Why is this question important?
Proliferative diabetic retinopathy (PDR) is the most advanced stage of diabetic retinopathy, which is a complication of diabetes. It is caused by abnormal new blood vessels that grow on the retina, the light sensitive layer at the back of the eye. Pars plana vitrectomy is an established surgical treatment for the complications of PDR. During this operation, the gel-like substance that exists inside the eye, called the vitreous, is removed. The most common reason for performing vitrectomy is non-clearing vitreous haemorrhage, where there is bleeding in the inner part of the eye called the vitreous cavity. When this occurs, vitreous loses transparency and the light cannot pass through it, causing vision loss. Anti-vascular endothelial growth factor agents (anti-VEGFs) are drugs that can stop these abnormal blood vessels growing and control the leaking blood, when they are injected inside the eye. The injection of anti-VEGF agents before vitrectomy for the complications of PDR may make surgery easier, reduce intra- and postoperative bleeding and improve outcomes. However, there is no clear evidence about the different types of anti-VEGF agents, the best time to use them or their effect on other outcomes. We reviewed published research to determine whether anti-VEGF injections around the time of surgery have an effect on the outcomes of vitrectomy for the treatment of complications of PDR.
What did we want to find out?
We wanted to find out if the additional use of anti-VEGF agents either before or during diabetic vitrectomy surgery was better than diabetic vitrectomy alone in terms of:
- visual outcomes;
- incidence of early and late POVCH;
- incidence of revision surgery for POVCH in the first six months postoperatively;
- incidence of revision surgery for recurrent traction/macular pucker (structural alteration in the macula, the part of the eye which is responsible for sharp, central vision, thus causing decline of visual function) in the first six months postoperatively;
- vision-related quality of life measures;
- proportion of people with poor visual acuity (counting fingers or worse);
- number of intraoperative retinal breaks (tears in the light sensitive layer of the eye);
- frequency of silicone oil tamponade (a tamponade agent used to push the retina towards the eye wall and keep it stable).
What did we do?
We searched for studies that compared any anti-VEGF combined with vitrectomy versus vitrectomy with no anti-VEGF or with sham treatment or with any other anti-VEGF in people undergoing vitrectomy for the complications of PDR. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 28 studies that involved 1914 eyes undergoing vitrectomy for complications of proliferative diabetic retinopathy. Sample sizes varied from 20 to 214 participants. The studies were from China (11), Iran (three), Italy (two) and Mexico (two), and the remaining studies were from South Korea, UK, Egypt, Brazil, Japan, Canada, USA, Indonesia and Pakistan. One study was multi-centre, including 13 clinical sites from nine countries. Two studies declared receiving funding from the manufacturer of the anti-VEGF drug studied.
The additional use of anti-VEGFs in diabetic vitrectomy may improve visual outcomes at six months postoperatively. Their use also reduces the risk of late POVCH and probably reduces the risk of early POVCH. Anti-VEGFs reduce intraoperative retinal breaks and may reduce the requirement for silicone oil tamponade.
Anti-VEGF use probably results in a lower need for revision vitrectomy for POVCH, and may reduce the need for revision surgery for recurrent traction and/or retinal detachment.
We found no studies to help us answer our question about quality of life and the proportion of people with visual acuity of counting fingers or less.
What are the limitations of the evidence?
We are confident that anti-VEGF injections reduce the incidence of late POVCH and intraoperative retinal breaks (high-certainty evidence), fairly certain that they reduce the incidence of early POVCH and the need for revision surgery for POVCH (moderate-certainty evidence) but less certain about the effects on visual outcomes, revision surgery for retinal detachment and silicone oil use (low-certainty evidence).
How up-to-date is this evidence?
This review updates our previous review. The evidence is up-to-date to 22 June 2022.
The perioperative use of anti-VEGF reduces the risk of late POVCH, probably results in lower early POVCH risk and may improve visual outcomes. It also reduces the incidence of intraoperative retinal breaks. The evidence is very uncertain about its effect on the need for silicone oil tamponade. The reported complications from its use appear to be low. Agreement on variables included and outcome standardisation is required in trials studying vitrectomy for PDR.
Vitrectomy is an established treatment for the complications of proliferative diabetic retinopathy (PDR). However, a number of complications can occur during and after vitrectomy for PDR. These include bleeding and the creation of retinal holes during surgery, and bleeding, retinal detachment and scar tissue on the retina after surgery. These complications can limit vision, require further surgery and delay recovery. The use of anti-vascular endothelial growth factor (anti-VEGF) agents injected into the eye before surgery has been proposed to reduce the occurrence of these complications. Anti-VEGF agents can reduce the amount and vascularity of abnormal new vessels associated with PDR, facilitating their dissection during surgery, reducing intra- and postoperative bleeding, and potentially improving outcomes.
To assess the effects of perioperative anti-VEGF use on the outcomes of vitrectomy for the treatment of complications for proliferative diabetic retinopathy (PDR).
We searched the Cochrane Central Register of Controlled Trials (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. The date of the search was 22 June 2022.
We included randomised controlled trials (RCTs) that looked at the use of anti-VEGFs and the incidence of complications in people undergoing vitrectomy for PDR.
Two review authors independently assessed and extracted the data. We used the standard methodological procedures expected by Cochrane.
The critical outcomes of the review were the mean difference in best corrected visual acuity (BCVA) between study arms at six (± three) months after the primary vitrectomy, the incidence of early postoperative vitreous cavity haemorrhage (POVCH, within four weeks postoperatively), the incidence of late POVCH (occurring more than four weeks postoperatively), the incidence of revision surgery for POVCH within six months, the incidence of revision surgery for recurrent traction/macular pucker of any type and/or rhegmatogenous retinal detachment within six months and vision-related quality of life (VRQOL) measures. Important outcomes included the proportion of people with a visual acuity of counting fingers (1.8 logMAR or worse), the number of operative retinal breaks reported and the frequency of silicone oil tamponade required at time of surgery.
The current review includes 28 RCTs that looked at the pre- or intraoperative use of intravitreal anti-VEGFs to improve the outcomes of pars plana vitrectomy for complications of PDR. The studies were conducted in a variety of countries (11 from China, three from Iran, two from Italy, two from Mexico and the remaining studies from South Korea, the UK, Egypt, Brazil, Japan, Canada, the USA, Indonesia and Pakistan). The inclusion criteria for entry into the studies were the well-recognised complications of proliferative retinopathy: non-clearing vitreous haemorrhage, tractional retinal detachment involving the macula or combined tractional rhegmatogenous detachment. The included studies randomised a total of 1914 eyes.
We identified methodological issues in all of the included studies. Risk of bias was highest for masking of participants and investigators, and a number of studies were unclear when describing randomisation methods and sequence allocation.
Participants receiving intravitreal anti-VEGF in addition to pars plana vitrectomy achieved better BCVA at six months compared to people undergoing vitrectomy alone (mean difference (MD) -0.25 logMAR, 95% confidence interval (CI) -0.39 to -0.11; 13 studies, 699 eyes; low-certainty evidence).
Pre- or intraoperative anti-VEGF reduced the incidence of early POVCH (12% versus 31%, risk ratio (RR) 0.44, 95% CI 0.34 to 0.58; 14 studies, 1038 eyes; moderate-certainty evidence).
Perioperative anti-VEGF use was also associated with a reduction in the incidence of late POVCH (10% versus 23%, RR 0.47, 95% CI 0.30 to 0.74; 11 studies, 579 eyes; high-certainty evidence).
The need for revision surgery for POVCH occurred less frequently in the anti-VEGF group compared with control, but the confidence intervals were wide and compatible with no effect (4% versus 13%, RR 0.44, 95% CI 0.15 to 1.28; 4 studies 207 eyes; moderate-certainty evidence). Similar imprecisely measured effects were seen for revision surgery for rhegmatogenous retinal detachment (5% versus 11%, RR 0.50, 95% CI 0.15 to 1.66; 4 studies, 145 eyes; low-certainty evidence).
Anti-VEGFs reduce the incidence of intraoperative retinal breaks (12% versus 31%, RR 0.37, 95% CI 0.24 to 0.59; 12 studies, 915 eyes; high-certainty evidence) and the need for silicone oil (19% versus 41%, RR 0.46, 95% CI 0.27 to 0.80; 10 studies, 591 eyes; very low-certainty evidence).
No data were available on quality of life outcomes or the proportion of participants with visual acuity of counting fingers or worse.