TY - JOUR
T1 - Anti-vascular endothelial growth factor for neovascular agerelated macular degeneration
AU - Solomon, Sharon D.
AU - Lindsley, Kristina
AU - Vedula, Satyanarayana S.
AU - Krzystolik, Magdalena G.
AU - Hawkins, Barbara S.
N1 - Funding Information:
Full study name: The Avastin (bevacizumab) for Choroidal Neovascularization (ABC) Trial Trial registration: ISRCTN83325075 Funding sources: special trustees of Moorfields Eye Hospital; Department of Health, through an award by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology; additional support from the National Eye Research Centre, Bristol Declarations of interest: “The authors who work at Moorfields Eye Hospital have no
Funding Information:
Primary outcome, as defined: change in BCVA in the study eye from baseline to 12 months assessed with ETDRS-like visual acuity charts at an initial distance of 4 meters Secondary outcomes, as defined: proportion of participants with loss of BCVA < 15 letters from baseline at 12 months (responders); proportion of participants with loss or gain of BCVA < 15 letters from baseline at 12 months (stabilizers); proportion of participants with loss of 15 or more letters of BCVA from baseline at 12 months (losers) ; proportion of participants with gain of 15 or more letters of BCVA from baseline at 12 months (gainers); absolute and percentage changes in CRT, as measured by SD-OCT at 4 and 12 months, as determined by the Study Reading Centre at the AMC; proportion of dropouts before final 12-month assessments; proportion of switchers after third injection; occurrence of (serious) adverse events during 12 months of the study and costs of the 2 treatments Intervals at which outcome assessed: monthly through 12 months Full study name: Comparison of Bevacizumab (Avastin) and Ranibizumab (Lucentis) in Exudative Age-related Macular Degeneration Trial registration: NTR1704 Funding sources: ”this work was funded by The Netherlands Organisation for Health Research and Development (http://www.zonmw.nl/en/) (r.s.). This study was supported by Dutch health insurance companies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript“ (page 1) Declarations of interest: ”the authors have declared that no competing interests exist“ (page 1) Study period: enrollment January 2009 to December 2011 Reported subgroup analyses: yes; treatment-naive participants or participants with a history of treatment Contacting study investigators: trial authors not contacted as data were available in
Funding Information:
• Cochrane Eyes and Vision US Project supported by Grant 1 U01 EY020522, National Eye Institute, National Institutes of Health, Bethesda, MD, USA. • SDS and BSH received support during preparation of this review from an unrestricted grant to the Wilmer Eye Institute from Research to Prevent Blindness, New York, New York, USA. • National Institute for Health Research (NIHR), UK. • Richard Wormald, Co-ordinating Editor for Cochrane Eyes and Vision (CEV), acknowledges financial support for his CEV research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology • This review update was supported by the NIHR, via Cochrane Infrastructure funding to the CEV UK Editorial base
Publisher Copyright:
© 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd..
PY - 2019/3/4
Y1 - 2019/3/4
N2 - Background Age-related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal neovascularization (CNV) secondary to AMD accounts for most cases of AMD-related severe vision loss. Intravitreous injection of anti-vascular endothelial growth factor (anti-VEGF) agents aims to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, to improve vision. Objectives • To investigate ocular and systemic effects of, and quality of life associated with, intravitreous injection of three anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) versus no anti-VEGF treatment for patients with neovascular AMD • To compare the relative effects of one of these anti-VEGF agents versus another when administered in comparable dosages and regimens Search methods To identify eligible studies for this review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register ( searched January 31, 2018); MEDLINE Ovid ( 1946 to January 31, 2018); Embase Ovid ( 1947 to January 31, 2018); the Latin American and Caribbean Health Sciences Literature Database ( LILACS) ( 1982 to January 31, 2018); the International Standard Randomized Controlled Trials Number ( ISRCTN) Registry ( www.isrctn.com/ editAdvancedSearch - searched January 31, 2018); ClinicalTrials.gov ( www.clinicaltrials.gov - searched November 28, 2018); and the World Health Organization ( WHO) International Clinical Trials Registry Platform ( ICTRP) ( www.who.int/ictrp/search/en - searched January 31, 2018). We did not impose any date or language restrictions in electronic searches for trials. Selection criteria We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or versus a control treatment (e.g. sham treatment, photodynamic therapy), in which participants were followed for at least one year. Data collection and analysis Two review authors independently screened records, extracted data, and assessed risks of bias. We contacted trial authors for additional data. We compared outcomes using risk ratios (RRs) or mean differences (MDS). We used the standard methodological procedures expected by Cochrane. Main results We included 16 RCTs that had enrolled a total of 6347 participants with neovascular AMD (the number of participants per trial ranged from 23 to 1208) and identified one potentially relevant ongoing trial. Six trials compared anti-VEGF treatment (pegaptanib, ranibizumab, or bevacizumab) versus control, and 10 trials compared bevacizumab versus ranibizumab. Pharmaceutical companies conducted or sponsored four trials but funded none of the studies that evaluated bevacizumab. Researchers conducted these trials at various centers across five continents (North and South America, Europe, Asia, and Australia). The overall certainty of the evidence was moderate to high, and most trials had an overall low risk of bias. All but one trial had been registered prospectively. When compared with those who received control treatment, more participants who received intravitreous injection of any of the three anti-VEGF agents had gained 15 letters or more of visual acuity (risk ratio [RR] 4.19, 95% confidence interval [CI] 2.32 to 7.55; moderate-certainty evidence), had lost fewer than 15 letters of visual acuity (RR 1.40, 95% CI 1.27 to 1.55; high-certainty evidence), and showed mean improvement in visual acuity (mean difference 6.7 letters, 95%CI 4.4 to 9.0 in one pegaptanib trial;mean difference 17.8 letters, 95% CI 16.0 to 19.7 in three ranibizumab trials; moderate-certainty evidence) after one year of follow-up. Participants treated with anti-VEGF agents showed improvement in morphologic outcomes (e.g. size of CNV, central retinal thickness) compared with participants not treated with anti-VEGF agents (moderate-certainty evidence). No trial directly compared pegaptanib versus another anti-VEGF agent and followed participants for one year; however, when compared with control treatments, ranibizumab and bevacizumab each yielded larger improvements in visual acuity outcomes than pegaptanib. Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same RCTs compared the same regimens with respect to gain of 15 or more letters of visual acuity (RR 0.95, 95%CI 0.81 to 1.12; high-certainty evidence) and loss of fewer than 15 letters of visual acuity (RR 1.00, 95%CI 0.98 to 1.02; high-certainty evidence); results showed similar mean improvement in visual acuity (mean difference [MD] -0.5 letters, 95%CI -1.5 to 0.5; high-certainty evidence) after one year of follow-up, despite the substantially lower cost of bevacizumab compared with ranibizumab. Reduction in central retinal thickness was less among bevacizumab-treated participants than among ranibizumab-treated participants after one year (MD -11.6 μm, 95% CI -21.6 to -1.7; high-certainty evidence); however, this difference is within the range of measurement error, and we did not interpret it to be clinically meaningful. Ocular inflammation and increased intraocular pressure (IOP) after intravitreal injection were the most frequently reported serious ocular adverse events. Researchers reported endophthalmitis in less than 1% of anti-VEGF-treated participants and in no cases among control groups. The occurrence of serious systemic adverse events was comparable across anti-VEGF-treated groups and control groups; however, the numbers of events and trial participants may have been insufficient to show a meaningful difference between groups (evidence of low- tomoderate-certainty). Investigators rarelymeasured and reported data on visual function, quality of life, or economic outcomes. Authors' conclusions Results of this review show the effectiveness of anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; studies show that ranibizumab and bevacizumab improved visual acuity in some eyes that received these agents and were equally effective. Available information on the adverse effects of each medication does not suggest a higher incidence of potentially vision-threatening complications with intravitreous injection of anti-VEGF agents compared with control interventions; however, clinical trial sample sizes were not sufficient to estimate differences in rare safety outcomes. Future Cochrane Reviews should incorporate research evaluating variable dosing regimens of anti-VEGF agents, effects of long-term use, use of combination therapies (e.g. anti- VEGF treatment plus photodynamic therapy), and other methods of delivering these agents.
AB - Background Age-related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal neovascularization (CNV) secondary to AMD accounts for most cases of AMD-related severe vision loss. Intravitreous injection of anti-vascular endothelial growth factor (anti-VEGF) agents aims to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, to improve vision. Objectives • To investigate ocular and systemic effects of, and quality of life associated with, intravitreous injection of three anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) versus no anti-VEGF treatment for patients with neovascular AMD • To compare the relative effects of one of these anti-VEGF agents versus another when administered in comparable dosages and regimens Search methods To identify eligible studies for this review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register ( searched January 31, 2018); MEDLINE Ovid ( 1946 to January 31, 2018); Embase Ovid ( 1947 to January 31, 2018); the Latin American and Caribbean Health Sciences Literature Database ( LILACS) ( 1982 to January 31, 2018); the International Standard Randomized Controlled Trials Number ( ISRCTN) Registry ( www.isrctn.com/ editAdvancedSearch - searched January 31, 2018); ClinicalTrials.gov ( www.clinicaltrials.gov - searched November 28, 2018); and the World Health Organization ( WHO) International Clinical Trials Registry Platform ( ICTRP) ( www.who.int/ictrp/search/en - searched January 31, 2018). We did not impose any date or language restrictions in electronic searches for trials. Selection criteria We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or versus a control treatment (e.g. sham treatment, photodynamic therapy), in which participants were followed for at least one year. Data collection and analysis Two review authors independently screened records, extracted data, and assessed risks of bias. We contacted trial authors for additional data. We compared outcomes using risk ratios (RRs) or mean differences (MDS). We used the standard methodological procedures expected by Cochrane. Main results We included 16 RCTs that had enrolled a total of 6347 participants with neovascular AMD (the number of participants per trial ranged from 23 to 1208) and identified one potentially relevant ongoing trial. Six trials compared anti-VEGF treatment (pegaptanib, ranibizumab, or bevacizumab) versus control, and 10 trials compared bevacizumab versus ranibizumab. Pharmaceutical companies conducted or sponsored four trials but funded none of the studies that evaluated bevacizumab. Researchers conducted these trials at various centers across five continents (North and South America, Europe, Asia, and Australia). The overall certainty of the evidence was moderate to high, and most trials had an overall low risk of bias. All but one trial had been registered prospectively. When compared with those who received control treatment, more participants who received intravitreous injection of any of the three anti-VEGF agents had gained 15 letters or more of visual acuity (risk ratio [RR] 4.19, 95% confidence interval [CI] 2.32 to 7.55; moderate-certainty evidence), had lost fewer than 15 letters of visual acuity (RR 1.40, 95% CI 1.27 to 1.55; high-certainty evidence), and showed mean improvement in visual acuity (mean difference 6.7 letters, 95%CI 4.4 to 9.0 in one pegaptanib trial;mean difference 17.8 letters, 95% CI 16.0 to 19.7 in three ranibizumab trials; moderate-certainty evidence) after one year of follow-up. Participants treated with anti-VEGF agents showed improvement in morphologic outcomes (e.g. size of CNV, central retinal thickness) compared with participants not treated with anti-VEGF agents (moderate-certainty evidence). No trial directly compared pegaptanib versus another anti-VEGF agent and followed participants for one year; however, when compared with control treatments, ranibizumab and bevacizumab each yielded larger improvements in visual acuity outcomes than pegaptanib. Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same RCTs compared the same regimens with respect to gain of 15 or more letters of visual acuity (RR 0.95, 95%CI 0.81 to 1.12; high-certainty evidence) and loss of fewer than 15 letters of visual acuity (RR 1.00, 95%CI 0.98 to 1.02; high-certainty evidence); results showed similar mean improvement in visual acuity (mean difference [MD] -0.5 letters, 95%CI -1.5 to 0.5; high-certainty evidence) after one year of follow-up, despite the substantially lower cost of bevacizumab compared with ranibizumab. Reduction in central retinal thickness was less among bevacizumab-treated participants than among ranibizumab-treated participants after one year (MD -11.6 μm, 95% CI -21.6 to -1.7; high-certainty evidence); however, this difference is within the range of measurement error, and we did not interpret it to be clinically meaningful. Ocular inflammation and increased intraocular pressure (IOP) after intravitreal injection were the most frequently reported serious ocular adverse events. Researchers reported endophthalmitis in less than 1% of anti-VEGF-treated participants and in no cases among control groups. The occurrence of serious systemic adverse events was comparable across anti-VEGF-treated groups and control groups; however, the numbers of events and trial participants may have been insufficient to show a meaningful difference between groups (evidence of low- tomoderate-certainty). Investigators rarelymeasured and reported data on visual function, quality of life, or economic outcomes. Authors' conclusions Results of this review show the effectiveness of anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; studies show that ranibizumab and bevacizumab improved visual acuity in some eyes that received these agents and were equally effective. Available information on the adverse effects of each medication does not suggest a higher incidence of potentially vision-threatening complications with intravitreous injection of anti-VEGF agents compared with control interventions; however, clinical trial sample sizes were not sufficient to estimate differences in rare safety outcomes. Future Cochrane Reviews should incorporate research evaluating variable dosing regimens of anti-VEGF agents, effects of long-term use, use of combination therapies (e.g. anti- VEGF treatment plus photodynamic therapy), and other methods of delivering these agents.
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U2 - 10.1002/14651858.CD005139.pub4
DO - 10.1002/14651858.CD005139.pub4
M3 - Review article
C2 - 30834517
AN - SCOPUS:85062639998
SN - 1465-1858
VL - 2019
JO - Cochrane Database of Systematic Reviews
JF - Cochrane Database of Systematic Reviews
IS - 3
M1 - CD005139
ER -