Anti-VEGF agents with or without anti-metabolites in trabeculectomy for glaucoma: a meta-analysis

Methodological quality of the review: Medium confidence

Author: Xiong Q, Li Z, Li Z, Zhu Y, Abdulhalim S, Wang P, Cai X

Geographical coverage: Not reported

Sector: Glaucoma

Sub-sector: Trabeculectomy and intra-ocular pressure

Equity focus: None specified

Review type: Effectiveness review

Quantitative synthesis method: Meta-analysis

Qualitative synthesis method: Not applicable

Background: Glaucoma treatments are usually geared towards reducing intra-ocular pressure (IOP) either surgically or pharmacologically. Trabeculectomy (Trab) has been the most effective therapy used since it was introduced in 1968 to reduce IOP in patients with medically uncontrollable glaucoma. For this filtrating surgery to be successful, the wound-healing process needs to be inhibited. The major reasons for the failure of Trab are reported to be due to excessive post-operative scarring of the conjunctiva and tendon’s capsules, which leads to new water channels being blocked thus resulting in poor post-operative control of IOP.

Anti-metabolites have been used in Trab to slow wound healing and inhibit the inflammation and fibroblastic activity which can help improve the success rate of surgery. However, they have adverse side effects that include cell damage, persistent low IOP with decreased vision, bleb leakage, corneal epithelium defect and endophthalmitis. Novel therapies are being investigated and developed to reduce the risk of these effects. Several studies have indicated promising results with either subconjunctival or intravitreal anti-vascular endothelial growth factor (VEGF) agents. These can aid in the reduction of incidence of fibroblast proliferation and scar formation post-Trab.

Recently, studies have compared the effect anti-metabolites with anti-VEGF agents have on scarring after Trab. Some of the studies showed significant results with anti-metabolites while others showed the same with anti-VEGF agents. Since the results are conflicting and no systematic evaluation or analysis has been carried out with the available data, this review performed a meta-analysis to assess the efficacy and tolerability of anti-metabolites and anti-VEGF agents in Trab for glaucoma. This, in turn, will help draw a consistent evidence-based conclusion that can be applied to clinical practice.

Objectives: The aim of this meta-analysis is to evaluate the intraoperative application of anti-metabolites compared to anti-VEGF agents with or without anti-metabolites in Trab for glaucoma.

Main findings:Nine studies were included in this meta-analysis, which used a range of measures that were clinically relevant. The thematic focus of this study was to determine if anti-VEGF agents, with or without anti-metabolites, have a significant effect on Trab outcomes in glaucoma. The studies included had population groups from both low/middle and high-income countries. This meta-analysis suggested that anti-metabolites were more effective than anti-VEGF in reducing the IOP in Trab. However, in terms of qualified success rate, complete success rate and incidence of adverse effects, they were both comparable with one another. There was no significant outcome in Trab with either agent. However, this study established that in terms of just IOP assessment, both agents had a significant reducing effect on IOP, but when compared to one another, anti-metabolites had a better IOP-lowering efficacy.

Methodology:The literature search was carried out by two investigators in the PUBMED, EMBASE, Cochrane Library and Web of Sciences databases for the relevant studies in August 2013. A manual search was also carried out by looking through the reference lists of the original reports and review articles to include studies not yet included in the computerised databases. There was no language restriction set.

The inclusion criteria for published studies included:

(a) Study design (controlled clinical trials)

(b) Population (patients that underwent Trab or phacotrabeculectomy)

(c) Intervention (intraoperative application of anti-metabolites versus anti-VEGF agents with or without anti-metabolites in Trab)

(d) Outcome variable

The data was then extracted independently by two reviewers and any differences were resolved by an independent third reviewer. The quality of the included clinical trials was assessed by a system that can assess randomised and non-randomised studies. Each trial’s total score was expressed as a percentage of the maximum achievable score. The studies achieving a score of  >50% were considered to be of high quality.

Intra-ocular pressure reduction (IOPR) percentage was the primary outcome for efficacy. The mean and standard deviation of IOP and IOPR were used directly when reported. When these were unavailable, they were calculated using the Cochrane Handbook for Systematic Reviews of Interventions. The RevMan 5.2 software was used for statistical analysis where the pooled odds ratio (OR) for dichotomous outcomes, and weighted mean difference (WMD) or standard mean difference (SMD) for continuous outcomes, were calculated.

Heterogeneity was assessed among the trials by inspection of graphical representations and using the Chi-square test or the I2 measure >50%. When there was no significant heterogeneity, a fixed-effects model was used to pool results; otherwise a random-effects model was used such as the inverse variance method and DerSimonian and Laird method. A sub-group analysis was also performed to calculate the effect of methodological characteristics with regards to the study designs (retrospective, prospective non-randomised and randomised).

Applicability/external validity: The reviewer discusses the need for more randomised clinical trials to confirm the results of this meta-analysis. Although the findings are encouraging, the limitations were acknowledged thus requiring more primary studies to be carried out in order to make the outcomes valid and applicable.

Geographic focus: The review included studies from different geographical locations, some of them being low/middle-income countries.

Summary of quality assessment:Overall, the authors used appropriate methods to conduct the review. However, it was not clear if two authors independently screened studies for inclusion, thus avoiding bias. In addition, authors did not conduct a thorough search of the literature to ensure that relevant studies were not omitted. Therefore, medium confidence was attributed in the conclusions about the effects of this study.

Publication source: Xiong Q, Li Z, Li Z, Zhu Y, Abdulhalim S, Wang P, Cai X. Anti-VEGF Agents with or without Antimetabolites in Trabeculectomy for Galucoma: A Meta-Analysis. PLoS ONE,2014: 9(2), e88403 Source