Review question
Do injections of anti-vascular endothelial growth factor (anti-VEGF) either with or without laser treatment help people with advanced diabetic retinopathy in terms of vision and progression of the disease? Is this treatment safe?
Key messages
· Anti-VEGFs (combined with or without laser) improve the vision, but the degree of improvement is not clinically meaningful. They also reduce the formation of new vessels, haemorrhages, and the need for removing the vitreous with surgery (vitrectomy).
· The safety of anti-VEGFs (combined with or without laser) remains uncertain because we have very little confidence in the evidence we found.
· More clinical trials of high quality are needed to better establish the appropriate treatment dosage and time of administration of anti-VEGFs.
Background
Proliferative diabetic retinopathy (PDR) is the medical name for advanced damage to the retina. PDR consists of the presence of new vessels in the retina and a vitreous or pre-retinal haemorrhage (leakage of blood in and around the gel that fills the space between the crystalline lens and the retina), and can cause blindness. Panretinal photocoagulation (PRP) using laser is the current treatment. However, it has secondary effects such as loss of vision. Anti-VEGFs stop new vessels from forming. We wanted to find out if anti-VEGFs, either combined with other treatments or alone, were safe and better than a standard alternative to improve PDR.
What did we do?
We searched for randomised controlled trials (RCTs) comparing anti-VEGFs (combined or not with laser) 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. We excluded studies in people undergoing vitrectomy or treatment to remove some or all of the gel that fills the space between the lens and the retina.
What did we find?
We found 23 studies that took place in North and South America, Europe, the Middle East and Asia. On average, people were studied for eight months, but one study followed participants for two years. In total we included 2334 eyes of 1755 people; 55% were men, and the average age was 56 years. About half of the studies did not declare their funding source and about half of the studies' authors did not report whether or not had any conflicts of interest.
Main results
On average, people treated with anti-VEGF with or without laser probably had better vision than people not treated with anti-VEGF (but the degree of improvement is small and may not be noticeable), and new vessels become smaller. They were also less likely to have bleeding in the eye and may be less likely to need vitrectomy. Only two studies reported on the quality of life, but we have low confidence in the evidence. Side effects were uncommon and there were not enough data to detect a difference in safety between the two groups.
What are the limitations of the evidence?
Some of the studies had flaws in their design/conduct and their results might be biased; in addition, they did not include many people. This leads us to have only little to moderate confidence in the main findings, and very little confidence in the evidence about side effects.
How up-to-date is this evidence?
This review updates our previous review published in 2014. The evidence is up-to-date until June 2022.
Anti-VEGFs ± PRP compared with PRP alone probably increase visual acuity, but the degree of improvement is not clinically meaningful. Regarding secondary outcomes, anti-VEGFs ± PRP produce a regression of new vessels, reduce vitreous haemorrhage, and may reduce the need for vitrectomy compared with eyes that received PRP alone. We do not know if anti-VEGFs ± PRP have an impact on the incidence of adverse events and they may have little or no effect on patients' quality of life. Carefully designed and conducted clinical trials are required, assessing the optimal schedule of anti-VEGFs alone compared with PRP, and with a longer follow-up.
Proliferative diabetic retinopathy (PDR) is an advanced complication of diabetic retinopathy that can cause blindness. It consists of the presence of new vessels in the retina and vitreous haemorrhage. Although panretinal photocoagulation (PRP) is the treatment of choice for PDR, it has secondary effects that can affect vision. Anti-vascular endothelial growth factor (anti-VEGF), which produces an inhibition of vascular proliferation, could improve the vision of people with PDR.
To assess the effectiveness and safety of anti-VEGFs for PDR and summarise any relevant economic evaluations of their use.
We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 6); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov, and the WHO ICTRP. We did not use any date or language restrictions. We last searched the electronic databases on 1 June 2022.
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. We excluded studies that used anti-VEGFs in people undergoing vitrectomy.
Two review authors independently selected studies for inclusion, extracted data, and assessed the risk of bias (RoB) for all included trials. We calculated the risk ratio (RR) or the mean difference (MD), and 95% confidence intervals (CI). We used GRADE to assess the certainty of evidence.
We included 15 new studies in this update, bringing the total to 23 RCTs with 1755 participants (2334 eyes). Forty-five per cent of participants were women and 55% were men, with a mean age of 56 years (range 48 to 77 years). The mean glycosylated haemoglobin (Hb1Ac) was 8.45% for the PRP group and 8.25% for people receiving anti-VEGFs alone or in combination. Twelve studies included people with PDR, and participants in 11 studies had high-risk PDR (HRPDR).
Twelve studies were of bevacizumab, seven of ranibizumab, one of conbercept, two of pegaptanib, and one of aflibercept. The mean number of participants per RCT was 76 (ranging from 15 to 305). Most studies had an unclear or high RoB, mainly in the blinding of interventions and outcome assessors. A few studies had selective reporting and attrition bias.
No study reported loss or gain of 3 or more lines of visual acuity (VA) at 12 months. Anti-VEGFs ± PRP probably increase VA compared with PRP alone (mean difference (MD) -0.08 logMAR, 95% CI -0.12 to -0.04; I2 = 28%; 10 RCTS, 1172 eyes; moderate-certainty evidence). Anti-VEGFs ± PRP may increase regression of new vessels (MD -4.14 mm2, 95% CI -6.84 to -1.43; I2 = 75%; 4 RCTS, 189 eyes; low-certainty evidence) and probably increase a complete regression of new vessels (RR 1.63, 95% CI 1.19 to 2.24; I2 = 46%; 5 RCTS, 405 eyes; moderate-certainty evidence). Anti-VEGFs ± PRP probably reduce vitreous haemorrhage (RR 0.72, 95% CI 0.57 to 0.90; I2 = 0%; 6 RCTS, 1008 eyes; moderate-certainty evidence). Anti-VEGFs ± PRP may reduce the need for vitrectomy compared with eyes that received PRP alone (RR 0.67, 95% CI 0.49 to 0.93; I2 = 43%; 8 RCTs, 1248 eyes; low-certainty evidence). Anti-VEGFs ± PRP may result in little to no difference in the quality of life compared with PRP alone (MD 0.62, 95% CI -3.99 to 5.23; I2 = 0%; 2 RCTs, 382 participants; low-certainty evidence). We do not know if anti-VEGFs ± PRP compared with PRP alone had an impact on adverse events (very low-certainty evidence). We did not find differences in visual acuity in subgroup analyses comparing the type of anti-VEGFs, the severity of the disease (PDR versus HRPDR), time to follow-up (< 12 months versus 12 or more months), and treatment with anti-VEGFs + PRP versus anti-VEGFs alone.
The main reasons for downgrading the certainty of evidence included a high RoB, imprecision, and inconsistency of effect estimates.