Anti-vascular endothelial growth factor for neovascular glaucoma

Author: Rittiphairoj T, Roberti G, Michelessi M.

Geographical coverage: China, Brazil, Egypt, and Japan

Sector: Glaucoma

Sub-sector: Treatment

Equity focus: Not explicitly stated

Study population: Patients with neovascular glaucoma

Review type: Effectiveness review

Quantitative synthesis method: Meta-analysis

Qualitative synthesis method: Not applicable

Background

Neovascular glaucoma (neovascular glaucoma (NVG)) is a secondary condition marked by the growth of abnormal blood vessels in the eye, leading to increased intraocular pressure (intraocular pressure (IOP)) and optic nerve damage. It is often associated with retinal ischemia from conditions like proliferative diabetic retinopathy (proliferative diabetic retinopathy (PDR)), ocular ischemic syndrome, and central retinal vein occlusion (central retinal vein occlusion (CRVO)). High levels of vascular endothelial growth factor (vascular endothelial growth factor (VEGF)) in the eye are a key factor, making anti-VEGF therapies a promising treatment. Agents such as bevacizumab, ranibizumab, and aflibercept are used to inhibit neovascularisation and are common treatments for diabetic macular oedema and age-related macular degeneration. While studies have shown that anti-VEGF injections can control IOP and reduce new iris vessels, their long-term effectiveness and safety remain uncertain.

Objectives

To assess the effectiveness of intraocular anti-VEGF medications, alone or with one or more types of conventional therapy, compared with no anti-VEGF medications for the treatment of NVG.

Main findings

Overall, authors stated that anti-VEGFs as an adjunct to conventional treatment could help reduce IOP in NVG in the short term (four to six weeks), but there is no evidence that this is likely in the longer term. Currently available evidence regarding the short- and long-term effectiveness and safety of anti-VEGFs in achieving control of IOP, visual acuity, and complete regression of new iris vessels in NVG is insufficient. More research is needed to investigate the effect of these medications compared with, or in addition to, conventional surgical or medical treatment in achieving these outcomes in NVG.

The review included five RCTs with 356 eyes of 353 participants. All but one randomised controlled trial (RCT) used a parallel-group design. Studies were conducted in China, Brazil, Egypt, and Japan. Two compared intravitreal bevacizumab combined with Ahmed valve implantation and panretinal photocoagulation (PRP) versus Ahmed valve implantation and PRP alone. Another randomised participants to intravitreal aflibercept or placebo at the first visit, followed by non-randomised treatment based on clinical findings after one week. The remaining two compared PRP with and without ranibizumab. Due to limited information, most RCTs were assessed with an unclear risk of bias. A meta-analysis addressed mean IOP despite high heterogeneity, while other outcomes were synthesised qualitatively.

Four RCTs looked at achieving IOP control, with three reporting relevant time points. One found the anti-VEGF group 1.3 times more likely to achieve IOP control at one month. Another reported a three-fold increase at one year, but a third showed inconclusive results between 1.5 and three years. The studies observed anti-VEGF’s effectiveness in reducing mean IOP by 6.37 mmHg at four to six weeks compared to no anti-VEGF. Effects at three months, six months, one year, and over one year were uncertain.

Two RCTs reported improvement in visual acuity at specified times. Anti-VEGF recipients had a 2.6 times higher chance of improving visual acuity at one month and a four-fold increase at 18 months. Two RCTs reported complete regression of new iris vessels. Anti-VEGFs had nearly three times higher chances of complete regression at initial time points and over one year. There was no evidence of differences in hypotony and tractional retinal detachment risks between groups. No RCTs reported endophthalmitis, vitreous haemorrhage, no light perception, or serious adverse events. Adverse event evidence was low due to study design limitations and small sample sizes. No trial reported relief of pain or resolution of redness.

Methodology

This review included randomised controlled trials involving NVG participants across various age groups and ocular conditions. Eligible studies compared intraocular anti-VEGF medications, either alone or with conventional therapies, against the same treatments without anti-VEGF. For NVG due to CRVO, the intervention group could receive anti-VEGF alone. Dosing studies were excluded unless they included a control group.

The search covered CENTRAL, MEDLINE, Embase, PubMed, LILACS, ClinicalTrials.gov, mRCT, and ICTRP databases, with no date or language restrictions. The last search was on 21 October 2021. Reference lists of eligible studies were screened, and investigators were contacted for ongoing studies.

Two reviewers independently screened articles and resolved disagreements through discussion or a third reviewer. Risk of bias was assessed using the Cochrane RoB 2 tool. Certainty of evidence was classified using GRADE.

Data extraction was done independently by two reviewers, with disagreements resolved through discussion or a third reviewer. Study investigators were contacted for missing data. Dichotomous outcomes were analysed using summary risk ratios (RRs) with 95% confidence intervals (CIs); continuous outcomes were analysed as mean differences (MDs) with 95% CIs. A random-effects model meta-analysis assessed heterogeneity with I2 statistics, interpreting 50% or more as substantial. Subgroup analysis identified the best therapeutic protocol. High heterogeneity led to narrative synthesis.

Applicability/external validity

The review authors noted that variations in locations, treatment protocols, and outcome measurements limited the evidence’s applicability. Although studies included populations from Brazil, China, Egypt, and Japan, their relevance to Caucasian populations is uncertain. Differences in anti-VEGF medications, treatments, and control interventions affected comparability. Additionally, inconsistencies in IOP measurement methods and outcome definitions hindered meta-analysis. These factors contribute to heterogeneity and should be considered in interpreting the findings.

Geographic focus

Included studies were conducted in China, and one each in Brazil, Egypt, and Japan.

Summary of quality assessment

Overall, there is high confidence in the conclusions of this review.