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Meta-Analysis
. 2014 Aug 29;8(8):CD005139.
doi: 10.1002/14651858.CD005139.pub3.

Anti-vascular endothelial growth factor for neovascular age-related macular degeneration

Sharon D Solomon  1 , Kristina Lindsley, Satyanarayana S Vedula, Magdalena G Krzystolik, Barbara S Hawkins
Affiliations
Meta-Analysis

Anti-vascular endothelial growth factor for neovascular age-related macular degeneration

Sharon D Solomon et al. Cochrane Database Syst Rev. .

Abstract

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 neovascular AMD accounts for most AMD-related severe vision loss. Anti-vascular endothelial growth factor (anti-VEGF) agents, injected intravitreally, aim to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, improve vision.

Objectives: To investigate: (1) the ocular and systemic effects of, and quality of life associated with, intravitreally injected anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) for the treatment of neovascular AMD compared with no anti-VEGF treatment; and (2) the relative effects of one anti-VEGF agent compared with another when administered in comparable dosages and regimens.

Search methods: We searched Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to March 2014), EMBASE (January 1980 to March 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to March 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We used no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 27 March 2014.

Selection criteria: We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or a control treatment (e.g., sham treatment or photodynamic therapy). All trials followed participants 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 analyzed outcomes as risk ratios (RRs) or mean differences (MDs). We used the standard methodological procedures expected by The Cochrane Collaboration.

Main results: We included 12 RCTs including a total of 5496 participants with neovascular AMD (the number of participants per trial ranged from 28 to 1208). One trial compared pegaptanib, three trials ranibizumab, and two trials bevacizumab versus controls; six trials compared bevacizumab with ranibizumab. Four trials were conducted by pharmaceutical companies; none of the eight studies which evaluated bevacizumab were funded by pharmaceutical companies. The trials were conducted at various centers across five continents (North and South America, Europe, Asia and Australia). The overall quality of the evidence was very good, with most trials having an overall low risk of bias.When compared with control treatments, participants who received any of the three anti-VEGF agents were more likely to have gained 15 letters or more of visual acuity, lost fewer than 15 letters of visual acuity, and had vision 20/200 or better after one year of follow up. Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same regimens were compared in the same RCTs, despite the substantially lower cost for bevacizumab compared with ranibizumab. No trial directly compared pegaptanib with other anti-VEGF agents; however, when compared with controls, ranibizumab or bevacizumab yielded larger improvements in visual acuity outcomes than pegaptanib.Participants treated with anti-VEGFs showed improvements in morphologic outcomes (e.g., size of CNV or central retinal thickness) compared with participants not treated with anti-VEGF agents. There was less reduction in central retinal thickness among bevacizumab-treated participants than among ranibizumab-treated participants after one year (MD -13.97 μm; 95% confidence interval (CI) -26.52 to -1.41); however, this difference is within the range of measurement error and we did not interpret it as being clinically meaningful.Ocular inflammation and increased intraocular pressure after intravitreal injection were the most frequently reported serious ocular adverse events. Endophthalmitis was reported in fewer than 1% of anti-VEGF treated participants; no cases were reported in 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 detect a meaningful difference between groups. Data for visual function, quality of life, and economic outcomes were sparsely measured and reported.

Authors' conclusions: The results of this review indicate the effectiveness of anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; ranibizumab and bevacizumab were also shown to improve visual acuity. The information available on the adverse effects of each medication do not suggest a higher incidence of potentially vision-threatening complications with intravitreal injection compared with control interventions; however, clinical trial sample sizes may not have been sufficient to detect rare safety outcomes. Research evaluating variable dosing regimens with anti-VEGF agents, effects of long-term use, combination therapies (e.g., anti-VEGF treatment plus photodynamic therapy), and other methods of delivering the agents should be incorporated into future Cochrane reviews.

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Conflict of interest statement

DECLARATIONS OF INTEREST

None known.

Figures

Analysis 1.1
Analysis 1.1
Comparison 1 Pegaptanib versus control, Outcome 1 Gain of 15 letters or more visual acuity at one year.
Analysis 1.2
Analysis 1.2
Comparison 1 Pegaptanib versus control, Outcome 2 Loss of fewer than 15 letters visual acuity at one year.
Analysis 1.3
Analysis 1.3
Comparison 1 Pegaptanib versus control, Outcome 3 Loss of fewer than 30 letters visual acuity at one year.
Analysis 1.4
Analysis 1.4
Comparison 1 Pegaptanib versus control, Outcome 4 Visual acuity better than 20/200 at one year.
Analysis 1.5
Analysis 1.5
Comparison 1 Pegaptanib versus control, Outcome 5 Maintenance of visual acuity at one year.
Analysis 1.6
Analysis 1.6
Comparison 1 Pegaptanib versus control, Outcome 6 Mean change in visual acuity at one year (number of letters).
Analysis 1.7
Analysis 1.7
Comparison 1 Pegaptanib versus control, Outcome 7 Reduction in size of CNV at one year (Mean number of disc areas).
Analysis 1.8
Analysis 1.8
Comparison 1 Pegaptanib versus control, Outcome 8 Reduction in size of lesion at one year (Mean number of disc areas).
Analysis 2.1
Analysis 2.1
Comparison 2 Ranibizumab versus control, Outcome 1 Gain of 15 letters or more visual acuity at one year.
Analysis 2.2
Analysis 2.2
Comparison 2 Ranibizumab versus control, Outcome 2 Gain of 15 letters or more visual acuity at two years.
Analysis 2.3
Analysis 2.3
Comparison 2 Ranibizumab versus control, Outcome 3 Loss of fewer than 15 letters visual acuity at one year.
Analysis 2.4
Analysis 2.4
Comparison 2 Ranibizumab versus control, Outcome 4 Loss of fewer than 15 letters visual acuity at two years.
Analysis 2.5
Analysis 2.5
Comparison 2 Ranibizumab versus control, Outcome 5 Loss of fewer than 30 letters visual acuity at one year.
Analysis 2.6
Analysis 2.6
Comparison 2 Ranibizumab versus control, Outcome 6 Loss of fewer than 30 letters visual acuity at two years.
Analysis 2.7
Analysis 2.7
Comparison 2 Ranibizumab versus control, Outcome 7 Visual acuity better than 20/200 at one year.
Analysis 2.8
Analysis 2.8
Comparison 2 Ranibizumab versus control, Outcome 8 Visual acuity better than 20/200 at two years.
Analysis 2.9
Analysis 2.9
Comparison 2 Ranibizumab versus control, Outcome 9 Maintenance of visual acuity at one year.
Analysis 2.10
Analysis 2.10
Comparison 2 Ranibizumab versus control, Outcome 10 Maintenance of visual acuity at two years.
Analysis 2.11
Analysis 2.11
Comparison 2 Ranibizumab versus control, Outcome 11 Mean change in visual acuity at one year (number of letters).
Analysis 2.12
Analysis 2.12
Comparison 2 Ranibizumab versus control, Outcome 12 Mean change in visual acuity at two years (number of letters).
Analysis 2.13
Analysis 2.13
Comparison 2 Ranibizumab versus control, Outcome 13 Reduction in size of lesion at one year (Mean number of disc areas).
Analysis 2.14
Analysis 2.14
Comparison 2 Ranibizumab versus control, Outcome 14 Reduction in size of lesion at two years (Mean number of disc areas).
Analysis 2.15
Analysis 2.15
Comparison 2 Ranibizumab versus control, Outcome 15 Mean change in quality of life scores at one year.
Analysis 2.15
Analysis 2.15
Comparison 2 Ranibizumab versus control, Outcome 15 Mean change in quality of life scores at one year.
Analysis 2.15
Analysis 2.15
Comparison 2 Ranibizumab versus control, Outcome 15 Mean change in quality of life scores at one year.
Analysis 2.16
Analysis 2.16
Comparison 2 Ranibizumab versus control, Outcome 16 Mean change in quality of life scores at two years.
Analysis 2.16
Analysis 2.16
Comparison 2 Ranibizumab versus control, Outcome 16 Mean change in quality of life scores at two years.
Analysis 2.16
Analysis 2.16
Comparison 2 Ranibizumab versus control, Outcome 16 Mean change in quality of life scores at two years.
Analysis 3.1
Analysis 3.1
Comparison 3 Bevacizumab versus control, Outcome 1 Gain of 15 letters or more visual acuity at one year.
Analysis 3.2
Analysis 3.2
Comparison 3 Bevacizumab versus control, Outcome 2 Loss of fewer than 15 letters visual acuity at one year.
Analysis 4.1
Analysis 4.1
Comparison 4 Bevacizumab versus ranibizumab, Outcome 1 Gain of 15 letters or more visual acuity at one year.
Analysis 4.2
Analysis 4.2
Comparison 4 Bevacizumab versus ranibizumab, Outcome 2 Gain of 15 letters or more visual acuity at two years.
Analysis 4.3
Analysis 4.3
Comparison 4 Bevacizumab versus ranibizumab, Outcome 3 Loss of fewer than 15 letters visual acuity at one year.
Analysis 4.4
Analysis 4.4
Comparison 4 Bevacizumab versus ranibizumab, Outcome 4 Loss of fewer than 15 letters visual acuity at two years.
Analysis 4.5
Analysis 4.5
Comparison 4 Bevacizumab versus ranibizumab, Outcome 5 Visual acuity better than 20/200 at one year.
Analysis 4.6
Analysis 4.6
Comparison 4 Bevacizumab versus ranibizumab, Outcome 6 Visual acuity better than 20/200 at two years.
Analysis 4.7
Analysis 4.7
Comparison 4 Bevacizumab versus ranibizumab, Outcome 7 Mean change in visual acuity at one year (number of letters).
Analysis 4.8
Analysis 4.8
Comparison 4 Bevacizumab versus ranibizumab, Outcome 8 Mean change in visual acuity at two years (number of letters).
Analysis 4.9
Analysis 4.9
Comparison 4 Bevacizumab versus ranibizumab, Outcome 9 Reduction in central retinal thickness at one year.
Analysis 4.10
Analysis 4.10
Comparison 4 Bevacizumab versus ranibizumab, Outcome 10 Reduction in central retinal thickness at two years.
Analysis 4.11
Analysis 4.11
Comparison 4 Bevacizumab versus ranibizumab, Outcome 11 No problems in quality of life domain at one year.
Analysis 4.12
Analysis 4.12
Comparison 4 Bevacizumab versus ranibizumab, Outcome 12 No problems in quality of life domain at two years.
Figure 1
Figure 1
Study flow diagram. Results of searches as of 27 March 2014.
Figure 2
Figure 2
Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.
Figure 3
Figure 3
Forest plot of comparison: 1 Pegaptanib versus control, outcome: 1.1 Gain of 15 letters or more visual acuity at one year.
Figure 4
Figure 4
Forest plot of comparison: 2 Ranibizumab versus control, outcome: 2.1 Gain of 15 letters or more visual acuity at one year.
Figure 5
Figure 5
Forest plot of comparison: 3 Bevacizumab versus control, outcome: 3.1 Gain of 15 letters or more visual acuity at one year.
Figure 6
Figure 6
Forest plot of comparison: 4 Bevacizumab versus ranibizumab, outcome: 4.1 Gain of 15 letters or more visual acuity at one year.
See this image and copyright information in PMC

Update of

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References to studies excluded from this review

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References to studies awaiting assessment

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References to ongoing studies

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Additional references

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References to other published versions of this review

    1. Krzystolik MG, Woodcome HA, Reddy U. Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration. Cochrane Database of Systematic Reviews. 2005;(1) doi: 10.1002/14651858.CD005139. - DOI - PMC - PubMed
    1. Vedula SS, Krzystolik M. Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration. Cochrane Database of Systematic Reviews. 2008;(2) doi: 10.1002/14651858.CD005139.pub2. - DOI - PMC - PubMed

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