4 injections 9 10 342 in patients treated with ranibizumab (Table 3 and Additional file 2: Appendix 6).29, 30 11 12 13 343 DISCUSSION 14 15 16 For peer review only 17 344 This systematic review synthesized results from 19 RCTs to evaluate the comparative 18 19 345 effectiveness and safety of intravitreal bevacizumab, ranibizumab, and aflibercept for patients 20 21 346 with cn-AMD, DME, RVO-ME and m-CNV. Intravitreal bevacizumab was as effective as 22 23 24 347 ranibizumab in patients with cn-AMD, DME, RVO-ME, and m-CNV for the outcomes we 25 26 348 examined. Ranibizumab was as effective as aflibercept in patients with cn-AMD. 27 28 349 In patients with DME that were treated for 2 years, vision gain was equally likely to be attained 29
30 http://bmjopen.bmj.com/ 31 350 with aflibercept, ranibizumab or aflibercept. In the first year of treatment, however, patients 32 33 351 treated with aflibercept were more likely to attain vision gain than patients treated with 34 35 352 ranibizumab or bevacizumab - differential effects that were observed mainly in patients with 36 37 353 initial BCVA < 69 letter scores (equivalent to 20/50 or worse) but not observed in patients with 38 on September 24, 2021 by guest. Protected copyright. 39 40 354 initial BCVA ≥ 69 letter scores (equivalent to 20/40 or better) based on the results from the sub- 41 42 355 group analyses. Rates of systemic serious harms were similarly low among the anti-VEGF drugs, 43 44 356 across the retinal conditions. None of the included RCTs were designed with sufficient statistical 45 46 47 357 power to detect significant differences between the treatments with respect to the incidence of 48 49 358 harms. In our post-hoc analysis, cn-AMD patients and compared to monthly treatment, an as- 50 51 359 needed treatment regimen (i.e., 6 to 9 monthly injections per year) was significantly associated 52 53 54 360 with a small loss in visual acuity, but a significant increase in mortality risk of 1.8% (RR: 2.0 55 56 18 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 361 [95% CI, 1.2, 3.5]). 4 5 6 7 362 Results from the CATT and IVAN trials showed that relative to monthly treatment, patients with 8 9 363 cn-AMD receiving as-needed treatment experienced a significant increase in risk of mortality. 10 11 364 Whether there are any biological explanations for the increased risk of mortality associated with 12 13 365 fewer monthly injections is unclear and this finding may have been attributable to chance. As 14 15 16 366 such, further researchFor should peerbe conducted review to verify this result. only In DME, RVO-ME and m-CNV 17 18 367 trials, patients tended to receive fewer monthly injections per year (Table 3). None of the trials in 19 20 368 DME, RVO-ME and m-CNV patients evaluated a monthly treatment regimen, and therefore the 21 22 23 369 safety risk between as-needed and monthly regimens could not be evaluated. This requires 24 25 370 further study. 26 27 28 371 Additional file 2: Appendix 12 displays the mean change in BCVA over time in patients treated 29
30 http://bmjopen.bmj.com/ 31 372 with bevacizumab or ranibizumab. For all of the retinal conditions, patients showed 32 33 373 improvement in mean BCVA by 3-6 months with initial monthly injections, and maintained a 34 35 374 plateau to 24 months in the treatment of cn-AMD patients (average improvement of 6 letters), 36 37 375 DME patients (8 letters), RVO-ME patients (16 letters), and m-CNV patients (11 letters). 38 on September 24, 2021 by guest. Protected copyright. 39 40 376 Comparative outcomes beyond 6 months in patients with RVO-ME and m-CNV were lacking 41 42 377 and as such, long-term comparative data of anti-VEGF drugs in these patients are needed. 43 44 378 Our findings are consistent with findings from previous systematic reviews. A meta-analysis of 6 45 46 47 379 head-to-head trials concluded that bevacizumab and ranibizumab had equivalent efficacy with 48 49 380 respect to visual acuity in cn-AMD patients.11 A meta-analysis of five RCTs suggested no 50 51 381 differences in effectiveness between ranibizumab and bevacizumab in DME patients.54 Other 52 53 9, 10, 55, 56 54 382 reviews in patients with RVO-ME and m-CNV came to similar conclusions. Although 55 56 19 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 383 findings were consistent with those in these recent reviews, our review serves as an update (with 4 5 6 384 the inclusion of data up to 2017) while also examining the additional factor of treatment regimen. 7 8 385 There are several limitations worth noting. First, none of our sensitivity and subgroup analyses 9 10 386 were specified a-priori and as such, these results should be interpreted with caution. This also 11 12 387 pertains to our post-hoc analysis on treatment regimen. Secondly, we limited our review to 13 14 15 388 English studies due to time and resources constraints. We believe, however, that the impact of 16 For peer review only 17 389 the restrictions is small since our findings are consistent with previous systematic reviews that 18 19 390 included RCTs reported in all languages, evaluating the same anti-VEGF drugs for specific 20 21 11, 54, 57 22 391 retinal conditions, and results were consistent across studies, so the impact of including 23 24 392 additional studies reported in other languages, if any, would be insignificant. We only identified 25 26 393 a few RCTs evaluating the anti-VEGF drugs in patients with DME, RVO-ME and m-CNV. We 27 28 29 394 did not include ziv-aflibercept (a low-cost anti-VEGF alternative to aflibercept and
30 http://bmjopen.bmj.com/ 31 395 bevacizumab58), the old anti-VEGF pegaptanib, or the newest anti-VEGF brolucizumab. 32 33 396 Although the rates of reported adverse events were similar across the anti-VEGF drugs, the 34 35 397 assessment of harms using comparative trial data is limited. We excluded RCTs which 36 37
38 398 randomized eyes (instead of patients) since the reported analyses failed to adjust for the on September 24, 2021 by guest. Protected copyright. 39 40 399 correlation between the outcomes of eyes from the same individuals.59 Similarly, we also 41 42 400 excluded one quasi-randomized trial,60 because we focused on randomized studies. 43 44 45 46 401 CONCLUSIONS 47 48 49 402 Intravitreal bevacizumab was a reasonable alternative to ranibizumab and aflibercept in patients 50 51 403 with cn-AMD, DME, RVO-ME and m-CNV. The only exception was for patients with DME and 52 53 54 404 low visual acuity (<69 ETDRS letters, 20/50 or worse), where treatment with aflibercept was 55 56 20 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 405 associated with significantly higher vision gain (≥15 ETDRS letters) than bevacizumab or 4 5 6 406 ranibizumab at 12 months; but the significant effects were not maintained at 24 months. The 7 8 407 choice of anti-VEGF drug may depend on specific retinal conditions, baseline visual acuity, and 9 10 408 treatment regimen. 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29
30 http://bmjopen.bmj.com/ 31 32 33 34 35 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 21 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 4 409 LIST OF ABBREVIATIONS 5 6 7 8 410 Adverse event (AE); Age-related macular degeneration (wet AMD); Arterial thromboembolic 9 10 411 events (ATE); Best-corrected visual acuity (BCVA); Bacterial endophthalmitis (BE); Confidence 11 12 412 interval (CI); Choroidal neovascularization (CNV); Diabetic macular edema (DME); Early 13 14 413 Treatment Diabetic Retinopathy Study (ETDRS); Randomized controlled trial (RCT); Risk ratio 15 16 For peer review only 17 414 (RR); Macular edema due to retinal vein occlusion (RVO-ME); Standardized mean difference 18 19 415 (SMD); Vascular endothelial growth factor (VEGF); Venous thromboembolic event (VTE) 20 21 22 416 ACKNOWLEDGEMENTS 23 24 25 26 417 We thank Becky Skidmore for drafting our search strategies, Kelly Farrah for peer reviewing the 27 28 418 search strategies (PRESS), and Alissa Epworth for de-duplicating search results and obtaining 29
30 419 full-text articles. We thank Meghan Kenny for helping screen studies for inclusion and http://bmjopen.bmj.com/ 31 32 33 420 performing quality appraisal and Jaimie Adams for helping screen studies for inclusion. We 34 35 421 would also like to thank Michel Boucher, Sarah Berglas, Hongbo Yuan, and Sarah Jennings for 36 37 422 their valuable contribution, insights, and for facilitating the production and dissemination of the
38 on September 24, 2021 by guest. Protected copyright. 39 423 synthesized evidence. In addition we would like to thank the clinical experts and stakeholders 40 41 42 424 who provided feedback on the previous therapeutic review report. Finally, we thank Susan Le, 43 44 425 Inthuja Selvaratnam, Katrina Chiu, and Krystle Amog for preparing tables and formatting the 45 46 426 manuscript for submission. 47 48 49 50 51 52 53 54 55 56 22 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 427 CONTRIBUTORS 4 5 6 7 428 BP screened titles, abstracts, and full-text articles; abstracted and cleaned data, conducted quality 8 9 429 assessment; and drafted the manuscript. SMT lead the coordination of the systematic review; 10 11 430 drafted the protocol; screened titles, abstracts, and full-text articles; abstracted and cleaned data; 12 13 431 conducted quality assessment; and helped draft and revise the manuscript. TL screened titles, 14 15 16 432 abstracts, and full-textFor articles; peer abstracted andreview cleaned data; conductedonly quality assessment; 17 18 433 helped conduct meta-analysis; and reviewed the manuscript. EL screened titles, abstracts, and 19 20 434 full-text articles; abstracted and cleaned data; conducted quality assessment; and reviewed the 21 22 23 435 manuscript. JH conducted the analysis and interpretation of data; and reviewed the manuscript. 24 25 436 TR helped with conceptualizing the research design, drafting and revising the protocol, 26 27 437 interpretation of data; and reviewed the manuscript. GJ helped draft and revise the protocol; 28 29 438 screened titles, abstracts, and full-text articles; abstracted data; conducted quality assessment; 30 http://bmjopen.bmj.com/ 31 32 439 helped interpret the data; and reviewed the manuscript. AA screened titles, abstracts, and full- 33 34 440 text articles; abstracted and cleaned data; conducted quality assessment; and reviewed the 35 36 441 manuscript. JPS screened titles, abstracts, and full-text articles; abstracted and cleaned data; 37
38 on September 24, 2021 by guest. Protected copyright. 39 442 conducted quality assessment; and reviewed the manuscript. AS screened titles, abstracts, and 40 41 443 full-text articles; abstracted and cleaned data, conducted quality assessment; and reviewed the 42 43 444 manuscript. RW screened titles, abstracts, and full-text articles; abstracted and cleaned data, 44 45 46 445 conducted quality assessment; and reviewed the manuscript. RB abstracted and cleaned data, 47 48 446 conducted quality assessment; and reviewed the manuscript. EM screened titles, abstracts, and 49 50 447 full-text articles; abstracted and cleaned data; and reviewed the manuscript. SES helped with 51 52 53 448 conceptualizing the research and design; interpretation of data, and reviewed the manuscript. 54 55 56 23 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 449 ACT conceptualized the research and design; drafted the protocol; obtained funding; assisted 4 5 6 450 with data acquisition and interpretation; and drafted and revised the manuscript. Authors ACT 7 8 451 and BP had full access to all the data in the study and takes responsibility for the integrity of the 9 10 452 data and the accuracy of the data analysis. 11 12 13 453 FUNDING 14 15 16 For peer review only 17 454 This work was supported by the Canadian Institutes of Health Research/Drug Safety and 18 19 455 Effectiveness Network (CIHR/DSEN). SES is funded by a Tier 1 Canada Research Chair in 20 21 456 Knowledge Translation. ACT is funded by a Tier 2 Canada Research Chair in Knowledge 22 23 24 457 Synthesis. The therapeutic review was commissioned by the Canadian Agency for Drugs and 25 26 458 Technology in Health (CADTH) and funded by a grant from the Canadian Institutes of Health 27 28 459 Research Drug Safety and Effectiveness Network. The funders had no role in design and conduct 29
30 http://bmjopen.bmj.com/ 31 460 of the study; collection, management, analysis, and interpretation of the data; preparation, 32 33 461 review, or approval of the manuscript; and decision to submit the manuscript for publication. 34 35 36 462 COMPETING INTERESTS 37
38 on September 24, 2021 by guest. Protected copyright. 39 463 All authors declare no competing interests. 40 41 42 43 464 PROVENANCE AND PEER REVIEW 44 45 46 465 Not commissioned; externally peer reviewed. 47 48 49 50 51 52 53 54 55 56 24 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 466 DATA SHARING STATEMENT 4 5 6 7 467 All datasets generated and/or analysed during the current study are available from the 8 9 468 corresponding author on reasonable request. 10 11 12 469 MEETING PRESENTATION 13 14 15 470 The data from the original therapeutic review was presented by ACT and SMT to the Canadian 16 For peer review only 17 18 471 Drug Expert Committee in Ottawa, Ontario, on Nov 17th, 2015. 19 20 21 472 OPEN ACCESS 22 23 24 473 This is an Open Access article distributed in accordance with the Creative Commons Attribution 25 26 27 474 Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, 28 29 475 build upon this work non-commercially, and license their derivative works on different terms,
30 http://bmjopen.bmj.com/ 31 476 provided the original work is properly cited and the use is non-commercial. See: 32 33 34 477 http://creativecommons.org/licenses/by-nc/4.0/ 35 36 37
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1 2 3 4 478 REFERENCES 5 6 7 8 479 1. Bourne RR, Jonas JB, Flaxman SR, et al. Prevalence and causes of vision loss in high-income 9 480 countries and in Eastern and Central Europe: 1990-2010. Br J Ophthalmol 10 481 2014;98(5):629-38. doi: 10.1136/bjophthalmol-2013-304033 [published Online First: 11 482 2014/03/26] 12 483 2. Congdon N, O'Colmain B, Klaver CC, et al. Causes and prevalence of visual impairment 13 484 among adults in the United States. Arch Ophthalmol 2004;122(4):477-85. doi: 14 485 10.1001/archopht.122.4.477 [published Online First: 2004/04/14] 15 16 486 3. Campochiaro PA.For Anti-vascular peer endothelial review growth factor treatmentonly for retinal vein 17 487 occlusions. Ophthalmologica 2012;227 Suppl 1:30-5. doi: 10.1159/000337157 [published 18 488 Online First: 2012/04/25] 19 489 4. Ehlers JP, Fekrat S. Retinal vein occlusion: beyond the acute event. Surv Ophthalmol 20 490 2011;56(4):281-99. doi: 10.1016/j.survophthal.2010.11.006 [published Online First: 21 491 2011/05/24] 22 23 492 5. Ford JA, Elders A, Shyangdan D, et al. The relative clinical effectiveness of ranibizumab and 24 493 bevacizumab in diabetic macular oedema: an indirect comparison in a systematic review. 25 494 BMJ 2012;345:e5182. 26 495 6. Silva R. Myopic maculopathy: a review. Ophthalmologica 2012;228(4):197-213. doi: 27 496 10.1159/000339893 [published Online First: 2012/08/01] 28 497 7. Wong TY, Ferreira A, Hughes R, et al. Epidemiology and disease burden of pathologic 29 498 myopia and myopic choroidal neovascularization: an evidence-based systematic review.
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38 595 age-related choroidal neovascularisation: 2-year findings of the IVAN randomised on September 24, 2021 by guest. Protected copyright. 39 596 controlled trial. Lancet 2013;382(9900):1258-67. doi: 10.1016/S0140-6736(13)61501-9. 40 597 Epub 2013 Jul 19 41 598 36. Kodjikian L, Souied EH, Mimoun G, et al. Ranibizumab versus bevacizumab for neovascular 42 599 age-related macular degeneration: results from the GEFAL noninferiority randomized 43 44 600 trial. Ophthalmology 2013;120(11):2300-09. doi: 10.1016/j.ophtha.2013.06.020. Epub 45 601 2013 Aug 2 46 602 37. Krebs I, Schmetterer L, Boltz A, et al. A randomised double-masked trial comparing the 47 603 visual outcome after treatment with ranibizumab or bevacizumab in patients with 48 604 neovascular age-related macular degeneration. Br J Ophthalmol 2013;97(3):266-71. doi: 49 605 10.1136/bjophthalmol-2012-302391. Epub 2013 Jan 3 50 606 38. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age- 51 52 607 related macular degeneration. Ophthalmology 2012;119(12):2537-48. 53 608 39. Biswas P, Sengupta S, Choudhary R, et al. Comparative role of intravitreal ranibizumab 54 609 versus bevacizumab in choroidal neovascular membrane in age-related macular 55 56 28 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 30BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 610 degeneration. Indian J Ophthalmol 2011;59(3):191-6. doi: 10.4103/0301-4738.81023 4 611 [published Online First: 2011/05/19] 5 6 612 40. Biswas P, Sengupta S, Choudhary R, et al. Comparing ranibizumab with bevacizumab. 7 613 Ophthalmology 2011;118(3):600-00. doi: 10.1016/j.ophtha.2010.10.027 8 614 41. The CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related 9 615 macular degeneration. N Engl J Med 2011;364(20):1897-908. 10 616 42. Subramanian ML, Abedi G, Ness S, et al. Bevacizumab vs ranibizumab for age-related 11 617 macular degeneration: 1-year outcomes of a prospective, double-masked randomised 12 618 clinical trial. Eye (Lond) 2010;24(11):1708-15. doi: 10.1038/eye.2010.147. Epub 2010 13 14 619 Oct 1 15 620 43. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: 16 621 results from For2 phase IIIpeer randomized review trials: RISE and RIDE.only Ophthalmology 17 622 2012;119(4):789-801. doi: 10.1016/j.ophtha.2011.12.039. Epub 2012 Feb 11 18 623 44. Heier JS, Korobelnik JF, Brown DM, et al. Intravitreal Aflibercept for Diabetic Macular 19 624 Edema: 148-Week Results from the VISTA and VIVID Studies. Ophthalmology 20 21 625 2016;123(11):2376-85. doi: 10.1016/j.ophtha.2016.07.032 [published Online First: 22 626 2016/10/25] 23 627 45. The Diabetic Retinopathy Clinical Research N, Elman MJ, Aiello LP, et al. Randomized 24 628 Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus 25 629 Prompt Laser for Diabetic Macular Edema. Ophthalmology 2010;117(6):1064-77.e35. 26 630 doi: 10.1016/j.ophtha.2010.02.031 27 631 46. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following 28 29 632 central retinal vein occlusion: six-month primary end point results of a phase III study.
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38 640 edema secondary to central retinal vein occlusion: six-month results of the phase 3 on September 24, 2021 by guest. Protected copyright. 39 641 COPERNICUS study. Ophthalmology 2012;119(5):1024-32. doi: 40 642 10.1016/j.ophtha.2012.01.042. Epub 2012 Mar 21 41 643 49. Holz FG, Roider J, Ogura Y, et al. VEGF Trap-Eye for macular oedema secondary to central 42 644 retinal vein occlusion: 6-month results of the phase III GALILEO study. Br J Ophthalmol 43 44 645 2013;97(3):278-84. doi: 10.1136/bjophthalmol-2012-301504. Epub 2013 Jan 7 45 646 50. Bucher HC, Guyatt GH, Griffith LE, et al. The results of direct and indirect treatment 46 647 comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol 47 648 1997;50(6):683-91. [published Online First: 1997/06/01] 48 649 51. Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular 49 650 age-related macular degeneration. N Engl J Med 2011;364(20):1897-908. doi: 50 651 10.1056/NEJMoa1102673. Epub 2011 Apr 28 51 52 652 52. Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for 53 653 diabetic macular edema. N Engl J Med 2015;372(13):1193-203. doi: 54 654 10.1056/NEJMoa1414264 [published Online First: 2015/02/19] 55 56 29 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 680 FIGURE LEGENDS 4 5 6 7 681 Figure 1. Study Flow 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29
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1 2 3 4 TABLE 1. SUMMARY STUDY CHARACTERISTICS 5 6 7 No. of No. of No. of 8 Total No. No. of studies studies studies 9 of trials studies 10 Study Characteristic with cn- with RVO- with m- included with DME 11 AMD ME (n=2) CNV (n=2) (n=19)a (%) (n=3) (%) 12 (n=12) (%) (%) (%) 13 14 Year of publication 15 2010–2011 5 (26.32) 4 (33.33) 0 (0) 0 (0) 1 (50) 16 2012–2013For6 (31.58) peer5 (41.67)review0 (0) only0 (0) 1 (50) 17 18 2014–2015 5 (26.32) 2 (16.67) 2 (66.67) 1 (50) 0 (0) 19 2016 3 (15.79) 1 (8.33) 1 (33.33) 1 (50) 0 (0) 20 Geographic region 21 22 Europe 8 (42.11) 6 (50) 0 (0) 0 (0) 2 (100) 23 North America 5 (26.32) 3 (25) 1 (33.33) 1 (50) 0 (0) 24 Asia 4 (21.05) 2 (16.67) 1 (33.33) 1 (50) 0 (0) 25 26 Africa 1 (5.26) 0 (0) 1 0 (0) 0 (0) 27 Multi-continent 1 (5.26) 1 (8.33) 1 (33.33) 0 (0) 0 (0) 28 29 Setting
30 Single-Centre 6 (31.58) 2 (16.67) 1 (33.33) 1 (50) 2 (100) http://bmjopen.bmj.com/ 31 Multi-Centre 12 (63.16) 10 (83.33) 1 (33.33) 1 (50) 0 (0) 32 33 NR 1 (5.26) 0 (0) 1 (33.33) 0 (0) 0 (0) 34 Follow-up duration 35 6-12 months 14 (73.68) 9 (75) 2 (66.67) 2 (100) 1 (50) 36 37 13-19 months 4 (21.05) 2 (16.67) 1 (33.33) 0 1 (50)
38 ≥20 months 1 (5.26) 1 (8.33) 0 0 0 (0) on September 24, 2021 by guest. Protected copyright. 39 Footnotes: 40 a 41 Total number of randomized controlled trials, n=19, from 18 publications 42 43 Abbreviations: cn-AMD, choroidal neovascular age-related macular degeneration; DME, 44 diabetic macular edema; m-CNV, myopic choroidal neovascularization; NR, not reported; RVO- 45 ME, macular edema due to retinal vein occlusion. 46 47 48 49 50 51 52 53 54 55 56 32 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 4 TABLE 2. COMPARATIVE EFFECTIVENESS RESULTS 5 6 7 Condition Treatment Outcomea # of RCTs Baseline ETDRS Treatment Effect Comparator Risk Ratio or I2c 8 vs. (# of lettersb ~Snellen Mean (Range)b effect Mean Difference 9 Comparator patients) equivalent Mean (Range)b Estimate (95% 10 CI) 11 Vision gain 9 (3245) 57 (35 to 61) ~ 22% (12 to 33) 23% (14 to 29) 0.95 (0.84, 1.07) 0% 20/80 12 Bevacizumab Vision loss For10 (3302) peer60 (35 to 61) ~ review6% (0 to 11) 7% (4only to 14) 0.91 (0.7, 1.19) 4% 13 vs. 20/63 14 Ranibizumab BCVA change 8 (3064) 56 (35 to 61) ~ 7.2 (4.1, 15.2) 5.9 (0.6, 11.4) -0.03 (-1.08, 1.02) 0% 15 20/80 http://bmjopen.bmj.com/ cn-AMD 16 Vision gain 2 (1815) 54 (53 to 55) ~ 32% (30 to 34) 32% (31 to 34) 0.99 (0.81 to 1.22) 52% 17 20/80 Aflibercept 18 Vision loss 2 (1815) 54 (53 to 55) ~ 5% (5 to 5) 6% (5 to 6) 0.90 (0.60 to 0% vs. 20/80 1.350) 19 Ranibizumab 20 BCVA change 2 (1793) 54 (53 to 55) ~ 8.8 (8.3, 9.4) 8.8 (8.1 to 9.4) -0.05 (-2.5, 2.4) 66% 21 20/80 Vision gain 1 (376) 65 ~ 20/50 35% 37% 0.94 (0.72, 1.23) NA 22 Bevacizumab vs. Vision loss 1 (376) 65 ~ 20/50 3% 2% 0.48 (0.12, 1.91) NA 23 Ranibizumab BCVA change 2 (456) 59 (54, 65) ~ 20/63 10.3 (10.0, 10.5) 12.1 (11.9 to 12.3) -2.0 (-3.9, on September 24, 2021 by guest. Protected copyright. -0.1) 0% 24 Bevacizumab Vision gain 1 (386) 65 ~ 20/50 35% 39% 1.06 (0.80, 1.38) NA 25 vs. Vision loss 1 (376) 65 ~ 20/50 2% 3% 2.08 (0.52, 8.33) NA DME 26 Aflibercept BCVA change 1 (386) 65 ~ 20/50 10.0 (SD: 11.8) 12.8 (SD: 12.4) -2.7 (-5.2, -0.3) NA 27 Vision gain 1 (392) 65 ~ 20/50 39% 37% 1.06 (0.73, 1.22) NA Aflibercept Vision loss 1 (392) 65 ~ 20/50 2% 2% 0.63 (0.15, 2.61) NA 28 vs. BCVA change 2 (462) 56 (47, 65) ~ 20/80 16.2 (12.8 to 14.0 (12.3 to 15.7) 1.4 (-1.6, 4.3) 27% 29 Ranibizumab 30 19.6) Bevacizumab Vision gain 1 (74) 56 ~ 20/80 59% 59% 1.00 (0.68, 1.45) NA 31 vs. BCVA change 1 (77) 56 ~ 20/80 15.6 18.1 -2.5 (-8.0, 5.0) NA 32 Ranibizumab RVO-ME 33 Bevacizumab Vision gain 1 (358) 50 ~ 20/100 65% 61% 1.06 (0.91, 1.25) NA 34 vs. BCVA change 1 (348) 50 ~ 20/100 18.6 18.9 1.5 (-1.2, 4.2) NA 35 Aflibercept 36 Vision gain 1 (32) 30 ~ 20/250 62% 56% 1.11 (0.63, 1.96) NA Bevacizumab Vision loss 1 (32) 30 ~ 20/250 0% 0% 0% NA 37 m-CNV vs. BCVA change 2 (80) 42 (30, 55) ~ 20/160 12.2 (8.5 to 15.9) 13.4 (9.5 to 17.3) -1.3 (-6.5, -4.0) 0% 38 Ranibizumab 39 40 41 33 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Footnotes: 4 a In terms of outcomes, vision gain was defined as a gain in BCVA of ≥15 EDTRS letters, vision loss of ≥15 EDTRS letters, and visual acuity was 5 expressed using ETDRS letters (with conversion, if necessary). The main analysis was conducted with outcomes at the longest follow-up duration 6 for each RCT. 7 b Mean (range) were derived across control groups of the included RCTs. 8 c I2 <75 was interpreted as low evidence of substantial variation across included RCTs. 9 10 11 Abbreviations: BCVA, best-corrected visual acuity; CI, confidence interval; cn-AMD, choroidal neovascular age-related macular degeneration; 12 DME, diabetic macular edema; ETDRS,For early treatmentpeer diabetic retinopathyreview study; m-CNV, onlymyopic choroidal neovascularization; NA, not 13 applicable; RCT, randomized controlled trials; RVO-ME, macular edema due to retinal vein occlusion. 14
15 http://bmjopen.bmj.com/ 16 17 18 19 20 21 22
23 on September 24, 2021 by guest. Protected copyright. 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 34 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 4 TABLE 3. SUMMARY OF TREATMENT REGIMENS 5 6 7 8 Condition Treatment regimen # of Mean monthly 9 RCT injections per 10 s year (range)a 11 cn-AMD Monthly treatment with ranibizumab 5 11.3 (10.9-11.7) 12 Monthly treatmentFor with bevacizumab peer review only3 11.5 (11.0-11.9) 13 14 Treat and extend with ranibizumab 1 8.0
15 Treat and extend with bevacizumab 1 http://bmjopen.bmj.com/ 8.9 16 3 initial monthly treatments + as-needed treatment (every month) with ranibizumab 6 5.7 (4.4-7.1) 17 3 initial monthly treatments + as-needed treatment (every month) with 5 6.3 (4.6-7.9) 18 bevacizumab 19 3 initial monthly treatments and as-needed treatment (every 3 months) with 1 8.5 20 ranibizumab 21 22 3 initial monthly treatments and as-needed treatment (every 3 months) with 1 8.7
23 bevacizumab on September 24, 2021 by guest. Protected copyright. 24 As-needed monthly treatment with ranibizumab 1 6.9 25 As-needed monthly treatment with bevacizumab 1 7.7 26 Monthly treatment with aflibercept 2 11.4b 27 b 28 3 initial monthly treatment and as-needed treatment (every 2 months) with 2 6.9 29 aflibercept 30 DME 3 initial monthly treatments + as-needed treatment (every month) with ranibizumab 1 6.0 31 3 initial monthly treatments + as-needed treatment (every month) with aflibercept 1 5.6 32 3 initial monthly treatments + as-needed treatment (every month for 3 months) + 1 6.5 33 as-needed treatment (every month) with ranibizumab 34 35 3 initial monthly treatments + as-needed treatment (every month for 3 months) + 1 5.1 36 as-needed treatment (every month) with bevacizumab 37 As-needed treatment till stable visual acuity (up to 6 months) + as-needed treatment 1 10c 38 (every month) with ranibizumab 39 As-needed treatment till stable visual acuity (up to 6 months) + as-needed treatment 1 10c 40 41 35 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 (every month) with bevacizumab 4 c 5 As-needed treatment till stable visual acuity (up to 6 months) + as-needed treatment 1 9 6 (every month) with aflibercept 7 RVO-ME 1 initial monthly treatment + as-needed treatment (every month) with ranibizumab 1 6.4 8 1 initial monthly treatment + as-needed treatment (every month) with bevacizumab 1 6.0 9 Monthly treatment with aflibercept 1 11.6 10 Monthly treatment with bevacizumab 1 11.5 11 12 m-CNV 1 initial monthly treatmentFor + as-neededpeer treatment review (every month) with ranibizumab only2 2.4 (1.7-3.1) 13 1 initial monthly treatment + as-needed treatment (every month) with bevacizumab 2 3.1 (1.9-4.3) 14
15 Footnotes: http://bmjopen.bmj.com/ 16 aMean and ranges were derived from trial-specific means. Cases, in which a single RCT reported on a regimen, do not have an associated range. 17 bValue was reported once for both trials in Heier et al. 2012. 18 cReported median values (Wells et al. 2015) 19 20 Abbreviations: cn-AMD, choroidal neovascular age-related macular degeneration; DME, diabetic macular edema; m-CNV, myopic choroidal 21 neovascularization; RCT, randomized controlled trial; RVO-ME, macular edema due to retinal vein occlusion. 22
23 on September 24, 2021 by guest. Protected copyright. 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 36 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 4 TABLE 4. COMPARISON OF MONTHLY VERSUS AS NEEDED ANTI-VEGF TREATMENT REGIMENS IN CN-AMD 5 6 7 PATIENTS 8 9 10 Comparison Outcome # of Baseline ETDRS As-needed regimen Monthly Regimen Risk Ratio or Mean I2c a b b b 11 RCTs , letters and Snellen Mean (Range) Mean (Range) Difference # of equivalent Estimate (95% CI) 12 patientsFor peer review only 13 Vision gain 2/1622 62 (61 to 63) ~ 20/63 20.8% (15.1 to 26.4) 28.9% (25.1 to 0.73 (0.55, 0.95) 0% 14 32.8) As-Needed Rx 15 BCVA 2/1622 62 (61 to 63) ~ 20/63 4.9 (3.5, 6.4) 6.9 (5.5, 8.3) -1.9 (-0.5, -3.3) http://bmjopen.bmj.com/ 0% vs. Monthly Rx 16 change 17 Mortality 2/1795 NA 4.6% (2.6 to 6.6) 2.3% (1.4 to 3.3) 2.00 (1.15, 3.45) 12% 18 19 Footnotes: 20 a CATT and IVAN trials.(Martin, 2011; Chakravarthy 2013) 21 b Mean (range) were derived across control groups of the included RCTs. 22 c I2 <75 was interpreted as low evidence of substantial variation across included RCTs. For each treatment regimen, patients were randomized to be
23 treated with bevacizumab or ranibizumab. on September 24, 2021 by guest. Protected copyright. 24 25 Abbreviations: CI, confidence interval; ETDRS, early treatment diabetic retinopathy study; NA, not applicable; RCT, randomized controlled 26 trials; Rx, treatment. 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 37 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 39 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 4 682 ADDITIONAL FILES 5 6 7 8 683 Additional File 1: PRISMA Checklist 9 10 684 Additional File 2: Supplementary Online Content 11 12 685 Appendix 1: Detailed methods 13 14 686 Appendix 2: Detailed study characteristics 15 16 For peer review only 17 687 Appendix 3: Detailed patient characteristics 18 19 688 Appendix 4: Cochrane risk of bias results for individual studies 20 21 689 Appendix 5: Risk of bias results 22 23 24 690 Appendix 6: Treatment effect estimates 25 26 691 Appendix 7: Forest plots for primary outcome in choroidal neovascular age related macular 27 28 692 degeneration (cn-AMD) population 29
30 http://bmjopen.bmj.com/ 31 693 Appendix 8: Summary data used in risk of bias results 32 33 694 Appendix 9: Sensitivity analysis estimates 34 35 695 Appendix 10: Summary of anti-VEGF treatment protocols 36 37 696 Appendix 11: Summary of results from the DRCR.net trial (Wells 2015a and Wells 2016b) 38 on September 24, 2021 by guest. Protected copyright. 39 40 697 Appendix 12: Mean change in best-corrected visual acuity letter scores over time in patients 41 42 698 treated with bevacizumab or ranibizumab 43 44 45 46 47 48 49 50 51 52 53 38 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29
30 http://bmjopen.bmj.com/ 31 32 33 34 35 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 Figure 1. Study Flow 46 47 215x279mm (300 x 300 DPI) 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 PRISMA Checklist 4 5 6 7 Reported on Section/topic # Checklist item 8 page # 9
10 TITLE 11 Title 1 Identify the report as a systematic review, meta-analysis, or both. 1 12 ABSTRACT For peer review only 13 14 Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; 3-4
15 study eligibility criteria, participants, and interventions; study appraisal and synthesishttp://bmjopen.bmj.com/ methods; 16 results; limitations; conclusions and implications of key findings; systematic review registration 17 number. 18 INTRODUCTION 19 20 Rationale 3 Describe the rationale for the review in the context of what is already known. 6 21 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, 6 22 interventions, comparisons, outcomes, and study design (PICOS).
23 on September 24, 2021 by guest. Protected copyright. 24 METHODS 25 Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if 6; Appendix 1 26 available, provide registration information including registration number. 27 28 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., 7-8; 29 years considered, language, publication status) used as criteria for eligibility, giving rationale. Appendix 1 30 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study 7; Appendix 1 31 authors to identify additional studies) in the search and date last searched. 32 33 Search 8 Present full electronic search strategy for at least one database, including any limits used, such Appendix 1 34 that it could be repeated. 35 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, 7-8; 36 and, if applicable, included in the meta-analysis). Appendix 1 37 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) 8; Appendix 1 38 and any processes for obtaining and confirming data from investigators. 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any 7-8, 4 assumptions and simplifications made. Appendix 1 5 6 Risk of bias in individual 12 Describe methods used for assessing risk of bias of individual studies (including specification of 8; Appendix 1 7 studies whether this was done at the study or outcome level), and how this information is to be used in 8 any data synthesis. 9 Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 8-9; 10 Appendix 1 11 Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including 8-9; 12 measuresFor of consistencypeer (e.g., I2review) for each meta-analysis. only Appendix 1 13 14
15 Risk of bias across 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g.,http://bmjopen.bmj.com/ publication 8; Appendix 1 16 studies bias, selective reporting within studies). 17 Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta- 8-9; 18 regression), if done, indicating which were pre-specified. Appendix 1 19 20 RESULTS 21 Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with 9; Fig. 1 22 reasons for exclusions at each stage, ideally with a flow diagram.
23 on September 24, 2021 by guest. Protected copyright. 24 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, 10; Appendix 25 follow-up period) and provide the citations. 2-3 26 Risk of bias within 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see 10; Appendix 27 studies item 12). 4-5 28 29 Results of individual 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary 9-18, studies data for each intervention group (b) effect estimates and confidence intervals, ideally with a Appendix 7 30 forest plot. 31 32 Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of 10-18 33 consistency. 34 Risk of bias across 22 Present results of any assessment of risk of bias across studies (see Item 15). 10; Appendix 35 studies 4-5 36 Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta- 11-16, 37 regression [see Item 16]). Appendix 9 38 39 DISCUSSION 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider 18-20 4 their relevance to key groups (e.g., healthcare providers, users, and policy makers). 5 6 Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., 19 7 incomplete retrieval of identified research, reporting bias). 8 Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications 19-20 9 for future research. 10
11 FUNDING 12 Funding 27 DescribeFor sources peer of funding for thereview systematic review and otheronly support (e.g., supply of data); 24 13 role of funders for the systematic review. 14
15 http://bmjopen.bmj.com/ From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS 16 Med 6(7): e1000097. doi:10.1371/journal.pmed1000097 17 18 19 20 21 22
23 on September 24, 2021 by guest. Protected copyright. 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 44BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 Supplementary Online Content 4 5 6 7 8 Appendix 1: Detailed methods ...... 2 9 10 Protocol ...... 2 11 Literature Search Strategy ...... 2 12 13 Keywords ...... 2 14 15 Eligibility Criteria ...... 2 16 Study selection ...... For peer review only 4 17 18 Data abstraction ...... 4 19 Risk of bias assessment ...... 4 20 21 Data Analysis in CADTH report ...... 5 22 23 Data analysis in manuscript ...... 5 24 Excluded RCT’S ...... 5 25 26 Medline Literature Search ...... 5 27 Appendix 2: Detailed study characteristics ...... 13 28 29 Appendix 3: Detailed patient characteristics ...... 16
30 http://bmjopen.bmj.com/ Appendix 4: Cochrane risk of bias results for individual studies ...... 18 31 32 Appendix 5: Risk of bias results ...... 20 33 34 Appendix 6: Treatment effect estimates ...... 21 35 Appendix 7: Forest plots for primary outcome in choroidal neovascular age related macular degeneration (cn- 36 AMD) population ...... 30 37
38 A: Vision gain in cn-AMD population ...... 30 on September 24, 2021 by guest. Protected copyright. 39 40 B: Sensitivity analyses for vision gain in cn-AMD population ...... 31 41 Sensitivity Analysis: 1 Year Follow-Up ...... 31 42 43 Sensitivity Analysis: Low Risk of Selection Bias ...... 31 44 Sensitivity Analysis: De Novo Patients ...... 32 45 46 Appendix 8: Summary data used in risk of bias results ...... 33 47 48 Appendix 9: Sensitivity analysis estimates ...... 35 49 Appendix 10: Summary of anti-VEGF treatment protocols ...... 37 50 a b 51 Appendix 11: Summary of results from the DRCR.net trial (Wells 2015 and Wells 2016 ) ...... 43 52 Appendix 12: Mean change in best-corrected visual acuity letter scores over time in patients treated with 53 bevacizumab or ranibizumab ...... 46 54 55 References ...... 47 56 57 58 1 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 45 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 Appendix 1: Detailed methods 4 5 6 We conducted a systematic review using methods from the Cochrane Handbook for Systematic Reviews and 7 reported the results using the PRISMA statement.1 The SR was commissioned by CADTH and funded by a grant 8 9 from the Canadian Institutes of Health Research Drug Safety and Effectiveness Network. The methods are outlined 2 10 briefly below, as they are outlined in full in the CADTH report. 11 12 Protocol 13 14 We drafted a protocol with input from clinical experts, patient advocacy groups, industry stakeholders and CADTH. 15 We posted the draft on the CADTH website to obtain feedback from additional stakeholders, revised the protocol as 16 necessary, and registeredFor the final versionpeer with PROSPERO review (CRD 42015022041). only 17 18 Literature Search Strategy 19 20 The following bibliographic databases were searched from inception until August 17th 2017, 2015: MEDLINE 21 (1946-) with in-process records & daily updates via Ovid; Embase (1974-) via Ovid; Cochrane Central Register of 22 Controlled Trials via Ovid, and PubMed. Grey literature (i.e., studies that are not widely available or commercially 23 published) was identified by searching relevant websites according to the “Clinical Trials” section of the CADTH 24 Grey Matters checklist.3 We used Google and other Internet search engines to search for additional web-based 25 materials, including conference abstracts. We obtained additional studies by reviewing the references of all included 26 27 studies and feedback from clinical experts, patient advocacy groups, and industry stakeholders. In addition, we 28 contacted the three manufacturers of the anti-VEGF drugs to identify further potentially relevant trials. 29 An experienced information specialist developed the literature search strategy. It was peer-reviewed by another 30 information specialist using the PRESS statement.4 The final search strategy can be found in Appendix A and the http://bmjopen.bmj.com/ 31 others are available upon request of the corresponding author. 32 33 The literature search consisted of both controlled vocabulary, such as the National Library of Medicine’s MeSH 34 (Medical Subject Headings), and keywords (see below). The main search concepts were anti-VEGF drugs and the 35 relevant retinal conditions. Validated methodological filters were applied to limit retrieval to RCTs.5 Where 36 possible, retrieval was limited to humans. Retrieval was not limited by publication year or by language, but non- 37 English language articles were excluded during screening, to increase feasibility of the study.
38 on September 24, 2021 by guest. Protected copyright. 39 Keywords 40 41 (intravitreal OR intra-vitreal or implant or implanted or implants or inject or injected or injects or injection or 42 injections or Anti-VEGF or antiVEGF or VEGF inhibitor or VEGF antagonist or visudyne or verteporfin or PDT or 43 44 PDTV or VPDT) 45 AND 46 47 (retinal degeneration OR wet macular degeneration OR wAMD OR neovascular macular degeneration OR exudative 48 macular degeneration or diabetic retinopathy or DRE or Macular Edema or Retinal Vein Occlusion or Choroidal 49 Neovascularization or BRVO or CRVO) 50 51 Eligibility Criteria 52 53 The inclusion criteria were specified as follows according to the Population, Intervention, Comparator, Outcome, 54 Study design and Time framework (Cochrane Handbook).5 55 56 57 58 2 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 46BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 Populations: patients ≥ 18 years of age and with retinal conditions including wet AMD, DME, ME/RVO 4 and myopic CNV. 5 6 Interventions: anti-VEGF drugs in use in Canada, namely ranibizumab, intravitreal bevacizumab and 7 aflibercept 8 9 Comparators: placebo, ranibizumab, intravitreal bevacizumab or aflibercept 10 Outcomes: 14 outcomes were selected a-priori at the protocol stage according to feedback from the 11 research team, clinical experts, patient advocacy groups, industry stakeholders and CADTH, including five 12 efficacy outcomes and nine safety outcomes (outlined below). 13 14 Study design: parallel- and cluster-RCTs. 15 Time: RCTs published at any time; all reports pertaining to an RCT were located to obtain data at the 16 For peer review only 17 longest follow-up duration. 18 We excluded studies reporting only results for pediatric patients (<18 years of age), studies evaluating the anti- 19 VEGF drug pegaptanib, as it is no longer licensed for use in Canada, studies that compared an anti-VEGF drug with 20 other comparators (such as intravitreal corticosteroids, grid laser photocoagulation or cataract removal surgery), and 21 studies reported in languages other than English. Studies fulfilling the last two exclusion criteria were excluded to 22 allow for the project timelines to be met, as outlined in the Limitations and Research Implications sections below. 23 24 We included the following efficacy outcomes: 25 26 1. Vision gain, defined as a gain in Best-Corrected Visual Acuity (BCVA) of ≥15 letters on the Early 27 Treatment Diabetic Retinopathy Study (ETDRS) chart, 28 2. Vision loss, defined as a loss in BCVA of ≥15 ETDRS letters, 29 3. Change from baseline in BCVA letters, 30 http://bmjopen.bmj.com/ 31 4. Legal blindness, 32 33 5. Vision-related function. 34 We included the following safety outcomes: 35 36 1. All-cause mortality, 37 2. Arterial venous thromboembolism (VT),
38 on September 24, 2021 by guest. Protected copyright. 39 3. Venous VT, 40 4. Bacterial endophthalmitis (BE), 41 42 5. Increased intraocular pressure, 43 6. Retinal detachment, 44 45 7. Adverse events (AEs) 46 8. Serious AEs, 47 48 9. Withdrawals due to AEs 49 We considered BCVA data derived from Snellen or ETDRS letter charts or the logarithm of the Minimum Angle of 50 Resolution (logMAR) chart for assessing efficacy outcomes 1-3.6 The Snellen chart is the current standard for 51 6-8 52 measurement of visual acuity in clinical practice. The ETDRS chart is the ‘gold standard’ for measuring visual 6 53 acuity in clinical trials. The Snellen chart has letters of different sizes arranged from largest at the top to smallest at 54 the bottom, which are read, one eye at a time, at a distance of 6 metres (20 feet). The test-retest variability of the 55 Snellen chart ranges from ±5 to 16.5 letters in normal patients.9 10 The test-retest variability of the ETDRS charts 56 ranges from ±3.5 to 10 letters.11 A change of at least 10 letters (or two lines) is required to capture a true clinical 57 58 3 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 47 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 change in visual acuity.6 12 With respect to vision-related function, we abstracted data from the 25-item National 4 Eye Institute Visual Function Questionnaire (NEI VFQ-25), which is a self-reported survey questionnaire that 5 assesses the influence of visual impairment on health-related quality of life.13 Changes in the NEI VFQ overall 6 scores of 10 points or more are associated with clinically relevant changes in vision.14 7 8 Study selection 9 10 Citations from the literature search were imported into an online systematic review software.15 Also imported were 11 12 the inclusion criteria, which were used for level-1 screening of citations (titles/abstracts) and level-2 screening of 13 potentially relevant full-text articles. The 14 members of the review team underwent two training exercises; each 14 involved a random sample of 50 citations, which were screened independently by all team members. Level-1 15 screening proceeded after 80% agreement had been achieved among the reviewers on the second training exercise.16 16 17 Paired reviewers conductedFor the level-1peer screening review of each citation, independently. only The estimated frequency of 17 disagreement was 8%, which was resolved by a third reviewer. We retrieved the full-text articles of potentially 18 relevant citations identified by at least one reviewer for level-2 screening. The team underwent a training exercise 19 using a random sample of 20 full-text articles, which resulted in 70% agreement. Paired reviewers independently 20 screened each full-text article. The estimated frequency of disagreement was 14%, which was resolved by a third 21 reviewer. This reviewer also verified all eligible studies. 22 23 Data abstraction 24 25 We developed a data abstraction form with inputs from two physicians. We piloted and refined the form two times, 26 27 each time using five randomly selected studies. Subsequently, paired reviewers conducted the abstraction, 18 28 independently. Numerical data available only in figures were extracted using WebPlotDigitizer. A third reviewer 29 conducted a quality check on all data, and resolved any remaining discrepancies.
30 We abstracted data pertaining to study characteristics, patient populations, interventions, and outcomes. Multiple http://bmjopen.bmj.com/ 31 reports of the same trial (hereafter companion reports) were identified using the trial registration identifier, trial 32 19 33 name, or a juxtaposition of the author names, treatment comparisons, sample sizes and outcomes, if necessary. We 34 abstracted data from all companion reports, identified differences, and reconciled the differences through discussion. 35 For each set of companion reports, we considered one as the major publication and others as companion reports. We 36 abstracted outcome data from all trial reports and used the data corresponding to the longest duration of follow-up in 37 the meta-analysis.5
38 on September 24, 2021 by guest. Protected copyright. 39 Risk of bias assessment 40 41 The risk of bias in the included trials was appraised using the Cochrane risk-of-bias tool, including selection bias, 42 performance bias, detection bias, attrition bias, reporting bias, and other biases such as funding sources.20 For 43 selection bias, we assessed the reporting of random sequence generation and allocation concealment. For 44 performance bias, we assessed the reporting of blinding of patients and trial personnel, and for detection bias, the 45 reporting of the blinding of outcome assessors. In the assessment of performance and detection biases, we 46 considered the objectivity of the primary outcome of individual trials in assessing performance and detection biases. 47 48 For RCTs that had been registered, the primary outcome was identified from the trial protocol, which was vision 49 gain or change in mean BCVA in the majority of the included RCTs. Otherwise, we identified the primary outcome 50 using an a-priori defined algorithm.21 22 In brief, we selected from the trial report the outcome that was listed in the 51 title or objectives, the most serious clinical outcome among all the trial outcomes, or the first reported outcome in 52 the results section. 53 54 Paired reviewers conducted the risk of bias assessment, independently. Discrepancies were resolved by discussion or 55 the involvement of a third reviewer. 56 57 58 4 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 48BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 Data Analysis in CADTH report 4 5 We derived treatment effect estimates using the odds ratio (OR) for binary outcomes such as vision gain, vision loss 6 or the presence or absence of a harmful event. The standardized mean difference (SMD) was used for treatment 7 comparisons involving BCVA data from different visual acuity charts, such as ETDRS or Snellen charts. The SMD 8 9 expresses the difference in the treatment means in terms of the standard deviations of the measurements. The mean 10 difference (MD) was used for comparison involving BCVA data that were consistently reported using the same 11 measurement scale, either the ETDRS or Snellen chart. This was also the case for vision-related function 12 measurements from the NEI VFQ questionnaire. 13 The results from multiple arms of the same anti-VEGF drugs at different dosages were combined according to the 14 guidance in the Cochrane handbook.5 When an RCT did not provide standard deviations for a continuous outcome 15 23 16 measure, missing data wereFor imputed peer from available review data from other RCTs only using established methods. This was 17 necessary in meta-analyses involving BCVA measures and vision-related functions. 18 We conducted meta-analyses of pairwise comparisons of all comparators, including the anti-VEGF drugs and 19 placebo. This was done separately for each of the four retinal conditions. The variation across RCTs in any outcome 20 2 2 5 measures was assessed using the I statistic, with values of I >75% indicating substantial statistical heterogeneity. 21 Pooled treatment effect estimates and 95% confidence intervals (CIs) were derived using the meta-analytical random 22 23 24 23 effects model. The meta-analyses were conducted using the "metafor” package in R (version 3.1.1). 24 25 Data analysis in manuscript 26 27 Study results were synthesized with respect to benefits and harms, trends in BCVA improvement over time, and 28 treatment regimens (e.g., monthly and as-needed regimens). To facilitate the synthesis of results, BCVA values 29 reported in logMAR and decimal measures were converted to approximate ETDRS letter scores,25 with approximate 26 30 standard deviations. Pairwise comparisons of drugs were assessed at the longest treatment duration, allowing for http://bmjopen.bmj.com/ 31 the inclusion of trials in the meta-analysis that reported outcome data at different time points. Subgroup analyses 32 were conducted at 12 months and 24 months, as these were the most frequently reported time points. For DME 33 patients, treatment effect estimates were obtained for all patients as well as pre-specified subgroups based upon 34 baseline BCVA, as reported in the DCRC.net trial.27 The meta-analysis was conducted using a random-effects 35 model, given the assumption of varying treatment effects across trials. A sensitivity analysis was conducted by 36 37 restricting to trials determined to be at low risk of selection bias. Between-study heterogeneity was assessed using the I² statistic, with values above 75% indicating substantial heterogeneity.5 38 on September 24, 2021 by guest. Protected copyright. 39 40 41 Excluded RCT’S 42 43 The RCT by Rajagopal et al. 201528 (n=98 participants) was excluded because the investigators reported in the 44 results section that an additional nine patients were included in the study but were not randomized to treatment due 45 to financial hardship and were instead assigned to the bevacizumab group. The study by Pece et al. 201429 was 46 excluded because the investigators randomized 78 eyes from 80 patients with myopic CNV to treatment with 47 48 bevacizumab or ranibizumab, and reported eye-based analyses. For this review we were only interested in patient- 49 based analyses. 50 51 Medline Literature Search 52 53 Interface: Ovid 54 Databases: 55 56 Embase <1974 to 2015 May 26> 57 58 5 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 49 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 MEDLINE Daily and MEDLINE 1946 to present 4 5 MEDLINE In-Process & Other Non-Indexed Citations 6 Cochrane Central Register of Controlled Trials
38 on September 24, 2021 by guest. Protected copyright. 39 11 Macular Edema/ 40 12 ((macula* or retina*) adj3 (edema$1 or oedema$1)).tw,kw. 41 42 13 (Irvine-Gass adj3 (edema$1 or oedema$1 or syndrome$1)).tw,kw. 43 14 (cystoid macula* adj dystroph*).tw,kw. 44 45 15 Retinal Vein Occlusion/ 46 16 (retinal vein adj3 (occlu* or obstruct* or clos* or stricture* or steno* or block* or embolism*)).tw,kw. 47 48 17 (BRVO or CRVO).tw,kw. 49 18 Choroidal Neovascularization/ 50 51 19 ((choroid* or subretinal or sub-retinal) adj1 neovasculari#ation*).tw,kw. 52 20 CNV.tw,kw. 53 54 21 or/2-20 [CONDITIONS – MEDLINE] 55 22 Vascular Endothelial Growth Factor A/ai 56 57 58 6 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 50BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 23 (anti adj2 VEGF$1).tw,kw. 4 5 24 antiVEGF$1.tw,kw. 6 25 (antivascular endothelial growth factor$1 or anti-vascular endothelial growth factor$1).tw,kw. 7 8 26 Antibodies, Monoclonal, Humanized/ 9 27 (monoclonal antibod* and humani#ed).tw,kw. 10 11 28 (antibod* adj2 humani#ed).tw,kw. 12 29 Angiogenesis Inhibitors/ 13 14 30 (angiogen* adj3 (inhibitor* or antagonist*)).tw,kw. 15 31 (anti-angiogen* or antiangiogen*).tw,kw. 16 For peer review only 17 32 aflibercept.tw,kw. 18 33 ("AVE 0005" or AVE0005 or "AVE 005" or AVE005 or "Bay 86-5321" or "Bay86-5321" or Eylea or "UNII- 19 15C2VL427D" or Zaltrap or ZIV-aflibercept).tw,kw. 20 21 34 ((vasculotropin or vascular endothelial growth factor or VEGF) adj trap*).tw,kw. 22 35 aflibercept.rn. 23 24 36 Bevacizumab.tw,kw. 25 37 (Altuzan or Avastin or "nsc 704865" or nsc704865 or "rhuMAb-VEGF" or "UNII-2S9ZZM9Q9V").tw,kw. 26 27 38 IVB injection$1.tw,kw. 28 39 Bevacizumab.rn. 29
30 40 Pegaptanib.tw,kw. http://bmjopen.bmj.com/ 31 32 41 ("EYE 001" or EYE001 or Macugen or "NX 1838" or NX1838 or "UNII-3HP012Q0FH").tw,kw. 33 42 Pegaptanib.rn. 34 35 43 Ranibizumab.tw,kw. 36 44 (Lucentis or "rhuFab V2" or "UNII-ZL1R02VT79").tw,kw. 37 45 IVR injection$1.tw,kw. 38 on September 24, 2021 by guest. Protected copyright. 39 46 Ranibizumab.rn. 40 41 47 or/22-46 [ANTI-VEGF AGENTS – MEDLINE] 42 48 21 and 47 [ANTI-VEGF AGENTS & CONDITIONS – MEDLINE] 43 44 49 exp Photochemotherapy/ 45 50 Photosensitizing Agents/ 46 47 51 (photochemo* or photo-chemo* or photodynamic* or photo-dynamic* or photosensiti* or photo- 48 sensiti*).tw,kw. 49 52 PDT.tw,kw. 50 51 53 or/49-52 52 54 verteporfin.tw,kw. 53 54 55 (verteporphin or "BPD-MA" or "CL 318,952" or "CL 318952" or "UNII-0X9PA28K43" or Visudyne).tw,kw. 55 56 verteporfin.rn. 56 57 58 7 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 51 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 57 or/54-56 4 5 58 53 and 57 6 59 (PDTV or "PDT-V" or VPDT or "V-PDT").tw,kw. 7 8 60 58 or 59 [VISUDYNE PDT – MEDLINE] 9 61 21 and 60 [VISUDYNE PDT & CONDITIONS – MEDLINE] 10 11 62 Triamcinolone Acetonide/ 12 63 ((Triamcinol* adj acet*) or Aristocort or Aristospan or Asmacort or Azmacort or "BRN 0060069" or "CCRIS 13 5231" or Cinonide or Clinacort or "EINECS 200-948-7" or Kenacort or Kenalog* or Kenlog or "NSC 21916" or 14 Triamcot or Triam-Forte or Triam-Injekt or Triamonide or Tricort* or Triesense or Tristoject or "UNII- 15 16 F446C597KA" or Volon).tw,kw.For peer review only 17 64 triamcinolone acetonide.rn. 18 19 65 Glucocorticoids/ 20 66 (glucocorticoid* or glucorticoid*).tw,kw. 21 22 67 (anecortave or "AL 3789" or "AL-3789" or "EINECS 231-812-5" or "NSC 15475" or "NSC 24345" or Retaane 23 or "UNII-Y0PC411K4T").tw,kw. 24 68 anecortave acetate.rn. 25 26 69 Pregnadienediols/ 27 70 (dihydroxypregnadiene* or di-hydroxypregnadiene* or pregnadienediol*).tw,kw. 28 29 71 exp Dexamethasone/
30 72 (Dexamethasone or Decaject* or Decameth or Dexasone or Dexpak or Hexadecadrol or Hexadrol or Maxidex http://bmjopen.bmj.com/ 31 or Millicorten or Oradexon or Ozurdex).tw,kw. 32 33 73 dexamethasone.rn. 34 74 (intravitreal adj3 (corticoid* or corticosteroid* or steroid*)).tw,kw. 35 36 75 or/62-74 37 76 exp Injections/
38 on September 24, 2021 by guest. Protected copyright. 39 77 (depot or implant* or infus* or inject* or intravitreal* or intra-vitreal* or microsphere* or micro-sphere* or 40 suspension*).tw,kw. 41 42 78 or/76-77 43 79 75 and 78 [CORTICOSTEROID/INTRAVITREAL INJECTIONS - MEDLINE] 44 45 80 21 and 79 (3513) [CORTICOSTEROID/INTRAVITREAL INJECTIONS & CONDITIONS - MEDLINE 46 81 (controlled clinical trial or randomized controlled trial).pt. 47 48 82 clinical trials as topic.sh. 49 83 (randomi#ed or randomly or RCT$1 or placebo*).tw. 50 51 84 ((singl* or doubl* or trebl* or tripl*) adj (mask* or blind* or dumm*)).tw. 52 85 trial.ti. 53 54 86 or/81-85 55 87 (48 or 61 or 80) and 86 56 57 58 8 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 52BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 88 exp Animals/ not (exp Animals/ and Humans/) 4 5 89 87 not 88 6 90 (comment or editorial or interview or news).pt. 7 8 91 (letter not (letter and randomized controlled trial)).pt. 9 92 89 not (90 or 91) 10 11 93 92 use prmz [MEDLINE RCTS] 12 94 macular degeneration/ 13 14 95 age related macular degeneration/ 15 96 wet macular degeneration/ 16 For peer review only 17 97 ((exudative or neovascular or wet) adj3 ((macula* adj2 degeneration) or (macula* adj2 deterioration) or 18 maculopath* or (macula* adj2 dystroph*))).tw,kw. 19 98 ((exudative or neovascular or wet) adj2 (AMD or ARMD)).tw,kw. 20 21 99 (wAMD or wARMD).tw,kw. 22 100 diabetic retinopathy/ 23 24 101 ((diabet* or DM) adj3 retinopath*).tw,kw. 25 102 diabetic macular edema/ 26 27 103 (PDR or DME or DMO).tw,kw. 28 104 exp macular edema/ 29
30 105 ((macula* or retina*) adj3 (edema$1 or oedema$1)).tw,kw. http://bmjopen.bmj.com/ 31 32 106 (Irvine-Gass adj3 (edema$1 or oedema$1 or syndrome$1)).tw,kw. 33 107 (cystoid macula* adj dystroph*).tw,kw. 34 35 108 exp retina vein occlusion/ 36 109 (retinal vein adj3 (occlu* or obstruct* or clos* or stricture* or steno* or block* or embolism*)).tw,kw. 37 110 (BRVO or CRVO).tw,kw. 38 on September 24, 2021 by guest. Protected copyright. 39 111 subretinal neovascularization/ 40 41 112 ((choroid* or subretinal or sub-retinal) adj1 neovasculari#ation*).tw,kw. 42 113 CNV.tw,kw. 43 44 114 or/94-113 [CONDITIONS – EMBASE] 45 115 vasculotropin inhibitor/ 46 47 116 (anti adj2 VEGF$1).tw,kw. 48 117 antiVEGF$1.tw,kw. 49 50 118 (antivascular endothelial growth factor$1 or anti-vascular endothelial growth factor$1).tw,kw. 51 119 monoclonal antibody/ 52 53 120 (monoclonal antibod* and humani#ed).tw,kw. 54 121 (antibod* adj2 humani#ed).tw,kw. 55 56 122 angiogenesis inhibitor/ 57 58 9 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 53 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 123 (angiogen* adj3 (inhibitor* or antagonist*)).tw,kw. 4 5 124 (anti-angiogen* or antiangiogen*).tw,kw. 6 125 aflibercept/ 7 8 126 (aflibercept or "AVE 0005" or AVE0005 or "AVE 005" or AVE005 or "Bay 86-5321" or "Bay86-5321" or 9 Eylea or "UNII-15C2VL427D" or Zaltrap or ZIV-aflibercept).tw,kw. 10 127 ((vasculotropin or vascular endothelial growth factor or VEGF) adj trap*).tw,kw. 11 12 128 aflibercept.rn. 13 129 bevacizumab/ 14 15 130 (bevacizumab or Altuzan or Avastin or "nsc 704865" or nsc704865 or "rhuMAb-VEGF" or "UNII- 16 2S9ZZM9Q9V").tw,kw.For peer review only 17 131 IVB injection$1.tw,kw. 18 19 132 Bevacizumab.rn. 20 133 pegaptanib/ 21 22 134 (Pegaptanib or "EYE 001" or EYE001 or Macugen or "NX 1838" or NX1838 or "UNII- 23 3HP012Q0FH").tw,kw. 24 25 135 Pegaptanib.rn. 26 136 ranibizumab/ 27 28 137 (Ranibizumab or Lucentis or "rhuFab V2" or "UNII-ZL1R02VT79").tw,kw. 29 138 IVR injection$1.tw,kw.
30 http://bmjopen.bmj.com/ 31 139 Ranibizumab.rn. 32 140 or/115-139 [ANTI-VEGF AGENTS – EMBASE] 33 34 141 114 and 140 [ANTI-VEGF AGENTS & CONDITIONS – EMBASE] 35 142 photodynamic therapy/ 36 37 143 photosensitizing agent/
38 144 (photochemo* or photo-chemo* or photodynamic* or photo-dynamic* or photosensiti* or photo- on September 24, 2021 by guest. Protected copyright. 39 sensiti*).tw,kw. 40 41 145 PDT.tw,kw. 42 146 or/142-145 43 44 147 verteporfin/ 45 148 (verteporphin or "BPD-MA" or "CL 318,952" or "CL 318952" or "UNII-0X9PA28K43" or Visudyne).tw,kw. 46 47 149 verteporfin.rn. 48 49 150 or/147-149 50 151 146 and 150 51 52 152 (PDTV or "PDT-V" or VPDT or "V-PDT").tw,kw. 53 153 151 or 152 [VISUDYNE PDT – EMBASE] 54 55 154 114 and 153 [VISUDYNE PDT & CONDITIONS – EMBASE] 56 155 triamcinolone/ 57 58 10 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 54BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 156 triamcinolone acetonide/ 4 5 157 ((Triamcinol* adj acet*) or Aristocort or Aristospan or Asmacort or Azmacort or "BRN 0060069" or "CCRIS 6 5231" or Cinonide or Clinacort or "EINECS 200-948-7" or Kenacort or Kenalog* or Kenlog or "NSC 21916" or 7 Triamcot or Triam-Forte or Triam-Injekt or Triamonide or Tricort* or Triesense or Tristoject or "UNII- 8 F446C597KA" or Volon).tw,kw. 9 158 triamcinolone.rn. 10 11 159 triamcinolone acetonide.rn. 12 160 exp glucocorticoid/ 13 14 161 (glucocorticoid* or glucorticoid*).tw,kw. 15 16 162 anecortave/ For peer review only 17 163 (anecortave or "AL 3789" or "AL-3789" or "EINECS 231-812-5" or "NSC 15475" or "NSC 24345" or 18 Retaane or "UNII-Y0PC411K4T").tw,kw. 19 20 164 anecortave.rn. 21 165 pregnane derivative/ 22 23 166 (dihydroxypregnadiene* or di-hydroxypregnadiene* or pregnadienediol*).tw,kw. 24 167 dexamethasone/ 25 26 168 dexamethasone isonicotinate/ 27 169 (Dexamethasone or Decaject* or Decameth or Dexasone or Dexpak or Hexadecadrol or Hexadrol or Maxidex 28 or Millicorten or Oradexon or Ozurdex).tw,kw. 29
30 170 dexamethasone.rn. http://bmjopen.bmj.com/ 31 171 dexamethasone isonicotinate.rn. 32 33 172 (intravitreal adj3 (corticoid* or corticosteroid* or steroid*)).tw,kw. 34 173 or/155-172 35 36 174 exp injection/ 37 175 intravitreal drug administration/
38 on September 24, 2021 by guest. Protected copyright. 39 176 vi.fs. [EMBASE FLOATING SUBJECT HEADING FOR INTRAVITREAL DRUG ADMIN] 40 177 (depot or implant* or infus* or inject* or intravitreal* or intra-vitreal* or microsphere* or micro-sphere* or 41 42 suspension*).tw,kw. 43 178 or/174-177 44 45 179 173 and 178 [CORTICOSTEROID/INTRAVITREAL INJECTIONS - EMBASE] 46 180 114 and 179 [CORTICOSTEROID/INTRAVITREAL INJECTIONS & CONDITIONS - EMBASE] 47 48 181 randomized controlled trial/ or controlled clinical trial/ 49 182 exp "clinical trial (topic)"/ 50 51 183 (randomi#ed or randomly or RCT$1 or placebo*).tw. 52 184 ((singl* or doubl* or trebl* or tripl*) adj (mask* or blind* or dumm*)).tw. 53 54 185 trial.ti. 55 186 or/181-185 56 57 58 11 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 55 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 187 (141 or 154 or 180) and 186 4 5 188 exp animal experimentation/ or exp models animal/ or exp animal experiment/ or nonhuman/ or exp 6 vertebrate/ 7 189 exp humans/ or exp human experimentation/ or exp human experiment/ 8 9 190 188 not 189 10 191 187 not 190 11 12 192 editorial.pt. 13 193 letter.pt. not (letter.pt. and randomized controlled trial/) 14 15 194 191 not (192 or 193) 16 195 194 use emczd [EMBASEFor RCTS]peer review only 17 18 196 93 or 195 [MEDLINE / EMBASE RCTS] 19 197 remove duplicates from 196 [TOTAL UNIQUE HITS] 20 21 198 197 use prmz [UNIQUE MEDLINE] 22 199 197 use emczd [UNIQUE EMBASE] 23 24 25 *************************** 26 27 28
29
30 http://bmjopen.bmj.com/ 31 32 33 34 35 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 12 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Appendix 2: Detailed study characteristics 4 5 6 7 Setting Year of Overall Study 8 Trial Study Study (multi/si First author public Trial identifier Country sample duration 9 name design period ngle ation size (months) 10 centre) 11 12 For peercn-AMD review (n = 12) only Netherlands 13 Netherla Parallel Jan 2009 - Schauwvlieghe30 2016 BRAMD Trial Register: Multi 332 12 14 nds RCT Dec 2011
15 NTR1704 http://bmjopen.bmj.com/ Parallel Mar 2009 16 Berg31 2015 LUCAS NCT01127360 Norway Multi 441 12 17 RCT - Jul 2012 18 EK-07-192-1007 32 Parallel 2008 - Scholler 2014 NR / EudraCT Nr. Austria Single 55 12 19 RCT 2011 20 2007-005157-33 Mar 27, 21 ISRCTN921665 Parallel Chakravarthy33 2013 IVAN UK 2008 - Oct Multi 610 24 22 60 RCT 15, 2010 23 on September 24, 2021 by guest. Protected copyright. Parallel 2009 - 24 Kodjikian34 2013 GEFAL NCT01170767 France Multi 501 12 25 RCT 2012 Parallel 2008 - 26 Krebs35 2013 MANTA NCT00710229 Austria Multi 321 12 27 RCT 2011 Aug 2007 28 US, Parallel Heier36 2012 VIEW 1 NCT00509795 - Sep Multi 1217 12 29 Canada RCT 2010 30 Argentina 31 , 32 Australia, 33 Austria, 34 Belgium, 35 Brazil, Parallel Apr 2008 - Heier36 2012 VIEW 2 NCT00637377 Multi 1240 12 36 Colombia RCT Sep 2010 37 , Czech 38 Republic, 39 France, 40 Germany 41 , 42 43 13 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Setting 4 Year of Overall Study Trial Study Study (multi/si 5 First author public Trial identifier Country sample duration name design period ngle 6 ation size (months) 7 centre) 8 Hungary, 9 India, 10 Israel, 11 Italy, 12 For peerJapan, review only 13 Republic 14 of Korea,
15 Latvia, http://bmjopen.bmj.com/ 16 Mexico, 17 Netherla 18 nds, 19 Poland, 20 Portugal, 21 Singapor 22 e,
23 Slovakia, on September 24, 2021 by guest. Protected copyright. 24 Spain, 25 Sweden, 26 Switzerla 27 nd, 28 United 29 Kingdom Parallel 2007 - 30 Biswas37 2011a NR NR India Multi 60 18 RCT 2009 31 Parallel 32 Biswas38 2011b NR NR India NA Multi 120 18 RCT 33 Parallel 2008 - 34 Martin39 2011 CATT NCT00593450 US Multi 1208 12 RCT 2010 35 ISRCTN733598 Parallel 2007 - 36 Subramanian40 2010 NR US Single 28 12 06 RCT 2009 37 DME (n = 3) 38 Parallel 39 Fouda41 2017 NR NR Egypt NR Single 42 15 RCT 40 27 41 Wells 2015 NR NCT01627249 US Parallel Aug 2012 Multi 660 12 42 43 14 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Setting 4 Year of Overall Study Trial Study Study (multi/si 5 First author public Trial identifier Country sample duration name design period ngle 6 ation size (months) 7 centre) 8 RCT - Oct 2014 9 Parallel 2011 - 10 Ekinci42 2014 NR NR Turkey NR 100 12 RCT 2014 11 RVO-ME (n = 2) 12 For peer reviewSep only 2014 13 43 Parallel Scott 2017 SCORE2 NCT01969708 US - Dec MULTI 362 6 14 RCT 2016
15 http://bmjopen.bmj.com/ CTRI/2012/01/0 Parallel Jan 2012 - 16 Narayanan44 2015 MARVEL India Single 75 6 03120 RCT Feb 2013 17 m-CNV (n = 2) 18 45 Parallel Apr 2006 - 19 Iacono 2012 NR NR Italy Single 55 18 20 RCT Jul 2007 Feb 2008 21 ISRCTN498032 Parallel Gharbiya46 2010 NR Italy - Dec Single 32 6 22 72 RCT 2008
23 on September 24, 2021 by guest. Protected copyright. 24 25 Abbreviations: cn-AMD – choroidal neovascular age-related macular degeneration; DME – diabetic macular oedema; m-CNV – myopic choroidal 26 neovascularization; NR – not reported; RCT – randomized controlled trials; RVO-ME – macular edema due to retinal vein occlusion 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 15 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Appendix 3: Detailed patient characteristics 4 5 6
7
8
year
9
10
11 mean age mean age mean age mean age mean age mean age mean age mean age mean
12 For peer- - review- - - - only- - 13
14 & First author # of eyes age mean Overall age mean Overall type variance age mean Overall value variance 1 TX 1 TX var value 2 TX 2 TX var value 3 TX 3 TX var value 4 TX 4 TX var value % female with % of patients diabetes value Mean A1C with % of patients A1C >8.5% with % of patients hypertension of Lens status patients
15 cn-AMD (n = 12) http://bmjopen.bmj.com/ 16 40 17 % 18 Schauwvlieghe pse 332 78 SD 7 79 7 78 7 NR NR NR NR 56 NR NR NR NR 19 201630 udo 20 pha 21 kic 22 Berg 201531 NR NR SD NR 78.7 7.6 78 8.2 NR NR NR NR NR NR NR NR NR NR 32 23 Scholler 2014 55 NR SD NR 79.5 6.8 80.8 6.6 NR NR NR NR 70.9 on September 24, 2021 by guest. Protected copyright. NR NR NR NR NR 24 Chakravarthy 201333 NR 77.7 SD 7.4 77.8 7.6 77.7 7.3 NR NR NR NR 60 NR NR NR NR NR 25 Kodjikian 201334 501 NR NR NR 79.6 6.9 78.7 7.3 NR NR NR NR 66 NR NR NR 57 NR 26 Krebs 201335 317 NR SD NR 76.7 7.8 77.6 8.1 NR NR NR NR 63.7 0 NR NR NR NR 27 Heier 2012 – VIEW 121 36 NR SD NR 78.2 7.6 77.7 7.9 78.4 8.1 77.9 8.4 58.8 NR NR NR NR NR 28 1 0 29 Heier 2012 – VIEW 120 NR SD NR 73 9 74.1 8.5 74.7 8.6 73.8 8.6 55.5 NR NR NR NR NR 30 236 2 31 Biswas 2011a37 60 60 NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR 32 Biswas 2011b38 104 NR NR NR 63.5 NR 64.4 NR NR NR NR NR 52 NR NR NR NR NR 33 120 Martin 201139 NR NR NR 79.2 7.4 80.1 7.3 78.4 7.8 79.3 7.6 62 NR NR NR NR NR 34 8 35 Subramanian 201040 28 78.6 SD NR 78 NR 80 NR NR NR NR NR 4.6 NR NR NR NR NR 36 DME (n = 3) 37 Fouda 201741 70 NR SD NR 55.1 4.7 56.6 5.8 NA NA NA NA NR 100 NR NR NR NR 38 Wells 201527 660 61 SD 10 60 10 62 10 60 11 NR NR 47 100 NR NR NR NR 39 Ekinci 201442 100 NR NR NR 68 9 65 14 NR NR NR NR 68 100 NR 0 NR NR 40 RVO-ME ( n = 2) 41 42 43 16 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3
4
year
5
6
7
8 mean age mean age mean age mean age mean age mean age mean age mean age mean
9 ------10
11 & First author # of eyes age mean Overall age mean Overall type variance age mean Overall value variance 1 TX 1 TX var value 2 TX 2 TX var value 3 TX 3 TX var value 4 TX 4 TX var value % female with % of patients diabetes value Mean A1C with % of patients A1C >8.5% with % of patients hypertension of Lens status patients 12 For peer review only 83.1 13 43 % Scott 2017 362 69 SD 12 69 11 69 13 NA NA NA NA 43.4 31.5 NR NR 76.8 14 cata
15 http://bmjopen.bmj.com/ ract 16 Narayanan 201544 75 NR NR NR 53 NR 50 NR NR NR NR NR 45.3 17 NR NR 50 NR 17 m-CNV (n = 2) 18 Iacono 201245 55 NR SD NR 65 12 61 11 NR NR NR NR 76.4 NR NR NR NR NR 19 Gharbiya 201046 32 NR SD NR 60.6 10.5 59.1 11.4 NR NR NR NR 68.8 NR NR NR NR NR 20 21 22 Abbreviations: cn-AMD – choroidal neovascular age-related macular degeneration; DME – diabetic macular oedema; m-CNV – myopic choroidal neovascularization; NA – not applicable; NR – not reported; RCT – randomized controlled trials; RVO-ME – macular edema due to retinal vein 23 on September 24, 2021 by guest. Protected copyright. 24 occlusion; SD – standard deviation; TX – treatment 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 17 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 61 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 Appendix 4: Cochrane risk of bias results for individual studies 4 5 6 Cochrane ROB item 7 STUDY 8 1 2 3 4 5 6 7 9 cn-AMD (n = 12) 10 Schauwvlieghe 11 30 Low risk Low risk Low risk Low risk Low risk Low risk Low risk 12 2016 13 Berg 201531 Low risk Low risk Low risk Low risk Low risk Low risk Low risk 14 Unclear Unclear Scholler 201432 Low risk Low risk Low risk Low risk Low risk 15 risk risk 16 Chakravarthy 201333 ForLow riskpeer Low risk review Low risk Low only risk Low risk Low risk Low risk 17 Unclear Unclear 18 Kodjikian 201334 Low risk Low risk Low risk Low risk Low risk risk risk 19 Unclear 20 Krebs 201335 Low risk Low risk Low risk Low risk Low risk Low risk risk 21 Heier 2012 – VIEW Unclear 22 36 Low risk Low risk Low risk Low risk Low risk High risk 1 risk 23 Heier 2012 – VIEW Unclear 24 36 Low risk Low risk Low risk Low risk Low risk High risk 2 risk 25 37 Unclear Unclear Unclear Unclear Unclear Biswas 2011a Low risk Low risk 26 risk risk risk risk risk 27 Unclear Unclear Unclear Biswas 2011b38 Low risk Low risk Low risk Low risk 28 risk risk risk 29 39 Unclear
Martin 2011 Low risk Low risk Low risk Low risk Low risk Low risk http://bmjopen.bmj.com/ 30 risk 31 Unclear Unclear Unclear Subramanian 201040 Low risk Low risk Low risk Low risk 32 risk risk risk 33 DME (n = 3) 34 Unclear Unclear Unclear Unclear Unclear Unclear Low risk 35 Fouda 201741 36 risk risk risk risk risk risk Unclear 37 Wells 201527 Low risk Low risk Low risk Low risk Low risk Low risk
38 risk on September 24, 2021 by guest. Protected copyright. Unclear Unclear Unclear Unclear 39 Ekinci 201442 Low risk Low risk Low risk 40 risk risk risk risk 41 RVO-ME (n = 2) 42 Scott 201743 Low risk Low risk Low risk Low risk Low risk Low risk High risk 43 44 Unclear Unclear Unclear 44 Narayanan 2015 Low risk Low risk Low risk Low risk 45 risk risk risk 46 m-CNV (n = 2) 47 Unclear Unclear Iacono 201245 Low risk Low risk Low risk Low risk Low risk 48 risk risk 49 Unclear Unclear Gharbiya 201046 Low risk Low risk Low risk Low risk Low risk 50 risk risk 51 52 Note: The legend for the ROB table is as follows: 53 1: Random sequence generation 54 2: Allocation concealment 55 3: Blinding of patients & personnel 56 4: Blinding of outcome assessment 57 58 18 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 62BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 5: Incomplete outcome data 4 6: Selective reporting 5 7: Other bias 6 7 Abbreviations: cn-AMD – choroidal neovascular age-related macular degeneration; DME – diabetic 8 macular oedema; m-CNV – myopic choroidal neovascularization; RVO-ME – macular edema due to 9 retinal vein occlusion 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29
30 http://bmjopen.bmj.com/ 31 32 33 34 35 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 19 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Appendix 5: Risk of bias results 4 5 6
7 8 9 10 11 12 For peer review only 13 14
15 http://bmjopen.bmj.com/ 16 17 18 19 20 21 22
23 on September 24, 2021 by guest. Protected copyright. 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 20 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Appendix 6: Treatment effect estimates 4 5 6 Mean treatment Mean comparator 7 Rx vs Ctrl No. of Total Risk Ratio (95% Risk Difference Outcome effect estimateb effect estimate I2 8 Comparison RCTsa patients CI) (95% CI) [Range] [Range] 9 10 Treatment Effects in choroidal neovascular Age-related Macular Degeneration Aflibercept vs. 11 Vision 12 Ranibizumab 2 1815 0.32 [0.3, 0.34] 0.32 [0.31, 0.34] 0.99 (0.81-1.22) -0.21 (-6.82, 6.4) 52%b gain in For peer review only 13 Bevacizumb vs. BCVA of 14 Ranibizumab 9 3245 0.22 [0.12, 0.33] 0.23 [0.14, 0.29] 0.95 (0.84-1.08) -1.62 (-4.86, 1.62) 0%
≥15 EDTRS http://bmjopen.bmj.com/ 15 Bevacizumb vs. 16 letters Aflibercept NR NR NR NR NR NR NR 17 18 Aflibercept vs. 19 Vision loss Ranibizumab 2 1815 0.05 [0.05, 0.05] 0.06 [0.05, 0.06] 0.9 (0.6-1.35) -0.51 (-2.75, 1.72) 0% 20 in BCVA of Bevacizumb vs. 21 ≥15 EDTRS Ranibizumab 10 3302 0.06 [0, 0.11] 0.07 [0.04, 0.14] 1.1 (0.84-1.43) 0.39 (-1.46, 2.23) 4% 22 letters Bevacizumb vs. 23 Aflibercept NR NR NR NR NR on September 24, 2021 by guest. Protected copyright. NR NR 24 Aflibercept vs. 25 Mean Ranibizumab 2 1793 8.83 [8.25, 9.41] 8.75 [8.1, 9.4] NA 0.05 (-2.36, 2.46) 66% 26 change in Bevacizumb vs. 27 BCVA (MD 28 Ranibizumab 8 3064 7.24 [4.1, 15.2] 5.85 [0.6, 11.43] NA 0.03 (-1.02, 1.08) 0% in # 29 Bevacizumb vs. letters) 30 Aflibercept NR NR NR NR NR NR NR 31 Aflibercept vs. 32 Ranibizumab 2 1632 5.32 ± 14.46 5.60 ± 14.40 NA -2.23 (-5.07, 0.61) 73% 33 Vision- Bevacizumb vs. 34 related Ranibizumab NR NR NR NR NR NR NR 35 function 36 Bevacizumb vs. 37 Aflibercept NR NR NR NR NR NR NR 38 Aflibercept vs. 39 Blindness Ranibizumab NR NR NR NR NR NR NR 40 41 Bevacizumb vs. 3 1823 0.04 [0, 0.12] 0.02 [0, 0.06] 2.04 (0.32-12.5) 0.11 (-0.25, 0.47) 0% 42 43 21 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Mean treatment Mean comparator Rx vs Ctrl No. of Total Risk Ratio (95% Risk Difference 4 Outcome effect estimateb effect estimate I2 Comparison RCTsa patients CI) (95% CI) 5 [Range] [Range] 6 Ranibizumab 7 Bevacizumb vs. 8 9 Aflibercept NR NR NR NR NR NR NR 10 Aflibercept vs. 11 Ranibizumab NR NR NR NR NR NR NR 12 Bevacizumb vs. Mortality For peer review only 13 Ranibizumab 6 2941 0.04 [0.01, 0.12] 0.03 [0.01, 0.06] 1.14 (0.72-1.79) 0.31 (-0.74, 0.36) 0% 14 Bevacizumb vs.
15 http://bmjopen.bmj.com/ Aflibercept NR NR NR NR NR NR NR 16 17 Aflibercept vs. Ranibizumab NR NR NR NR NR NR NR 18 Serious 19 Bevacizumb vs. adverse 20 Ranibizumab 5 3026 0.19 [0.12, 0.28] 0.18 [0.09, 0.28] 1.09 (0.93-1.27) 0.02 (-0.01, 0.05) 12% events 21 Bevacizumb vs. 22 Aflibercept NR NR NR NR NR NR NR
23 on September 24, 2021 by guest. Protected copyright. Aflibercept vs. 24 25 Arterial Ranibizumab 2 1818 0.02 [0.01, 0.02] 0.02 [0.02, 0.02] 0.96 (0.45-2.04) -0.07 (-1.32, 1.18) 0% 26 thromboe Bevacizumb vs. 27 mbolic Ranibizumab 4 2033 0.03 [0, 0.05] 0.04 [0, 0.08] 0.86 (0.51-1.47) -0.03 (-0.97, 0.9) 0% 28 events Bevacizumb vs. 29 Aflibercept NR NR NR NR NR NR NR 30 Aflibercept vs. 31 Venous Ranibizumab 1 913 0.0033 0 0.25 (0.01-7.69) -0.25 (-0.93, 0.44) NA 32 33 thromboe Bevacizumb vs. 34 mbolic Ranibizumab 3 2135 0 [0, 0.01] 0 [0, 0.01] 1.59 (0.42-5.88) 0.18 (-0.43, 0.79) 0% 35 events Bevacizumb vs. 36 Aflibercept NR NR NR NR NR NR NR 37 Aflibercept vs. Bacterial 38 Ranibizumab NR NR NR NR NR NR NR endophth 39 Bevacizumb vs. 40 almitis 41 Ranibizumab 3 2011 0 [0, 0.01] 0 [0, 0] 1.75 (0.44-6.67) 0.18 (-0.40, 0.77) 0% 42 43 22 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Mean treatment Mean comparator Rx vs Ctrl No. of Total Risk Ratio (95% Risk Difference 4 Outcome effect estimateb effect estimate I2 Comparison RCTsa patients CI) (95% CI) 5 [Range] [Range] 6 Bevacizumb vs. 7 Aflibercept NR NR NR NR NR NR NR 8 Aflibercept vs. 9 Ranibizumab NR NR NR NR NR NR NR 10 Retinal Bevacizumb vs. 11 detachme 12 Ranibizumab 2 1526 0.01 [0.01, 0.01] 0 [0, 0.01] 2.33 (0.31-16.67) 0.38 (-0.2, 0.96) 0% nt For peer review only 13 Bevacizumb vs. 14 Aflibercept NR NR NR NR NR NR NR 15 Treatment Effects in Diabetic Macular Edema http://bmjopen.bmj.com/ 16 Aflibercept vs. 17 Vision Ranibizumab 1 392 0.39 0.37 1.06 (0.82-1.37) 2.16 (-7.44, 11.75) NA 18 gain in 19 Bevacizumb vs. BCVA of 20 Ranibizumab 1 376 0.35 0.37 0.94 (0.72-1.23) 2.05 (-7.62, 11.73) NA ≥15 EDTRS 21 Bevacizumb vs. -2.05 (-11.73, letters 22 Aflibercept 1 386 0.35 0.37 0.94 (0.72, 1.24) 7.62) NA
23 on September 24, 2021 by guest. Protected copyright. Aflibercept vs. 24 25 Vision loss Ranibizumab 1 392 0.02 0.02 1.59 (0.38-6.67) 0.92 (-1.87, 3.7) NA 26 in BCVA of Bevacizumb vs. 27 ≥15 EDTRS Ranibizumab 1 376 0.03 0.02 2.08 (0.52-8.33) 1.67 (-1.43, 4.78) NA 28 letters Bevacizumb vs. 29 Aflibercept 1 376 0.02 0.03 0.48 (0.12, 1.91) -1.67 (-4.78, 1.43) NA 30 Aflibercept vs. 31 Mean Ranibizumab 2 462 16.22 (12.8, 19.64) 13.97 (12.3, 15.65) NA 1.36 (-1.59, 4.31) 27% 32 33 change in Bevacizumb vs. 34 BCVA Ranibizumab 2 456 10.27 (10.0, 10.54) 12.08 (11.87, 12.3) NA -2.0 (-3.90, -0.09) 0% 35 letters Bevacizumb vs. 36 Aflibercept 1 386 10.0 ± 11.8 12.8 ± 12.4 NA -2.7 (-0.3, -5.2) NA 37 Aflibercept vs. Vision- 38 Ranibizumab NR NR NR NR NR NR NR related 39 Bevacizumb vs. 40 function 41 Ranibizumab NR NR NR NR NR NR NR 42 43 23 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Mean treatment Mean comparator Rx vs Ctrl No. of Total Risk Ratio (95% Risk Difference 4 Outcome effect estimateb effect estimate I2 Comparison RCTsa patients CI) (95% CI) 5 [Range] [Range] 6 Bevacizumb vs. 7 Aflibercept NR NR NR NR NR NR NR 8 Aflibercept vs. 9 10 Ranibizumab NR NR NR NR NR NR NR Bevacizumb vs. 11 Blindness 12 Ranibizumab NR ForNR peerNR reviewNR onlyNR NR NR 13 Bevacizumb vs. 14 Aflibercept NR NR NR NR NR NR NR 15 Aflibercept vs. http://bmjopen.bmj.com/ 16 Ranibizumab 2 513 0.02 (0.01, 0.02) 0.03 (0.01, 0.05) 0.47 (0.17-1.28) -2.00 (-4.95, 0.94) NA 17 Bevacizumb vs. 18 Mortality 19 Ranibizumab 1 436 0.06 0.05 1.18 (0.54-2.56) 0.92 (-3.36, 5.2) NA 20 Bevacizumb vs. 21 Aflibercept 1 436 0.05 0.06 0.85 (0.39, 1.85) -0.92 (-5.2, 3.36) NA 22 Aflibercept vs. 23 Ranibizumab 2 507 0.14 (0.01 , 0.27) 0.13 (0.01, 0.25) 1.08 (0.78-1.47) on September 24, 2021 by guest. Protected copyright. 0.56 (-4.00 , 5.13) 0% 24 Serious Bevacizumb vs. -4.13 (-12.04, 25 adverse Ranibizumab 1 436 0.21 0.25 0.83 (0.59-1.18) 3.78) NA 26 events 27 Bevacizumb vs. 28 Aflibercept 1 436 0.25 0.21 1.2 (0.85, 1.69) 4.13 (-3.78, 12.04) NA 29 Aflibercept vs. 30 Arterial Ranibizumab 1 436 0.05 0.03 0.6 (0.22-1.61) -1.83 (-5.36, 1.69) NA 31 thromboe Bevacizumb vs. 32 mbolic Ranibizumab 1 436 0.05 0.04 0.9 (0.37-2.17) -0.46 (-4.29, 3.37) NA 33 34 events Bevacizumb vs. 35 Aflibercept 1 436 0.05 0.04 1.11 (0.46, 2.68) 0.46 (-3.37, 4.29) NA 36 Aflibercept vs. Venous 37 Ranibizumab NR NR NR NR NR NR NR thromboe 38 Bevacizumb vs. mbolic 39 Ranibizumab NR NR NR NR NR NR NR 40 events 41 Bevacizumb vs. NR NR NR NR NR NR NR 42 43 24 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Mean treatment Mean comparator Rx vs Ctrl No. of Total Risk Ratio (95% Risk Difference 4 Outcome effect estimateb effect estimate I2 Comparison RCTsa patients CI) (95% CI) 5 [Range] [Range] 6 Aflibercept 7 Aflibercept vs. 8 Ranibizumab 2 512 0 0 NE NE NE 9 Bacterial Bevacizumb vs. 10 endophth 11 Ranibizumab 1 436 0.01 0 3.03 (0.12-100) 0.46 (-0.81, 1.72) NA almitis 12 Bevacizumb vs. For peer review only 13 Aflibercept 1 436 0.01 0 0.33 (0.01, 8.14) -0.46 (-1.72, 0.81) NA 14 Aflibercept vs.
15 http://bmjopen.bmj.com/ Ranibizumab 2 512 0.004 (0, 0.01) 0 1.61 (0.21-12.5) 0.4 (-1.06, 1.87) 0% 16 Retinal Bevacizumb vs. 17 detachme Ranibizumab 1 436 0.0092 0.0046 2 (0.18-20) NR NA 18 nt 19 Bevacizumb vs. 20 Aflibercept 1 436 0.0046 0.0092 0.5 (0.05, 5.47) -0.46 (-2.01, 1.09) NA 21 Treatment Effects in Retinal Vein Occlusion – Macular Edema 22 Aflibercept vs. 23 Vision on September 24, 2021 by guest. Protected copyright. Ranibizumab NR NR NR NR NR NR NR 24 gain in Bevacizumb vs. 25 BCVA of 26 Ranibizumab 1 74 0.59 0.59 1 (0.68-1.45) 0 (-22.37, 22.37) NA ≥15 EDTRS 27 Bevacizumb vs. letters 28 Aflibercept 1 358 0.65 0.61 1.06 (0.91, 1.25) 3.87 ( -6.25 , 14) NR 29 Aflibercept vs. 30 Vision loss Ranibizumab NR NR NR NR NR NR NR 31 32 in BCVA of Bevacizumb vs. 33 ≥15 EDTRS Ranibizumab NR NR NR NR NR NR NR 34 letters Bevacizumb vs. 35 Aflibercept NR NR NR NR NR NR NR 36 Mean Aflibercept vs. 37 change in Ranibizumab NR NR NR NR NR NR NR 38 BCVA (MD Bevacizumb vs. 39 40 in # Ranibizumab 1 77 15.6 18.1 NA -2.5 (-8.0, 5.0) NA 41 letters) Bevacizumb vs. 1 362 18.6 18.9 NA -1.5 (-4.2, 1.2) NA 42 43 25 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Mean treatment Mean comparator Rx vs Ctrl No. of Total Risk Ratio (95% Risk Difference 4 Outcome effect estimateb effect estimate I2 Comparison RCTsa patients CI) (95% CI) 5 [Range] [Range] 6 Aflibercept 7 Aflibercept vs. 8 Ranibizumab NR NR NR NR NR NR NR 9 Vision- Bevacizumb vs. 10 related 11 Ranibizumab NR NR NR NR NR NR NR function 12 Bevacizumb vs. For peer review only 13 Aflibercept NR NR NR NR NR NR NR 14 Aflibercept vs.
15 http://bmjopen.bmj.com/ Ranibizumab NR NR NR NR NR NR NR 16 Bevacizumb vs. 17 Blindness 18 Ranibizumab NR NR NR NR NR NR NR 19 Bevacizumb vs. 20 Aflibercept NR NR NR NR NR NR NR 21 Aflibercept vs. 22 Ranibizumab NR NR NR NR NR NR NR
23 on September 24, 2021 by guest. Protected copyright. Bevacizumb vs. 24 Mortality 25 Ranibizumab NR NR NR NR NR NR NR 26 Bevacizumb vs. 27 Aflibercept 1 362 0.0056 0.0055 1.01 (0.06, 16.04) 0.01 (-1.52 , 1.53) NR 28 Aflibercept vs. 29 Ranibizumab NR NR NR NR NR NR NR Serious 30 Bevacizumb vs. adverse 31 Ranibizumab 1 74 0.03 0.05 0.5 (0.05-5.26) -2.7 (-11.67, 6.26) NA 32 events 33 Bevacizumb vs. 34 Aflibercept 1 362 0.079 0.0769 1.01 (0.5, 2.06) 0.09 (-5.42, 5.59) NR 35 Aflibercept vs. 36 Arterial Ranibizumab NR NR NR NR NR NR NR 37 thromboe Bevacizumb vs. 38 mbolic Ranibizumab NR NR NR NR NR NR NR 39 events Bevacizumb vs. 40 41 Aflibercept 1 362 0.0056 0.011 0.51 (0.05, 5.53 ) -0.54 (-2.41, 1.32) NR 42 43 26 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Mean treatment Mean comparator Rx vs Ctrl No. of Total Risk Ratio (95% Risk Difference 4 Outcome effect estimateb effect estimate I2 Comparison RCTsa patients CI) (95% CI) 5 [Range] [Range] 6 Aflibercept vs. 7 Venous Ranibizumab NR NR NR NR NR NR NR 8 thromboe Bevacizumb vs. 9 10 mbolic Ranibizumab NR NR NR NR NR NR NR 11 events Bevacizumb vs. 12 Aflibercept NR ForNR peerNR reviewNR onlyNR NR NR 13 Aflibercept vs. 14 Ranibizumab NR NR NR NR NR NR NR
Bacterial http://bmjopen.bmj.com/ 15 Bevacizumb vs. 16 endophth Ranibizumab NR NR NR NR NR NR NR 17 almitis 18 Bevacizumb vs. 19 Aflibercept 1 362 0 0.006 0.34 (0.01, 8.22) -0.54 (-2.06, 0.97 ) NR 20 Aflibercept vs. 21 Ranibizumab NR NR NR NR NR NR NR Retinal 22 Bevacizumb vs.
detachme on September 24, 2021 by guest. Protected copyright. 23 Ranibizumab NR NR NR NR NR NR NR 24 nt Bevacizumb vs. 25 26 Aflibercept 1 362 0 0 NE NE NA 27 Treatment Effects in Myopic Choroidal Neovascularization 28 Aflibercept vs. Vision 29 Ranibizumab NR NR NR NR NR NR NR gain in 30 Bevacizumb vs. 6.25 (-27.71, BCVA of 31 Ranibizumab 1 32 0.62 0.56 1.11 (0.63-1.96) 40.21) NA 32 ≥15 EDTRS Bevacizumb vs. 33 letters 34 Aflibercept NR NR NR NR NR NR NR 35 Aflibercept vs. 36 Vision loss Ranibizumab NR NR NR NR NR NR NR 37 in BCVA of Bevacizumb vs. 38 ≥15 EDTRS Ranibizumab 1 32 0 0 NA NA NA 39 letters Bevacizumb vs. 40 41 Aflibercept NR NR NR NR NR NR NR 42 43 27 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Mean treatment Mean comparator Rx vs Ctrl No. of Total Risk Ratio (95% Risk Difference 4 Outcome effect estimateb effect estimate I2 Comparison RCTsa patients CI) (95% CI) 5 [Range] [Range] 6 Aflibercept vs. Mean 7 Ranibizumab NR NR NR NR NR NR NR 8 change in Bevacizumb vs. 9 BCVA (MD Ranibizumab 2 80 12.18 (8.5, 15.87) 13.4 (9.5, 17.31) NA -1.26 (-6.52, 4.00) 0% 10 in # Bevacizumb vs. 11 letters) 12 Aflibercept NR ForNR peerNR reviewNR onlyNR NR NR 13 Aflibercept vs. 14 Ranibizumab NR NR NR NR NR NR NR
Vision- http://bmjopen.bmj.com/ 15 Bevacizumb vs. 16 related Ranibizumab NR NR NR NR NR NR NR 17 function 18 Bevacizumb vs. 19 Aflibercept NR NR NR NR NR NR NR 20 Aflibercept vs. 21 Ranibizumab NR NR NR NR NR NR NR 22 Bevacizumb vs.
Blindness on September 24, 2021 by guest. Protected copyright. 23 Ranibizumab NR NR NR NR NR NR NR 24 Bevacizumb vs. 25 26 Aflibercept NR NR NR NR NR NR NR 27 Aflibercept vs. 28 Ranibizumab NR NR NR NR NR NR NR 29 Bevacizumb vs. Mortality 30 Ranibizumab NR NR NR NR NR NR NR 31 Bevacizumb vs. 32 Aflibercept NR NR NR NR NR NR NR 33 34 Aflibercept vs. Ranibizumab NR NR NR NR NR NR NR 35 Serious Bevacizumb vs. 36 adverse 37 Ranibizumab NR NR NR NR NR NR NR events 38 Bevacizumb vs. 39 Aflibercept NR NR NR NR NR NR NR 40 Arterial 41 Aflibercept vs. NR NR NR NR NR NR NR 42 43 28 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Mean treatment Mean comparator Rx vs Ctrl No. of Total Risk Ratio (95% Risk Difference 4 Outcome effect estimateb effect estimate I2 Comparison RCTsa patients CI) (95% CI) 5 [Range] [Range] 6 thromboe Ranibizumab 7 mbolic Bevacizumb vs. 8 events 9 Ranibizumab NR NR NR NR NR NR NR 10 Bevacizumb vs. 11 Aflibercept NR NR NR NR NR NR NR 12 Aflibercept vs. For peer review only 13 Venous Ranibizumab NR NR NR NR NR NR NR 14 thromboe Bevacizumb vs.
15 http://bmjopen.bmj.com/ mbolic Ranibizumab NR NR NR NR NR NR NR 16 17 events Bevacizumb vs. 18 Aflibercept NR NR NR NR NR NR NR 19 Aflibercept vs. 20 Ranibizumab NR NR NR NR NR NR NR Bacterial 21 Bevacizumb vs. endophth 22 Ranibizumab NR NR NR NR NR NR NR
23 almitis on September 24, 2021 by guest. Protected copyright. Bevacizumb vs. 24 25 Aflibercept NR NR NR NR NR NR NR 26 Aflibercept vs. 27 Ranibizumab NR NR NR NR NR NR NR Retinal 28 Bevacizumb vs. detachme 29 Ranibizumab NR NR NR NR NR NR NR nt 30 Bevacizumb vs. 31 Aflibercept NR NR NR NR NR NR NR 32 Footnotes: 33 a Meta-analysis was not conducted for comparisons with 1 RCT; the point estimate and 95% confidence interval were calculated using data from 34 a single trial. 35 b The summary statistics were derived by taking the mean and range across estimates from included studies. 36 37 Abbreviations: BCVA - best-corrected visual acuity; CI - confidence interval; Ctrl - control; ETDRS - Early Treatment Diabetic Retinopathy 38 Study; MD - mean difference; NA - not applicable; NE - not estimable; NR - not reported; RCT - randomized controlled trials; Rx - treatment; 39 SMD - standardized mean difference 40 41 42 43 29 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 73 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 Appendix 7: Forest plots for primary outcome in choroidal neovascular age 4 5 6 related macular degeneration (cn-AMD) population 7 8 9 A: Vision gain in cn-AMD population 10 11 Bevacizumab Ranibizumab 12 13 Author(s) and Year Gain Total Gain Total Relative Risk [95% CI] 14 15 Berg 2015 50 167 50 172 1.03 [0.74, 1.43] 16 For peer review only 17 Kodjikian 2013 39 191 39 183 0.96 [0.65, 1.42] 18 Subramanian 2010 5 15 1 7 2.33 [0.33, 16.41] 19 Biswas 2011a 3 25 7 27 0.46 [0.13, 1.60] 20 21 Krebs 2013 35 154 34 163 1.09 [0.72, 1.65] 22 Martin 2011 159 586 168 599 0.97 [0.80, 1.16] 23 Chakravarthy 2013 41 254 63 271 0.69 [0.49, 0.99] 24 25 Biswas 2011 6 50 14 54 0.46 [0.19, 1.11] 26 Schauwvlieghe 2016 39 161 32 166 1.26 [0.83, 1.90] 27 28 29 RE Model 0.95 [0.84, 1.07]
30 http://bmjopen.bmj.com/ 31 32 0.05 0.25 1 4 33 Risk Ratio (log scale) 34 Aflibercept Ranibizumab 35 36 37 Author(s) and Year Gain Total Gain Total Relative Risk [95% CI]
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 Heier 2012 - VIEW 1 206 605 94 304 1.10 [0.90, 1.35] 43
44 Heier 2012 - VIEW 2 187 615 99 291 0.89 [0.73, 1.09] 45 46 47 48
49 RE Model 0.99 [0.81, 1.22] 50 51
52 0.05 0.25 1 4 53 Risk Ratio (log scale) 54 55 56 57 58 30 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 74BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
1 2 3 4 B: Sensitivity analyses for vision gain in cn-AMD population 5 6 Sensitivity Analysis: 1 Year Follow-Up 7 Bevacizumab Ranibizumab 8 9 Author(s) and Year Gain Total Gain Total Relative Risk [95% CI] 10 11 12 Berg 2015 47 184 50 187 0.96 [0.68, 1.35]
13 Kodjikian 2013 39 191 39 183 0.96 [0.65, 1.42] 14 15 Subramanian 2010 5 15 1 7 2.33 [0.33, 16.41] 16 Krebs 2013 For 35peer154 review34 163 only 1.09 [0.72, 1.65] 17 18 Martin 2011 159 586 168 599 0.97 [0.80, 1.16] 19 Chakravarthy 2012 83 288 97 275 0.82 [0.64, 1.04] 20 21 Schauwvlieghe 2016 39 161 32 166 1.26 [0.83, 1.90] 22 23 24 RE Model 0.96 [0.85, 1.08] 25 26 0.05 0.25 1 4 27 Risk Ratio (log scale) 28 29 Sensitivity Analysis: Low Risk of Selection Bias 30 http://bmjopen.bmj.com/
31 Bevacizumab Ranibizumab 32 33 34 Author(s) and Year Gain Total Gain Total Relative Risk [95% CI] 35 36 37
38 Berg 2015 50 167 50 172 1.03 [0.74, 1.43] on September 24, 2021 by guest. Protected copyright. 39 40 Chakravarthy 2013 41 254 63 271 0.69 [0.49, 0.99] 41 42 43 Schauwvlieghe 2016 39 161 32 166 1.26 [0.83, 1.90] 44 45 46
47 RE Model 0.96 [0.68, 1.33] 48 49 50 51 0.05 0.25 1 4 52 Risk Ratio (log scale) 53
54 55 56 57 58 31 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 75 of 91 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
1 2 3 Sensitivity Analysis: De Novo Patients 4 5 Bevacizumab Ranibizumab 6 7 Author(s) and Year Gain Total Gain Total Relative Risk [95% CI] 8 9 10 11 12 Subramanian 2010 5 15 1 7 2.33 [0.33, 16.41] 13
14 Krebs 2013 35 154 34 163 1.09 [0.72, 1.65] 15 16 Martin 2011 For 159peer586 review168 599 only 0.97 [0.80, 1.16] 17 18 19 20 21 RE Model 0.99 [0.84, 1.17] 22 23 24 0.05 0.25 1 4 25 26 Risk Ratio (log scale) 27 28 29
30 http://bmjopen.bmj.com/ 31 32 33 34 35 36 37
38 on September 24, 2021 by guest. Protected copyright. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 32 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Appendix 8: Summary data used in risk of bias results 4 5 6 7 Length of follow-up (months)
8 1 3 4 6 8 12 18 24 9 cn-AMD 10 11 # of RCTs 0 4 0 4 0 8 0 2 12 For peer review only 13 14 Bevacizumab NA 5.14 (0.45) NA 5.66 (0.45) NA 6.35 (0.52) NA 5.84 (1.85)
15 Ranibizumab NA 5.19 (0.43) NA 6.02 (0.38) NA 6.23 (0.8) http://bmjopen.bmj.com/ NA 6.10 (1.30) 16
17 18 DME 19 # of RCTs 1 0 1 0 1 2 0 1 20 21 Mean 22 improvement Bevacizumab 4.48 (0.19) NA 7.90 (0.45) NA 9.30 (0.59) 10.06 (0.60) NA 10.00 (0.75)
23 in BCVA Ranibizumab 4.46 (0.24) NA 9.05 (0.24) NA 10.44 (0.36) 11.37 (0.58) on September 24, 2021 by guest. Protected copyright. NA 12.30 (0.52) 24 letter score 25 (SEM) 26 RVO-ME 27 # of RCTs 0 1 0 1 0 0 0 0 28 29 30 Bevacizumab NA 13.23 (0.35) NA 15.60 (0.35) NA NA NA NA 31 32 Ranibizumab NA 15.91 (0.42) NA 18.10 (0.42) NA NA NA NA 33 m-CNV 34 # of RCTs 0 2 0 2 0 1 1 0 35 36 37 Bevacizumab NA 10.28 (31.00) NA 10.42 (33.00) NA 28.00 (35.00) 28.00 (37.00) NA 38 Ranibizumab NA 11.09 (30.00) NA 12.38 (32.00) NA 27.00 (34.00) 27.00 (36.00) NA 39
40 41 42 43 33 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Abbreviations: BCVA - best-corrected visual acuity; cn-AMD – choroidal neovascular age-related macular degeneration; DME – diabetic macular 4 oedema; m-CNV – myopic choroidal neovascularization; NA – not applicable; RCT – randomized controlled trial; RVO-ME – macular edema due 5 to retinal vein occlusion; SEM – standard error of the mean 6 7 8 9 10 11 12 For peer review only 13 14
15 http://bmjopen.bmj.com/ 16 17 18 19 20 21 22
23 on September 24, 2021 by guest. Protected copyright. 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 34 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Appendix 9: Sensitivity analysis estimates 4 5 6 Mean treatment Mean Proportion 7 No. of Total effect comparator Risk Ratio Difference (%) / 8 Outcome Analysis I2 RCTs patients estimate[Range effect estimatea (95% CI) Mean Difference 9 ] [Range] (95% CI) 10 Sensitivity Analyses of Bevacizumab vs. Ranibizumab 11 in choroidal neovascular age-related macular 12 For peer review onlydegeneration (cn-AMD) 13 Main - Longest follow-up 0.95 (0.84, 14 9 3245 0.22 [0.12, 0.33] 0.23 [0.14, 0.29] -1.62 (-4.86, 1.62,) 0% duration 1.08,)
15 http://bmjopen.bmj.com/ Vision SA - Follow-up for 12 0.96 (0.85, 1.08 16 7 3159 0.26 [0.2, 0.33] 0.24 [0.14, 0.35] -0.67 (-3.72, 2.38,) 0% 17 gain in months ) 18 BCVA of SA - Trials with low risk of 19 ≥15 selection bias (random- 3 1191 0.23 [0.16, 0.3] 0.24 [0.19, 0.29] 0.95 (0.68, 1.33) -0.97 (-8.42,6.49,) 61% EDTRS 20 effects model) letters 21 SA - Trials with low risk of 22 selection bias (fixed- 3 1191 0.23 [0.16, 0.3] 0.24 [0.19, 0.29] 0.94 (0.77, 1.16) -1.87 (-6.58, 2.85,) NA
23 effects model) on September 24, 2021 by guest. Protected copyright. 24 Main - Longest follow-up 10 3302 0.06 [0, 0.11] 0.07 [0.04, 0.14] 1.10 (0.84, 1.43) 0.39 (-1.46, 2.23,) 4% 25 duration 26 Vision SA - Follow-up for 12 8 3214 0.06 [0, 0.11] 0.07 [0.03, 0.14] 1.18 (0.86, 1.54) 0.57 ( -0.98, (2.11) 2% 27 loss in months 28 BCVA of SA - Trials with low risk of 1.42 (6.34, -3.5, 29 ≥15 selection bias (random- 3 1191 0.09 [0.08, 0.11] 0.08 [0.05, 0.1] 1.18 (0.65, 2.13) 59% 6.34) 30 EDTRS effects model) 31 letters SA - Trials with low risk of 32 selection bias (fixed- 3 1191 0.09 [0.08, 0.11] 0.08 [0.05, 0.1] 1.14 (0.78, 1.67) 1.4 (-1.79, 4.59) NA 33 effects model) 34 35 Mean 36 Main - Longest follow-up change in 8 3064 7.24 [4.1, 15.2] 5.85 [0.6, 11.43] NA 0.03 ( -1.02, 1.08) 0% 37 duration 38 BCVA 39 40 41 42 43 35 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Mean treatment Mean Proportion 4 No. of Total effect comparator Risk Ratio Difference (%) / Outcome Analysis I2 5 RCTs patients estimate[Range effect estimatea (95% CI) Mean Difference 6 ] [Range] (95% CI) 7 SA - Follow-up for 12 -0.30 (0.70, -1.29, 8 3134 7.33 [4.7, 15.2] 6.12 [0.6, 11.43] NA 2% 8 months 0.70) 9 SA - Trials with low risk of 10 selection bias (random- 3 1191 5.95 [4.1, 7.8] 6.36 [4.9, 7.5] NA -0.52 ( -2.14, 1.10) 0%
11 effects model) 12 SA - Trials with low Forrisk of peer review only 13 selection bias (fixed- 3 1191 5.95 [4.1, 7.8] 6.36 [4.9, 7.5] NA -0.52 ( -2.14, 1.10) NA
14 effects model) 15 http://bmjopen.bmj.com/ 16 Footnote: 17 a The summary statistics were derived by taking the mean and range across estimates from included studies. 18 19 Abbreviations: BCVA - best-corrected visual acuity; CI - confidence interval; ETDRS - Early Treatment Diabetic Retinopathy Study; NA - not 20 applicable; RCT - randomized controlled trials; SA - sensitivity analysis 21 22
23 on September 24, 2021 by guest. Protected copyright. 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 36 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Appendix 10: Summary of anti-VEGF treatment protocols 4 5 6 7 Reconstitution of 8 bevacizumab for 9 Author, year Treatment arms Treatment protocol As needed treatment criteria intravitreal injection reported 10 (Yes/No) 11 12 For peer cnreview-AMD (n = 12) only 13 14 TX 1: ranibizumab
15 0.5 mg/0.05 ml http://bmjopen.bmj.com/ 16 Schauwvlieghe 30 Monthly injections for 12 months. None Yes 17 2016 18 TX 2: bevacizumab 19 1.25 mg/0.05 ml 20 Treat-and-extend protocol: 21 Monthly injections till no signs of 22 active AMD were found.
23 TX 1: ranibizumab Subsequently, injection intervals on September 24, 2021 by guest. Protected copyright. 24 0.5 mg/0.05 ml can be extended by 2 wks to max 12 wks, or shortened by 2 wks 25 Berg 201531 Sign of recurrence Yes depending on AMD activities. 26 TX 2: bevacizumab Follow-up for 12 months. 27 1.25 mg/0.05 ml 28 Initial injections and repeated 29 injections as needed (treat-and- 30 extend) 31 32 loss of VA of ≥5 letters with OCT evidence of TX 1: ranibizumab 33 3 monthly injections. Repeated fluid in the macula; increase in OCT central 0.5 mg/0.05 ml 34 Scholler injections as needed treatment retinal thickness of at least 100 um; new area No 35 201432 criteria. Follow-up duration for 9 of nAMD; new macular haemorrhage; TX 2: bevacizumab 36 months. persistent fluid on OCT at least 1 month after 1.25 mg/0.05 ml 37 the previous intravitreal injection. 38 39 40 41 42 43 37 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Reconstitution of 4 bevacizumab for 5 Author, year Treatment arms Treatment protocol As needed treatment criteria intravitreal 6 injection reported 7 (Yes/No) 8 TX 1: ranibizumab 9 0.5 mg/0.05 ml 10 TX 1 & TX 2: 3 monthly injections 11 TX 2: bevacizumab + monthly injections for 24 12 1.25 mg/0.05 ml months. Chakravarthy For peer reviewPrespecified clinicalonly and OCT criteria for 13 33 Yes 2013 active disease were met. 14 TX 3: ranibizumab TX 3 & TX 4: 3 monthly injections
15 0.5 mg/0.05 ml + repeated 3 monthly injections as http://bmjopen.bmj.com/ 16 needed treatment criteria. 17 TX 4: bevacizumab 18 1.25 mg/0.05 ml 19 loss of ≥5 letters from the previous visit with 20 TX 1: ranibizumab no obvious atrophy or subretinal fibrosis and 21 0.5 mg/0.05 ml 3 monthly injections. Repeated with fluid on OCT; and/or active exudation on 22 Kodjikian 34 injections as needed treatment OCT; and/or increased CNV area or Yes
2013 on September 24, 2021 by guest. Protected copyright. 23 TX 2: bevacizumab criteria. Follow-up for 9 months. persistence of leakage on angiography since 24 1.25 mg/0.05 ml the previous visit; and/or new or persistent 25 subretinal or intraretinal macular hemorrhage. 26 27 visual acuity loss of at least 5 letters with OCT 28 TX 1: ranibizumab or fluorescein angiographic evidence of fluid 29 0.5 mg/0.05 ml 3 monthly injections. Repeated in the macula; an increase in OCT central 30 Krebs 201335 injections as needed treatment retinal thickness of at least 100 um; new Yes 31 TX 2: bevacizumab criteria. Follow-up for 12 months. macular haemorrhage; new area of classic 32 1.25 mg/0.05 ml CNV; or evidence of persistent fluid on OCT 33 at least 1 month after the previous injection. 34 35 36 37 38 39 40 41 42 43 38 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Reconstitution of 4 bevacizumab for 5 Author, year Treatment arms Treatment protocol As needed treatment criteria intravitreal 6 injection reported 7 (Yes/No) 8 TX 1: ranibizumab 9 0.5 mg/0.05 ml 10 TX 1, 2, & 3: Approximately 11 TX 2: aflibercept monthly injections for 12 months. 12 0.5 mg/0.05 ml Heier 2012 – For peer review only None NA 13 VIEW 136 TX 3: aflibercept TX 4: 3 monthly injections and 14 2 mg/0.05 ml every bimonthly injections for 12 15 months. http://bmjopen.bmj.com/ 16 TX 4: aflibercept 17 2 mg/0.05 ml 18 19 TX 1: ranibizumab 0.5 mg/0.05 ml 20 TX 1, 2, & 3: Approximately 21 TX 2: aflibercept monthly injections for 12 months. 22 Heier 2012 – 0.5 mg/0.05 ml
23 36 None on September 24, 2021 by guest. Protected copyright. NA VIEW 2 TX 3: aflibercept TX 4: 3 monthly injections and 24 2 mg/0.05 ml every bimonthly injections for 12 25 months. 26 TX 4: aflibercept 27 2 mg/0.05 ml 28 TX 1: ranibizumab 29 0.5 mg/0.05 ml 3 monthly injections. Repeated Biswas an increase in CMT of more than 100 um or a 30 injections as needed treatment No 2011a37 fall in BCVA by more than 5 ETDRS letters 31 TX 2: bevacizumab criteria. Follow-up for 18 months. 32 1.25 mg/0.05 ml 33 TX 1: ranibizumab 34 0.5 mg/0.05 ml 3 monthly injections. Repeated 35 Biswas an increase in CMT of more than 100 um or a 38 injections as needed treatment No 2011b fall in BCVA by more than 5 ETDRS letters 36 TX 2: bevacizumab criteria. Follow-up for 18 months. 37 1.25 mg/0.05 ml 38 39 40 41 42 43 39 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Reconstitution of 4 bevacizumab for 5 Author, year Treatment arms Treatment protocol As needed treatment criteria intravitreal 6 injection reported 7 (Yes/No) 8 TX 1: ranibizumab 9 0.5 mg/0.05 ml 10 11 TX 2: bevacizumab TX 1 & TX 2: monthly injections Fluid on OCT, new or persistent hemorrhage, 12 1.25 mg/0.05 ml for 12 months. decreased visual acuity as compared with the Martin 201139 For peer reviewprevious examination, only or dye leakage or Yes 13 TX 3: ranibizumab TX 3 & TX 4: monthly injections as increased lesion size on fluorescein 14 0.5 mg/0.05 ml needed treatment criteria. angiography. 15 http://bmjopen.bmj.com/ 16 TX 4: bevacizumab 1.25 mg/0.05 ml 17 18 TX 1: ranibizumab Patients returned monthly to undergo visual 19 3 monthly injections. Repeated acuity measurements (ETDRS chart, OCT Subramanian 0.5 mg/0.05 ml 20 injections as needed treatment and clinical exam) If patients showed a Yes 201040 21 TX 2: bevacizumab criteria. Follow-up for 12 months. qualitative increase in intraretinal fluid or 22 1.25 mg/0.05 ml subretinal fluid by OCT
23 on September 24, 2021 by guest. Protected copyright. 24 DME (n = 3) 25 Re-injection if macular edema persisted or 26 worsened and visual acuity worsened in 27 comparison with the preceding 28 The drugs were injected into the visit. The treatment was withheld if there was 29 study eyes at baseline and then no change of macular thickness or visual TX 1: ranibizumab 30 every 1 month until the 3rd month acuity for two successive visits but was 41 0.5 mg/0.05 ml 31 Fouda 2017 (loading dose of three injections). reinstated once vision or macular edema None Tx 2: aflibercept 2 32 During the follow-up period, the worsened again. Improvement or worsening mg/0.05 ml 33 drug re-injection was considered of macular edema was defined as a 10% 34 on monthly basis change of CMT in comparison with last visit 35 while 0.1 change of visual acuity in 36 comparison with last visit was considered a 37 significant change. 38 39 40 41 42 43 40 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Reconstitution of 4 bevacizumab for 5 Author, year Treatment arms Treatment protocol As needed treatment criteria intravitreal 6 injection reported 7 (Yes/No) 8 Monthly injections until stable 9 visual acuity within 6 months. Patients were injected at baseline and then 10 Subsequently, irrespective of every month unless visual acuity was 20/20 or 11 visual acuity and central subfield TX 1: ranibizumab better with a central subfield thickness below 12 thickness, an injection was 0.5 mg/0.05 ml For peer reviewthe eligibility threshold only and there was no 13 withheld if there was no improvement or worsening in response to the 14 improvement or worsening after 27 TX 2: bevacizumab past two injections. Starting at 6 months, 15 Wells 2015 two consecutive injections, but http://bmjopen.bmj.com/ Yes 1.25 mg/0.05 ml irrespective of visual acuity and central 16 treatment was reinitiated if the subfield thickness, an injection was withheld if 17 visual-acuity letter score or the TX 3: aflibercept there was no improvement or worsening after central subfield thickness 18 2 mg/0.05 ml two consecutive injections, but treatment was worsened. Laser PCT was 19 reinitiated if the visual-acuity letter score or initiated at or after the 24 week 20 the central subfield thickness worsened. 21 visit for persistent DME. Follow-up 22 for 12 months.
23 Start with 3 monthly injections. on September 24, 2021 by guest. Protected copyright. 24 TX 1: ranibizumab Subsequently, 3 additional 0.5 mg/0.05 ml monthly injections as needed. Central macular thickness was >275 um or if 25 42 26 Ekinci 2014 After 6 injections, additional there was an increase in BCVA of at least 3 No 27 TX 2: bevacizumab injections were used till stable letters compared with baseline 28 1.25 mg/0.05 ml visual acuity was obtained. 29 Follow-up for 12 months. 30 RVO-ME (n = 2) 31 32 TX 1: aflibercept 2 33 mg/0.05 ml Scott 201743 Monthly injections for 6 months Not applicable No 34 TX 2: bevacizumab 35 1.25 mg/0.05 ml 36 37 38 39 40 41 42 43 41 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Reconstitution of 4 bevacizumab for 5 Author, year Treatment arms Treatment protocol As needed treatment criteria intravitreal 6 injection reported 7 (Yes/No) 8 >50um increase in CRT compared with the Initial injection. Repeated monthly 9 thinnest previous measurement; new or TX 1: ranibizumab injections according to as needed 10 persistent cystoid retinal changes or sub- 0.5 mg/0.05 ml treatment criteria for 6 months. 11 Narayanan retinal fluid on OCT; loss of >5 letters from the Macular grid laser No 12 201544 best previous VA measurement in conjunction TX 2: bevacizumabFor photocoagulation peer was allowed review only 13 with any increase in CRT; increase in VA of 1.25 mg/0.05 ml concurrently with injections after 3 14 >5 letters between the current and most months. 15 recent visits. http://bmjopen.bmj.com/ 16 17 m-CNV (n = 2) 18 19 TX 1: ranibizumab 0.5 mg/0.05 ml Initial injection. Repeated monthly 20 subretinal/intraretinal fluid on OCT, leakage Iacono 201245 injections according to as needed Yes 21 on FA or appearance of a new hemorrhage. TX 2: bevacizumab treatment criteria for 18 months. 22 1.25 mg/0.05 ml
23 on September 24, 2021 by guest. Protected copyright. TX 1: ranibizumab 24 Monthly additional injections were performed 0.5 mg/0.05 ml Initial injection. Repeated monthly 25 Gharbiya until absence of fluorescein leakage from the injections according to as needed Yes 26 201046 CNV and absence of any fluid collections on TX 2: bevacizumab treatment criteria for 6 months. 27 OCT were obtained. 28 1.25 mg/0.05 ml 29 30 Abbreviations: BCVA – Best-corrected visual acuity; cn-AMD – choroidal neovascular age-related macular degeneration; CRT – central retinal 31 thickness; DME – diabetic macular oedema; ETDRS – Early Treatment Diabetic Retinopathy Study; m-CNV – myopic choroidal 32 neovascularization; NA – not applicable; NR – not reported; OCT – optical coherence tomography; RCT – randomized controlled trials; RVO-ME – 33 34 macular edema due to retinal vein occlusion; SD – standard deviation; TX – treatment; VA – visual acuity 35 36 37 38 39 40 41 42 43 42 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Appendix 11: Summary of results from the DRCR.net trial (Wells 2015a and Wells 2016b) 4 5 6 Mean Mean 7 Proportion treatment comparator 8 No. of Total Risk Ratio (95% Difference (%) / 2 Outcome Rx vs Ctrl Comparison a effect effect I RCTs patients CI) Mean Difference 9 estimate estimateb (95% CI) 10 [Range] [Range] 11 12 Subgroup Analysis of AntiFor-VEGF Treatment peer Effects in review Diabetic Macular Edema only (DME) According to the DRCR.net RCT 13 14 Aflibercept vs. Ranibizumab
15 http://bmjopen.bmj.com/ 16 Follow-up for 24 months 1 392 0.37 0.39 1.06 (0.82, 1.37) 2.16 (- 7.44, 11.75) NA 17 18 Participants with baseline 19 1 192 0.55 0.58 1.05 (0.82, 1.35) 2.84 (-11.17, 16.86) NA Vision BCVA < 69 letters 20 gain in Participants with baseline 21 1 200 0.19 0.2 1.10 (0.63, 1.92) 1.83 (-9.14, 12.8) NA BCVA of BCVA ≥ 69 letters 22 ≥15
23 on September 24, 2021 by guest. Protected copyright. EDTRS Follow-up for 12 months 1 414 0.32 0.42 1.30 (1.01, 1.69) 10.1 (1.00, 19.00) NA 24 letters 25 Participants with baseline 1 203 0.50 0.67 1.35 (1.06, 1.72) 17.16 (3.79, 30.53) NA 26 BCVA < 69 letters 27 Participants with baseline 28 1 211 0.15 0.18 1.18 (0.64, 2.17) 2.69 (- 7.34, 12.72) NA BCVA ≥ 69 letters 29 30 Vision 31 loss in Follow-up for 24 months 1 392 0.02 0.02 1.59 (0.38, 6.67) 0.92 (-1.87, 3.7) NA 32 BCVA of ≥15 33 EDTRS Follow-up for 12 months 1 414 0.01 0.01 0.99 (0.20, 4.76) 0 (-2.00, 2.02) NA 34 letters 35 12.3 ± 36 Mean Follow-up for 24 months 1 392 12.8 ± 12.4 NA 0.7 (-1.3, 2.8) NA 10.5 37 change in BCVA Participants with baseline 16.1 ± 38 1 192 18.1 ± 13.8 NA 2.3 (-1.1, 5.6) NA 39 (SMD) BCVA < 69 letters 12.1 40 41 42 43 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Participants with baseline 1 200 8.6 ± 7.0 7.8 ± 8.4 NA -0.7 (-2.9, 1.5) NA 4 BCVA ≥ 69 letters 5 6 Follow-up for 12 months 1 414 11.2 ± 9.4 13.3 ± 11.1 NA 2.1 (0.1, 4.2) NA 7 Participants with baseline 14.2 ± 8 1 203 18.9 ± 11.5 NA 4.7 (1.4, 8.0) NA 9 BCVA < 69 letters 10.6 10 Participants with baseline 1 211 8.3 ± 6.8 8.0 ± 7.6 NA -0.4 (-2.3, 1.5) NA 11 BCVA ≥ 69 letters 12 For peer review only 13 Bevacizumab vs Aflibercept 14
15 http://bmjopen.bmj.com/ Follow-up for 24 months 1 386 0.35 0.39 0.89 (0.69, 1.16) -4.21 (-13.82, 5.4) NA 16 17 Participants with baseline 1 190 0.52 0.58 0.9 (0.69, 1.16) -5.99 (-20.12, 8.14) NA 18 BCVA < 69 letters 19 Vision Participants with baseline 20 gain in 1 196 0.17 0.2 0.84 (0.47, 1.52) -3.18 (-14.11, 7.74) NA 21 BCVA of BCVA ≥ 69 letters 22 ≥15 Follow-up for 12 months 1 414 0.29 0.42 0.68 (0.52, 0.89) -14.0 (-23.00, -4.04) NA
23 EDTRS on September 24, 2021 by guest. Protected copyright. letters 24 Participants with baseline -25.49 (-38.72, - 1 204 0.41 0.67 0.62 (0.47, 0.81) NA 25 BCVA < 69 letters 12.26) 26 27 Participants with baseline 1 210 0.16 0.18 0.91 (0.5, 1.65) -1.58 (-11.77, 8.61) NA 28 BCVA ≥ 69 letters 29 Vision 30 loss in Follow-up for 24 months 1 386 0.03 0.02 1.3 (0.4, 4.2) 0.76 (-2.58, 4.1) NA 31 BCVA of 32 ≥15 SA - Follow-up for 12 33 EDTRS 1 412 0.01 0.01 1 (0.2, 4.9) 0 (-2.02, 2.00) NA 34 letters months 35 10.0 ± Follow-up for 24 months 1 386 12.8 ± 12.4 NA -2.7 (-5.2, -0.3) NA 36 11.8 Mean 37 Participants with baseline 13.3 ± 38 change in 1 190 18.1 ± 13.8 NA -4.7 (-8.8, -0.5) NA BCVA BCVA < 69 letters 13.4 39 (SMD) Participants with baseline 40 1 196 6.8 ± 8.8 7.8 ± 8.4 NA -1.1 (-3.4, 1.1) NA 41 BCVA ≥ 69 letters 42 43 44 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 4 Follow-up for 12 months 1 414 9.7 ± 10.1 13.3 ± 11.1 NA -3.5 (-1.4, -5.7) NA 5 Participants with baseline 11.8 ± 6 1 204 18.9 ± 11.5 NA -6.5 (-10.1, -2.9) NA 7 BCVA < 69 letters 12.0 Participants with baseline 8 1 210 7.5 ± 7.4 8.0 ± 7.6 NA -0.7 (-2.7, 1.3) NA 9 BCVA ≥ 69 letters 10 Footnote: Bolded estimates indicate statistical significance. 11 a Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 12 2015;372(13):1193-1203. b For peer review only 13 Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a 14 Comparative Effectiveness Randomized Clinical Trial. Ophthalmology. 2016;123(6):1351-1359.
15 http://bmjopen.bmj.com/ 16 Abbreviations: BCVA - best-corrected visual acuity; CI - confidence interval; ETDRS - Early Treatment Diabetic Retinopathy Study; NA - not 17 applicable; RCT - randomized controlled trials; Rx - treatment; SA - sensitivity analysis; SMD - standardized mean difference 18 19 20 21 22
23 on September 24, 2021 by guest. Protected copyright. 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 45 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from
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1 2 3 Appendix 12: Mean change in best-corrected visual acuity letter scores over time in patients treated with 4 5 6 bevacizumab or ranibizumab 7 8 9 10 11 12 For peer review only 13 14
15 http://bmjopen.bmj.com/ 16 17 18 19 20 21 22
23 on September 24, 2021 by guest. Protected copyright. 24 25 26 27 28 29 30 31 32 33 34 35 36 37 Abbreviations: BCVA – Best-corrected visual acuity; cn-AMD – choroidal neovascular age-related macular degeneration; DME – diabetic 38 39 macular oedema; ETDRS – Early Treatment Diabetic Retinopathy Study; m-CNV – myopic choroidal neovascularization; RCT – randomized 40 controlled trials; RVO-ME – macular edema due to retinal vein occlusion 41 42 43 46 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 90BMJ Open: first published as 10.1136/bmjopen-2018-022031 on 28 May 2019. Downloaded from of 91
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