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Meta-Analysis
. 2014 Nov 24;2014(11):CD008721.
doi: 10.1002/14651858.CD008721.pub2.

Anti-vascular endothelial growth factor for proliferative diabetic retinopathy

Maria José Martinez-Zapata  1 , Arturo J Martí-Carvajal, Ivan Solà, José I Pijoán, José A Buil-Calvo, Josep A Cordero, Jennifer R Evans
Affiliations
Meta-Analysis

Anti-vascular endothelial growth factor for proliferative diabetic retinopathy

Maria José Martinez-Zapata et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Proliferative diabetic retinopathy (PDR) is a complication of diabetic retinopathy that can cause blindness. Although panretinal photocoagulation (PRP) is the treatment of choice for PDR, it has secondary effects that can affect vision. An alternative treatment such as anti-vascular endothelial growth factor (anti-VEGF), which produces an inhibition of vascular proliferation, could improve the vision of people with PDR.

Objectives: To assess the effectiveness and safety of anti-VEGFs for PDR.

Search methods: We searched 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 April 2014), EMBASE (January 1980 to April 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 did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 April 2014.

Selection criteria: We included randomised controlled trials (RCTs) comparing anti-VEGFs to another active treatment, sham treatment or no treatment for people with PDR. We also included studies that assessed the combination of anti-VEGFs with other treatments.

Data collection and analysis: Two review authors independently selected studies for inclusion, extracted data and assessed risk of bias for all included trials. We calculated the risk ratio (RR) or the mean difference (MD), and 95% confidence intervals (CI).

Main results: We included 18 RCTs with 1005 participants (1131 eyes) of whom 57% were men. The median number of participants per RCT was 40 (range 15 to 261). The studies took place in Asia (three studies), Europe (two studies), the Middle East (seven studies), North America (three studies) and South America (three studies). Eight RCTs recruited people eligible for PRP, nine RCTs enrolled people with diabetes requiring vitrectomy and one RCT recruited people undergoing cataract surgery. The median follow-up was six months (range one to 12 months). Seven studies were at high risk of bias and the remainder were unclear risk of bias in one or more domains.Very low quality evidence from one study of 61 people showed that people treated with bevacizumab and PRP were less likely to lose 3 or more lines of visual acuity at 12 months compared with people treated with PRP alone (RR 0.19, 95% CI 0.05 to 0.81). People treated with anti-VEGF had an increased chance of gaining 3 or more lines of visual acuity but the effect was imprecise and compatible with no effect or being less likely to gain vision (RR 6.78, 95% CI 0.37 to 125.95). No other study reported these two outcomes. On average, people treated with anti-VEGF (bevacizumab, pegaptanib or ranibizumab) had better visual acuity at 12 months compared with people not receiving anti-VEGF (MD -0.07 logMAR, 95% CI -0.12 to -0.02; 5 RCTs, 373 participants, low quality evidence). There was some evidence to suggest a regression of PDR with smaller leakage on fluorescein angiography but it was difficult to estimate a pooled result from the two trials reporting this outcome. People receiving anti-VEGF were less likely to have vitreous or pre-retinal haemorrhage at 12 months (RR 0.32, 95% CI 0.16 to 0.65; 3 RCTs, 342 participants, low quality evidence). No study reported on fluorescein leakage or quality of life.All of the nine trials of anti-VEGF before or during vitrectomy investigated bevacizumab; most studies investigated bevacizumab before vitrectomy, one study investigated bevacizumab during surgery.People treated with bevacizumab and vitrectomy were less likely to lose 3 or more lines of visual acuity at 12 months compared with people given vitrectomy alone but the effect was imprecise and compatible with no effect or being more likely to lose vision (RR 0.49, 95% CI 0.08 to 3.14; 3 RCTs, 94 participants, low quality evidence). People treated with bevacizumab were more likely to gain 3 or more lines of visual acuity (RR 1.62, 95% CI 1.20 to 2.17; 3 RCTs, 94 participants, low quality evidence). On average, people treated with bevacizumab had better visual acuity at 12 months compared with people not receiving bevacizumab but there was uncertainty in the estimate (the CIs included 0; i.e. were compatible with no effect, and there was considerable inconsistency between studies; MD -0.24 logMAR, 95% CI -0.50 to 0.01; 6 RCTs, 335 participants, I(2) = 67%; low quality evidence). People receiving bevacizumab were less likely to have vitreous or pre-retinal haemorrhage at 12 months (RR 0.30, 95% CI 0.18 to 0.52; 7 RCTs, 393 participants, low quality evidence). No study reported on quality of life.Reasons for downgrading the quality of the evidence included risk of bias in included studies, imprecision of the estimates, inconsistency of effect estimates and indirectness (few studies reported at 12 months).Adverse effects were rarely reported and there was no evidence for any increased risk with anti-VEGF but given the relatively few studies that reported these, and the low event rate, the power of the analysis to detect any differences was low.

Authors' conclusions: There was very low or low quality evidence from RCTs for the efficacy and safety of anti-VEGF agents when used to treat PDR over and above current standard treatments. However, the results suggest that anti-VEGFs can reduce the risk of intraocular bleeding in people with PDR. Further carefully designed clinical trials should be able to improve this evidence.

PubMed Disclaimer

Conflict of interest statement

None.

Figures

1
1
Results from searching for studies for inclusion in the review.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 Anti‐vascular endothelial growth factor (anti‐VEGF) versus photocoagulation, outcome: 1.3 Visual acuity [logMAR].
5
5
Forest plot of comparison: 2 Anti‐vascular endothelial growth factor (anti‐VEGF) plus surgery versus surgery alone or surgery plus sham or placebo, outcome: 2.3 Visual acuity [logMAR].
1.1
1.1. Analysis
Comparison 1 Anti‐vascular endothelial growth factor (anti‐VEGF) with or without panretinal photocoagulation (PRP) versus PRP alone, Outcome 1 Visual acuity.
1.2
1.2. Analysis
Comparison 1 Anti‐vascular endothelial growth factor (anti‐VEGF) with or without panretinal photocoagulation (PRP) versus PRP alone, Outcome 2 Regression of proliferative diabetic retinopathy.
1.3
1.3. Analysis
Comparison 1 Anti‐vascular endothelial growth factor (anti‐VEGF) with or without panretinal photocoagulation (PRP) versus PRP alone, Outcome 3 Presence of vitreous or pre‐retinal haemorrhage.
1.4
1.4. Analysis
Comparison 1 Anti‐vascular endothelial growth factor (anti‐VEGF) with or without panretinal photocoagulation (PRP) versus PRP alone, Outcome 4 Adverse effects.
2.1
2.1. Analysis
Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 1 Loss of 3 or more lines of ETDRS visual acuity.
2.2
2.2. Analysis
Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 2 Gain of 3 or more lines of ETDRS visual acuity.
2.3
2.3. Analysis
Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 3 Visual acuity.
2.4
2.4. Analysis
Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 4 Presence of vitreous or pre‐retinal haemorrhage.
2.5
2.5. Analysis
Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 5 Adverse effects.
See this image and copyright information in PMC

References

References to studies included in this review

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Cheema 2009 {published data only}
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Cho 2010 {published data only}
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References to studies excluded from this review

Arimura 2009 {published data only}
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Tonello 2008 {published data only}
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References to ongoing studies

EUCTR2013‐003272‐12‐GB {published data only}
    1. EUCTR2013‐003272‐12‐GB. Clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy. www.clinicaltrialsregister.eu/ctr‐search/trial/2013‐003272‐12/GB (accessed 2 November 2014).
NCT01854593 {published data only}
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NCT01941329 (PROTEUS) {published data only}
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NCT01976923 (PACORES) {published data only}
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NCT01988246 {published data only}
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References to other published versions of this review

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