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Cochrane Database of Systematic Reviews Protocol - Intervention

Anti‐vascular endothelial growth factor for control of wound healing in glaucoma surgery

Authors' declarations of interest

Version published: 18 April 2012 Version history

https://doi.org/10.1002/14651858.CD009782

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view the current version 15 January 2016
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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effectiveness of anti‐VEGF therapies administered by subconjunctival injection for the outcome of trabeculectomy and to examine the balance of risk and benefit at one‐year follow‐up when compared with any other anti‐scarring agents or no any additional anti‐scarring agents.

Background

Description of the condition

Glaucoma is a group of heterogeneous disorders which result in progressive optic neuropathy and irreversible blindness if not appropriately treated. It is the leading cause of irreversible blindness in the world, affecting approximately 60.5 million people worldwide in 2010, of which 8.4 million are bilaterally blind (Quigley 2006). Elevated intraocular pressure (IOP) is the major risk factor for glaucoma, and reducing IOP to the normal level is the primary goal of treatment (AGIS 2000; Wax 2002). A published meta‐analysis of randomised controlled trials (RCTs) suggests that lowering IOP in patients with ocular hypertension or open angle glaucoma is beneficial in reducing the risk of visual field loss in the long term (Maier 2005).

Glaucoma filtration surgery is the most frequently used IOP‐lowering procedure in patients with medically uncontrolled glaucoma. A published Cochrane review evaluated the effectiveness of surgery and medication in the treatment of glaucoma and found that surgery provided significantly greater IOP‐lowering efficacy than medication, though there was no evidence that surgery was associated with less visual field deterioration (Burr 2004). The basic principle of glaucoma filtration surgery is to create a drainage bypass of aqueous humor from the anterior chamber to the subconjunctival space with filtering bleb formation. However, the scarring response within the filtration area may lead to the restriction of aqueous flow across the filtering bleb, resulting in the loss of the IOP‐lowering effect. A retrospective cohort study which included 234 participants (330 procedures) undergoing trabeculectomy surgery found that trabeculectomy survival at 20 years may be approximately 60% with no topical medication (Landers 2011).

In an attempt to reduce postoperative scarring, antimetabolites such as mitomycin C (MMC) and 5‐fluorouracil (5‐FU) have been commonly used to inhibit fibroblast activity (Wilkins 2005; Wormald 2001). "However, because of their nonspecific mechanisms of action, both antimetabolites can cause widespread cell death, resulting in vision threatening complications such as ocular hypotony, hypotonous maculopathy, bleb leaks, blebitis, and bleb‐related endophthalmitis" (Lama 2003; O'Neill 2010). Although antimetabolites can reduce the risk of surgical failure in eyes that have undergone no previous surgery and in eyes at high risk of failure (Wilkins 2005; Wormald 2001), many patients still need adjunctive therapies because of filtering failure. The 'Tube Versus Trabeculectomy' study was a multicentre clinical trial that prospectively enrolled patients with medically uncontrolled glaucoma who had previous cataract extraction with intraocular lens implantation, failed filtering surgery, or both, and found that the cumulative probability of failure during five years of follow‐up was 46.9% in patients treated with trabeculectomy with MMC (Gedde 2012). Therefore, alternative physiological anti‐scarring agents are needed.

Description of the intervention

Vascular endothelial growth factor (VEGF), "an endothelial growth and permeability factor, plays a major role in physiological vasculogenesis and angiogenesis" (Li 2009). Currently used monoclonal antibodies against VEGF are pegaptanib, ranibizumab and bevacizumab. Pegaptanib (Macugen®), a "28‐base ribonucleic acid aptamer covalently linked to two branched 20‐kD polyethylene glycol moieties", binds to extracellular VEGF, specifically the 165‐amino‐acid isoform (VEGF‐165) and antagonises its biological effects (Gragoudas 2004). Ranibizumab (Lucentis®) is a recombinant humanised monoclonal antibody Fab that neutralises all active forms of VEGF‐A (Rosenfeld 2006). Bevacizumab (Avastin®) is a recombinant full‐length humanised antibody that binds to all types of VEGF and is used successfully in the treatment of many types of malignancy as a systemic drug (Escudier 2007; Hurwitz 2004; Miller 2007; Sandler 2006). All three anti‐VEGF agents have shown promise in the treatment of various ocular neovascular diseases, such as age‐related macular degeneration (CATT 2011; Gragoudas 2004; Rosenfeld 2006; Tufail 2010; Vedula 2008), diabetic retinopathy (Michaelides 2010; Nguyen 2009), retinal vein occlusion (Braithwaite 2010; Brown 2010; Campochiaro 2010; Kinge 2010; Wroblewski 2009) and retinopathy of prematurity (Mintz‐Hittner 2011). Anti‐VEGF agents were also used as an effective medication for rescuing failing filtering blebs that exhibit neovascularisation (Kahook 2006). Recently, several studies have suggested the potential usefulness of subconjunctival anti‐VEGF antibodies as an adjunctive treatment to trabeculectomy to reduce the incidence of bleb failure (Bochmann 2011; Choi 2010; Grewal 2008).

How the intervention might work

Wound healing is a cascade of overlapping processes that include angiogenesis (Li 2003) and fibroblast proliferation (Diegelmann 2004). VEGF stimulates wound healing via multiple mechanisms (Bao 2009). Angiogenesis mediated by VEGF plays a critical role in the wound‐healing process of wound closure by enabling inflammatory cells and fibroblasts to migrate to the wound and by providing the vascular scaffold for granulation tissue formation (Nissen 1998). A recent study showed that VEGF receptors were expressed in Tenon fibroblasts, which "are the most important mediators of scar formation after filtration surgery" (Li 2009). After filtration surgery, VEGF was upregulated and stimulated fibroblast proliferation. This suggests that VEGF was involved in the scarring process after filtration surgery. Anti‐VEGF antibodies reduce wound healing and scar formation after filtration surgery through inhibiting angiogenesis, but are also likely to inhibit fibroblast proliferation and induce fibroblast cell death (O'Neill 2010).

Why it is important to do this review

Postoperative scarring is the major factor for bleb failure after trabeculectomy, affecting long‐term success. Recent studies suggest that anti‐VEGF agents may be a promising therapeutic option and the off‐label use of anti‐VEGF agents is increasing for wound healing in glaucoma surgery. In a pilot study, bevacizumab 1.25 mg by subconjunctival injection was used after trabeculectomy (Grewal 2008). This dose has been used intravitreally for neovascular glaucoma (Costagliola 2008; Gheith 2007; Yuzbasioglu 2009) and for filtering surgery (Jonas 2007). In a case series, bevacizumab 1.25 mg was administered by subconjunctival injection after trabeculectomy augmented with mitomycin C. Based on the favourable results of this study, it was suggested that subconjunctival bevacizumab may be effective in improving the efficacy of trabeculectomy (Choi 2010). However, there is still no well‐established evidence for anti‐VEGF augmentation in trabeculectomy. This systematic review is therefore designed to investigate the effectiveness of anti‐VEGF agents administered by subconjunctival injection for the outcome of trabeculectomy.

Objectives

To assess the effectiveness of anti‐VEGF therapies administered by subconjunctival injection for the outcome of trabeculectomy and to examine the balance of risk and benefit at one‐year follow‐up when compared with any other anti‐scarring agents or no any additional anti‐scarring agents.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised clinical trials only.

Types of participants

We will include studies of people undergoing trabeculectomy. We will exclude studies that included patients receiving anti‐VEGF treatment in combination with a needling procedure. Three separate subgroup populations will be involved (Clarke 2006; Wilkins 2005; Wormald 2001), as follows.

  • "High risk of failure: people with previous glaucoma or cataract surgery and people with secondary glaucoma or congenital glaucoma.

  • Medium risk of failure (combined surgery): people undergoing trabeculectomy with cataract surgery.

  • Low risk of failure (primary trabeculectomy): people who have received no previous intraocular surgical intervention. This group may include people who have had previous medical therapy, laser procedures or both".

Types of interventions

We will include trials in which anti‐VEGF agents were administered by subconjunctival injection at any concentration and dose compared to any other anti‐scarring agents or no additional anti‐scarring agents used (no treatment or placebo).

Types of outcome measures

Primary outcomes

The primary outcome of this review will be the proportion of complete successful trabeculectomies at 12 months after surgery. Complete success is defined as a target IOP (usually less than 21 mmHg) without any intervention, such as additional IOP‐lowering medications, laser goniopuncture, repeat surgery or further postoperative interventions.

Secondary outcomes
Intraocular pressure

  • Qualified success at 12 months after surgery, defined as a target IOP (usually less than 21 mmHg) with or without additional topical IOP‐lowering medications and/or laser goniopuncture (Eldaly 2008)

  • The mean IOP (failure/success for each treatment) at 12 months after surgery (Wilkins 2005)

Adverse events

We will also report the ocular adverse event rates in either group, including wound leaks, hypotony, expulsive haemorrhage, shallow anterior chamber, late endophthalmitis and cataract as secondary outcomes. The definition of the event rates will be as follows (Wilkins 2005; Wormald 2001).

  • Wound leaks: the presence of a positive Seidel test (visible aqueous flow with the tear film stained with Fluorescein)

  • Hypotony: the IOP is below 5 mmHg or associated with complications such as macular oedema and sight loss or choroidal detachments, or both

  • Expulsive haemorrhage: choroidal haemorrhage, usually at the time of surgery or during the early postoperative period while the eye is still soft, leading to a marked rise in IOP

  • Shallow anterior chamber: prolonged shallowing of the anterior chamber giving rise to concern over possible contact of the lens with the cornea, occurring as a result of excessive drainage or choroidal effusions, or both, leading to anterior displacement of the ciliary body, iris and lens

  • Endophthalmitis: an infection of the globe contents that even with prompt aggressive treatment results in substantial loss of visual function

  • Cataract: reduction in the clarity of the natural lens requiring surgery during the follow‐up period of 12 months

We will report systemic adverse events including gastrointestinal perforation, arterial hypertony, arterial and venous thromboembolic events, if available.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library), MEDLINE, EMBASE, the metaRegister of Controlled Trials (mRCT) (www.controlled‐trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). There will be no date or language restrictions in the electronic searches for trials.

See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), mRCT (Appendix 4), ClinicalTrials.gov (Appendix 5) and the ICTRP (Appendix 6).

Searching other resources

We will search the abstracts of the Association for Research in Vision and Ophthalmology using the keywords: pegaptanib, ranibizumab, bevacizumab or anti‐VEGF, from 2009 onwards. We will also search the reference lists of identified trial reports to find additional trials. We will obtain information about ongoing studies by contacting the relevant trial investigators.

Data collection and analysis

Selection of studies

After completion of the searches, two review authors will independently select the studies for inclusion. The same two authors will independently screen the titles and abstracts of all the reports of studies identified by the electronic and manual searches for a rough judgement of the study's eligibility. Each review author will classify the abstracts as follows: (1) relevant, (2) potentially relevant and (3) not relevant. We will obtain the full‐text copies of articles for those abstracts designated relevant or potentially relevant and two review authors will independently examine each study to see whether to (1) definitely include, (2) possibly include and (3) definitely exclude. Each author will obtain and independently assess the full‐text of each study classified by either review author as (1) or (2) and reclassify the study as: (a) include, (b) awaiting classification or (c) exclude. Disagreements will be resolved by discussion between the review authors. For any studies classified as (b), we will contact the study investigators to request additional information in an attempt to include or exclude the study from the review. We will include studies identified as (a) include and assess them for methodological quality. We will also document any studies classified as (c) exclude.

Data extraction and management

Two authors will independently extract data in relation to the outcome measures from studies included in the review using a form developed by the Cochrane Eyes and Vision Group. We will resolve discrepancies by consensus. One author will enter data into Review Manager 5 software (Review Manager 2011) and the second author will verify the data entries. We will extract the following details and report them in a table format.

  • Method: randomisation technique, allocation concealment method, masking (patients, provider, outcome assessors), losses to follow‐up, treatment compliance, analysis set (intention‐to‐treat, per protocol)

  • Participants: randomised sampling, age, sex, ethnicity, type of glaucoma

  • Interventions: type of surgical procedure, interventions (dose, route, duration), comparison interventions (dose, route, duration), co‐medications (dose, route, duration)

  • Outcomes: primary and secondary outcomes, times of assessment, length of follow‐up

  • Notes: general information such as publication status, title, authors, source, language of publication, year of publication

Assessment of risk of bias in included studies

Two review authors will independently assess the potential sources of systematic bias of each included study as recommended in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We will assess the following parameters.

  • Random sequence generation (selection bias)

  • Allocation concealment (selection bias)

  • Masking (blinding) of participants and personnel (performance bias)

  • Masking of outcome assessment (detection bias)

  • Incomplete outcome data (attrition bias)

  • Selective reporting (reporting bias)

  • Other sources of bias

We will assess each parameter of trial quality and grade as low risk of bias, unclear (unclear or unknown risk of bias) and high risk of bias. If any parameter is categorised as unclear, we will contact the trial authors for clarification. If they do not respond within two months, we will assign a judgement based on the available information. We will not exclude any trials graded as high risk of bias, but will assess the effect of these trials in a sensitivity analysis.

Measures of treatment effect

Data analysis will follow the guidelines set out in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). For dichotomous outcomes, we will calculate risk ratio (failure, success, adverse events). We will calculate mean difference for continuous outcomes (mean IOP).

Unit of analysis issues

The unit of analysis will be the eye of an individual participant. If there are studies using a paired design, we will use the generic inverse variance method to combine the results of such studies with those of studies randomising only one eye of each participant.

Dealing with missing data

To deal with missing participants due to drop‐out, we will conduct an intention‐to‐treat analysis and summarise data statistically if they are available. When data are not available, we will attempt to contact the study authors. If the authors do not respond within two months, we will attempt to compute the data according to the methods described in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). If drop‐outs are very high or are different across treatment groups we will assess the study as low quality and conduct sensitivity analyses to investigate the influence of studies with missing data.

Assessment of heterogeneity

We will identify clinical heterogeneity by examination of the study characteristics then assess statistical heterogeneity between trials by means of the I² statistic if a meta‐analysis of three or more studies is possible. We will consider an I² statistic of less than 25% as low heterogeneity, between 25% and 50% as moderate heterogeneity and over 50% as high heterogeneity. We will also examine the funnel plot for other sources of heterogeneity if at least 10 studies are found.

Assessment of reporting biases

We will use funnel plots to assess for reporting bias when at least 10 studies are included. When small included studies tend to show larger treatment effects, we will consider other causes, including selection bias, poor methodological quality, heterogeneity, artefact and chance (Eldaly 2008).

Data synthesis

We will analyse the data using a random‐effects model unless there are fewer than three trials, in which case we will use a fixed‐effect model. If significant heterogeneity is found, we will only present the study results in a tabulated summary and not combine them in a meta‐analysis.

Subgroup analysis and investigation of heterogeneity

If sufficient data are available, we will conduct subgroup analyses to investigate for heterogeneity. The subgroups will be based on: the type of participants (high, mid and low risk of failure), the type of study design (paired design and independent group design), the type of outcome criteria, the types of interventions (intraoperative or postoperative) and the type of controls.

Sensitivity analysis

We will perform a sensitivity analysis to investigate the impact of studies with lower methodological quality (e.g. domains judged to be inadequate with regard to risk of bias, marked 'high' or 'unclear' in the 'Risk of bias' table), unpublished data and industry‐funded studies, on the overall estimates of effect. We will also perform a sensitivity analysis to determine the impact of excluding studies in which more than 10% had both eyes randomised to treatment.