Injections of anti-vascular endothelial growth factor for advanced diabetic retinopathy

Review question
Do injections of anti-vascular endothelial growth factor (anti-VEGF) help people with advanced diabetic retinopathy in terms of vision and progression of the disease? Is this treatment safe?

Background
Diabetic retinopathy is a problem of the back of the eye that occurs in people with diabetes. In later stages of the disease, new blood vessels grow in the back of the eye and cause problems with vision. This advanced form of the disease is known as proliferative diabetic retinopathy. Anti-VEGF has been developed to block the growth of these new vessels. It has to be injected into the eye.

Search date
We examined research published up to 28 April 2014.

Study characteristics
We found 18 trials. They took place in Asia (three trials), Europe (two trials), the Middle East (seven trials), North America (three trials) and South America (three trials). A total of 1005 people took part in these trials and 1131 eyes were studied. Eight trials studied anti-VEGF with another commonly used treatment for diabetic retinopathy (laser), nine studies looked at anti-VEGF at the time of diabetic eye surgery (vitrectomy) and one study investigated use of anti-VEGF in people with diabetic retinopathy having cataract surgery. Most studies followed up the participants for six months but some studies followed up for one year.

Study funding sources
One study was industry funded, one study was funded by a mixture of government and industry, and three studies were funded by government and non-government organisations. The remainder of the studies did not report a funding source.

Key results
In one small study, we found that people treated with anti-VEGF plus laser were less likely to lose some vision compared with people treated with laser alone but the estimate was imprecise: around 30% of people treated with laser lost some vision compared with 6% and 24% of people treated with anti-VEGF plus laser.

On average, people treated with anti-VEGF had slightly better vision than people not treated with anti-VEGF. They were also less likely to have bleeding in the eye. None of the studies reported on quality of life. One study suggested that injection of anti-VEGF was less painful than having laser treatment.

People treated with anti-VEGF before or during diabetic eye surgery (vitrectomy) were less likely to lose some vision compared with people treated with surgery alone, but the estimate was uncertain and it could be that anti-VEGF did not make a difference, or increased the risk of losing vision. On average, people receiving anti-VEGF before or during diabetic eye surgery had slightly better vision than people not treated with anti-VEGF, but again the estimate was uncertain. They were also less likely to have bleeding in the eye. None of the studies reported on quality of life.

Side effects were uncommon and there were not enough data to detect a difference between the two groups.

Quality of the evidence
The quality of the evidence was low or very low. We judged some of the included trials to be at risk of bias because of lack of masking of treatments and problems with follow-up. Some of the findings were based on too small a numbers of participants. Few studies followed up participants for more than six months.

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.

Read the full 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 strategy: 

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, I2 = 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.

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