Anti-vascular endothelial growth factors in combination with vitrectomy for complications of proliferative diabetic retinopathy

Background 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. Objectives To assess the effects of perioperative anti‐VEGF use on the outcomes of vitrectomy for the treatment of complications for proliferative diabetic retinopathy (PDR). Search methods 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. Selection criteria 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. Data collection and analysis 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. Main results 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. Authors' conclusions 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.