Mitomycin C versus 5‐Fluorouracil for wound healing in glaucoma surgery
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of this review is to assess the effectiveness of 5‐FU compared to MMC on the outcome of trabeculectomy and to examine the balance of risk and benefit after long term follow‐up.
Background
Description of the condition
Glaucoma is a chronic progressive optic neuropathy characterised by a progressive loss of ganglion cells that leads to a characteristic visual function loss. Intraocular pressure (IOP) is often considered to be a major risk factor for glaucoma and it is the only factor that can be modified to try to change the course of the condition. With the publication of a series of randomised controlled trials (RCTs) the evidence of treating glaucoma with IOP reduction has been established (AGIS 1998; CNTGSG 1998; Heijl 2002; Kass 2002).
Glaucoma drainage surgery remains an important treatment option for the control of IOP despite the addition of several new IOP lowering drugs. There is some evidence suggesting that trabeculectomy is more effective than either medicine or laser treatment alternatives (Migdal 1994). However, a Cochrane systematic review from 2004 (Burr 2004) found that visual field (VF) deterioration up to five‐years is not significantly different whether treatment is initiated with medication or trabeculectomy.
Optimum success rates are achieved when the eye has been exposed to no previous interventions, either surgical or medical although this is not the usual situation in developed countries. Risk factors for trabeculectomy failure are thought to be those that increase the scarring response and include previous exposure to topical medication, previous surgical manipulation of the conjunctiva or other injury, young age, African origin, a history of uveitis and neovascular glaucoma (EGS 2003).
Presentation and diagnosis
The diagnosis of glaucoma is made by the identification of a progressive optic neuropathy or a characteristic visual field defect. There are subgroups of glaucoma; primary open angle glaucoma (POAG) being most common in European and Afro‐Caribbean populations. A person with POAG is often unaware of any symptoms until the late stages of the disease. Early diagnosis is essential.
Description of the intervention
Treatment is usually initiated with topical treatment and surgical options are considered if topical treatment fails to prevent progression of the disease. The trabeculectomy produces a guarded fistula between the anterior chamber and the subconjunctival space. There have been numerous modifications since its first description (Cairns 1968) including the use of antimetabolites to reduce fibroblast activity and postoperative scarring at the site of the scleral flap and the subconjunctival space.
How the intervention might work
Once trabeculectomy has been selected the treatment decisions are whether to augment the surgery with anti‐scarring agents such as antimetabolites. In an attempt to reduce postoperative scarring antimetabolites have been applied to the surgical site to inhibit fibroblast activity and the two agents commonly in use are mitomycin C (MMC) and 5‐Fluorouracil (5‐FU). Due to the reported side effects such as increased risk of bleb leak, hypotony and endophthalmitis (DeBry 2002) there is concern that the use of these agents should be restricted to high risk cases only. The use of MMC has been reported in a number of randomised controlled trials (RCTs) (Andreanos 1997; Carlson 1997; Cohen 1996; Costa 1996; Martini 1997; Robin 1997; Shin 1995; Shin 1998; Wu 1996). The conclusion of a Cochrane systematic review found that compared to placebo MMC reduces mean IOP at 12 months in all groups of participants (Wilkins 2005). Apart from increase in cataract formation there was insufficient power to detect any increase in other serious side effects. Postoperative 5‐FU injections to augment trabeculectomy have also been assessed with RCTs (FFSSG 1989; Goldenfeld 1994; Ophir 1992; Ruderman 1987) and also confer an improvement in IOP control at one year compared to placebo (Wormald 2001). Clinically these drugs can be applied intraoperatively (MMC and 5‐FU) on a sponge placed for one to five minutes between the conjunctiva and sclera at the start of the operation. Alternatively they may be given as one or more postoperative subconjunctival injections (5‐FU). There is marked variation in the concentrations of both drugs used, in the time of intraoperative application, and in the position and volume of postoperative injections.
Why it is important to do this review
The results of two Cochrane reviews comparing MMC (Wilkins 2005) and 5‐FU (Wormald 2001) to placebo suggest a similar effect for the two agents in inhibiting scarring after trabeculectomy. However, many clinicians consider MMC to be many times more powerful than 5‐FU in its effects. The purpose of this review is to summarise systematically RCTs in which MMC has been compared to 5‐FU in an attempt to identify treatment benefits of one agent over the other and in what circumstances.
Objectives
The objective of this review is to assess the effectiveness of 5‐FU compared to MMC on the outcome of trabeculectomy and to examine the balance of risk and benefit after long term follow‐up.
Methods
Criteria for considering studies for this review
Types of studies
We will include all randomised controlled trials where wound healing has been modified with one of the antimetabolites in one group of people undergoing trabeculectomy compared to the other antimetabolite in the other group.
Types of participants
There will be three separate subgroup populations:
-
High risk of trabeculectomy failure: people with previous glaucoma or cataract surgery and people with secondary glaucoma or congenital glaucoma.
-
Medium risk of trabeculectomy failure: (combined surgery) people undergoing trabeculectomy with cataract surgery.
-
Low risk of trabeculectomy failure: (primary trabeculectomy): people who have received no previous surgical eye intervention. People who underwent previous laser procedures may be included in this group.
For the purpose of this review there will be no restrictions regarding age, gender or race.
Types of interventions
The following interventions will be included:
(1) Use of intraoperative MMC versus intraoperative 5‐FU.
(2) Use of intraoperative MMC versus postoperative 5‐FU.
(3) Use of intraoperative MMC versus intraoperative and postoperative 5‐FU.
(4) Use of intraoperative MMC and postoperative 5‐FU versus intraoperative and postoperative 5‐FU.
(5) Use of intraoperative MMC and postoperative MMC versus intraoperative and postoperative 5‐FU.
Types of outcome measures
Primary outcomes
The primary outcome will be failure of a functioning trabeculectomy at one year from surgery (dichotomous).
Secondary outcomes
The secondary outcome will be survival analysis (time to event) for the previously given definition of failure.
Tertiary outcomes
Weighted mean differences (WMD) of mean intraocular pressure (IOP) for each group (failure/success for each treatment) will also be analysed at one year from surgery.
Adverse outcomes
Adverse event rates in either group with reference to leaking blebs, hypotony, late endophthalmitis and non attendance rates will be reported.
Where available, quality of life measures and economic data will be assessed.
We will use the following definitions:
Success: adequate pressure control (< 22 mm Hg) without additional treatment.
Failure: need for repeat filtration surgery or uncontrolled IOP (= 22 mm Hg).
Bleb leakage: presence of a positive Seidel test (visible aqueous flow with the tear film stained with fluorescein).
Hypotony: IOP below 5 mm Hg and/or associated with complications such as macular oedema and sight loss or choroidal detachments.
Endophthalmitis: an infection of the globe contents that even with prompt aggressive treatment results in substantial loss of visual function.
Search methods for identification of studies
Electronic searches
We will identify trials from the Cochrane Controlled Trials Register ‐ CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register), MEDLINE and EMBASE. There will be no language or date restriction in the selection of trials.
See: Appendix 1 for details of the MEDLINE search strategy. This strategy will be adapted for the other databases.
Searching other resources
We will search the reference lists of identified trial reports to find additional trials. We will contact investigators to identify additional published and unpublished studies.
Data collection and analysis
Selection of studies
Both authors will independently review the titles and abstracts resulting from the searches. We will obtain full copies of any report referring to possibly or definitely relevant trials. We will assess the full copies according to the definitions in the 'Criteria for considering studies for this review'. Only trials meeting these predefined criteria will be assessed for methodological quality. We will resolve disagreements by discussion.
Assessment of methodological quality of included studies
Both authors will assess trial quality according to methods set out in Section 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005b). Five parameters will be considered: allocation concealment, method of allocation to treatment, documentation of exclusions, masking of outcome assessment and completeness of follow‐up. Each parameter of trial quality will be graded: A ‐ low risk of bias; B ‐ moderate risk of bias; and C ‐ high risk of bias. (e.g. Allocation concealment: A= centralised randomisation; B = envelopes but no qualifying statement; C = alternation). We will resolve disagreements by discussion. Authors will not be masked to trial details during the quality assessment. We will exclude trials scoring C on allocation concealment. In the case where missing or confusing data does not permit a clear grading of the trial, the study authors will be contacted to obtain further information from them directly. Studies in which both eyes of the same patient have been included will be graded as moderate risk of bias.
Data extraction and management
Both authors will independently extract data with relation to the outcome measures outlined above and resolve discrepancies by discussion. One author will enter the data into RevMan and the other author will use the double‐data entry facility.
Measures of treatment effect
Dichotomous data: the effect will be measured by risk ratio (RR).
Continuous data: difference in means (MD) or standardised difference in means (SMD) will be used.
Time‐to‐event data: survival analysis will be used.
Unit of analysis issues
Data from studies collecting similar outcome measures with similar follow‐up times will be summarised.
Dealing with missing data
When data is not available or authors do not respond within a reasonable time, trial parameters will be graded as quality C (high risk of bias).
Assessment of heterogeneity
Inconsistency across studies will be quantified by means of the I² statistic.
Assessment of reporting biases
To investigate reporting bias we will prepare a "funnel plot" and examine this for signs of asymmetry.
Data synthesis
A fixed or random‐effects model will be used according to the number of studies available at time of review.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis (high, mid and low risk of failure) will only be performed if trial numbers are high enough to justify this.
Differences between two or more subgroups will be investigated using the method described by Deeks et al (Deeks 2001).
Sensitivity analysis
We will conduct sensitivity analyses to determine the impact of study quality on effect size. A sensitivity analysis will be performed to determine the effect of including or excluding trials that fall below a certain quality threshold (A, B or C).
