Anti-VEGF drugs compared with laser photocoagulation for the treatment of proliferative diabetic retinopathy:a systematic review and IPD meta-analysis

Background Proliferative diabetic retinopathy (PDR) is a major cause of sight loss in people with diabetes, with a high risk of vitreous haemorrhage, tractional retinal detachment and other complications. Panretinal photocoagulation (PRP) is the primary established treatment for PDR. Anti-vascular endothelial growth factor (anti-VEGF) drugs are used to treat various eye conditions and may be beneficial for people with PDR. Objective To investigate the efficacy and safety of anti-VEGF therapy for the treatment of proliferative diabetic retinopathy when compared to PRP. Methods A systematic review and network meta-analysis of randomised controlled trials comparing anti-VEGF (alone or in combination) to PRP in people with PDR. Trials where the primary focus was treatment of macular oedema or vitreous haemorrhage were excluded. Key outcomes were best corrected visual acuity (BCVA), diabetic macular oedema (DMO) and vitreous haemorrhage. Individual participant data (IPD) was obtained and analysed for three large, high-quality trials in combination with published data from other trials. Network meta-analyses of BCVA and meta-analyses of other outcomes combined IPD with published data from other trials; regression analyses against patient covariates used just the IPD. Results Twelve trials were included: 1 of aflibercept, 5 of bevacizumab and 6 of ranibizumab. When considered together, anti-VEGFs produced a modest, but not clinically meaningful, benefit over PRP in BCVA, after 1 year of follow-up (mean difference in logMAR -0.116, 95% credible interval (CrI) -0.183 to -0.038). There was no clear evidence of a difference in effectiveness between the anti-VEGFs. The benefit of anti-VEGF appears to decline over time. Analysis of the IPD trials suggested that anti-VEGF therapy may be more effective in people with poorer visual acuity, in those who have vitreous haemorrhage, and possibly in people with poorer vision generally. Anti-VEGF was superior to PRP at preventing macular oedema after 1 year (Relative risk (RR) 0.48, 95% CI 0.28 to 0.83) and possibly at preventing vitreous haemorrhage (RR 0.72, 95% CI 0.47 to 1.10). Anti-VEGF reduced the incidence of retinal detachment when compared to PRP (RR 0.41, 95% CI 0.22 to 0.77). Data on other adverse events was generally too limited to identify any differences between anti-VEGF and PRP. Conclusions Anti-VEGF has no clinically meaningful benefit over PRP for preserving visual acuity. However, anti-VEGF therapy appears to delay or prevent progression to macular oedema and vitreous haemorrhage. The possibility that anti-VEGF therapy may be more effective in patients with poorer health and poorer vision merits further clinical investigation. The long-term effectiveness and safety of anti-VEGF treatment is unclear, particularly as additional PRP and anti-VEGF treatment will be required over time. Registration This review is registered on PROSPERO (CRD42021272642) Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR132948).