Adjunctive modulation of wound healing during cataract surgery to promote survival of a previous trabeculectomy

Abstract

Background

Trabeculectomy is a surgical treatment for glaucoma to lower intraocular pressure with high success rates; however, it is often associated with an increased rate of cataract formation. Cataract can cause symptoms such as glare in bright conditions, foggy vision, and difficulty in driving at night. Cataract extraction surgery is highly successful in improving vision, but it comes at a cost of trabeculectomy failure, with a reported risk of 30% to 40%. An additional intervention to promote trabeculectomy survival after cataract extraction is needed. This review encompassed all adjunctive therapies used at the time of cataract surgery to increase trabeculectomy survival rate.

Objectives

To investigate the effect of the adjunctive modulation of wound healing during cataract surgery on the survival of a previously functioning trabeculectomy.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2021, Issue 4); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov; and the WHO ICTRP. We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 14 April 2021.

Selection criteria

We planned to include all randomised controlled trials (RCTs) of participants who had a functioning trabeculectomy and were undergoing cataract surgery that compared any adjunctive therapy intended to modulate wound healing (such as 5‐fluorouracil, mitomycin C, or anti‐vascular endothelial growth factor (VEGF) therapy) with no adjuvant therapy. 

Data collection and analysis

We used standard methods expected by Cochrane. Our primary outcome was trabeculectomy failure at 6 months and 12 months after cataract surgery. Secondary outcomes were mean intraocular pressure difference from pre‐cataract surgery baseline to 6 to 18 months post‐cataract surgery; number of medications required to control eye pressure compared to before cataract surgery; bleb appearance as measured by a summation score of the Moorfields bleb grading system or other equivalent numerical grading systems; visual field progression measured by difference in mean deviation from baseline; and any complications.

Main results

We did not identify any RCTs of adjunctive modulation of wound healing during cataract surgery to promote survival of a previous trabeculectomy.

Authors' conclusions

There is a need for an RCT to investigate the role of adjuvant wound modulating therapy at the time of cataract surgery to promote survival of a functioning trabeculectomy.

Plain language summary

The use of additional medication during cataract surgery to improve the continued success of a pre‐existing operation (trabeculectomy)

Why is this question important?
Glaucoma and cataract are a global problem that can impact a person's economic and social circumstances. Vision loss from glaucoma is permanent, as the increased eye pressure that occurs in glaucoma damages the optic nerve which carries signals from the eye to the brain. The primary aim of treatment for glaucoma is to reduce this pressure, hence slowing down any progressive damage to vision.

Although medical and laser treatments are effective in treating glaucoma, an operation known as a trabeculectomy is required when these treatments do not stop progression of damage to vision. A small hole is cut in the white of the eye to allow excess fluid to drain from the eye. When a person with a trabeculectomy undergoes cataract surgery, an additional medication is often used to stop the eye healing too much and creating scar tissue, which can block the drainage hole and cause the trabeculectomy to fail.

In this review, we looked at patients with a functioning trabeculectomy who were undergoing cataract surgery and who received additional medication (5‐fluorouracil, mitomycin C, or anti‐vascular endothelial growth factor therapy) versus those who did not receive any additional medication.

How did we identify and evaluate the evidence?
We searched for randomised controlled trials (studies in which people are randomly assigned to one of two or more treatment groups), because these studies provide the strongest evidence about the effects of a given treatment. We planned to combine the results of the included studies to arrive at an answer to our research question.

What did we find?
We found no randomised controlled trials that met our inclusion criteria.

What does this mean?
We do not know whether an additional medical treatment during cataract surgery improves the chances of the drainage hole remaining open, as there is no evidence at present. It would be helpful if more studies were conducted in this area in future.

How up‐to‐date is this review?
The evidence in this Cochrane Review is current to April 2021.

Background

Glaucoma and cataract are a global problem with a high socioeconomic impact. Amongst 33.6 million cases of global blindness, 45% were attributed to cataract, and 11% to glaucoma in adults 50 years and older in 2020 (GBD 2021).

Glaucoma is an progressive optic neuropathy often associated with raised intraocular pressure (IOP), resulting in characteristic optic nerve features ('cupping') and a corresponding defect in the field of vision (Weinreb 2004). The damage is irreversible, and if left untreated can lead to blindness. The causes of glaucoma are multifactorial and include inherited factors (Wiggs 2017), environmental factors (Hecht 2017), and IOP (Garway‐Heath 2015).

The primary aim of treatment for glaucoma is a reduction of IOP, with the aim of slowing down any progressive damage to vision. This is achieved either by reducing the production of fluid in the eye (aqueous humour), using eye drops including beta‐blockers (e.g. timolol) or carbonic anhydrase inhibitors (e.g. brinzolamide, dorzolamide), or increasing fluid outflow by using drops such as prostaglandin analogues (e.g. latanoprost, travaprost, or bimatoprost), or through laser treatment to enhance the outflow mechanisms of the eye (trabecular meshwork) by selective laser trabeculoplasty (Gazzard 2019).

Although medical and laser treatments are effective in treating glaucoma (Rolim de Moura 2007; Vass 2007), many individuals continue to progress and require escalation to surgical intervention. Surgical interventions aim to reduce IOP through creating a direct outflow passage for the flow of aqueous humour out of the eye. These options include trabeculectomy, non‐penetrating filtration surgery, glaucoma drainage devices, and minimally invasive glaucoma interventions.

Description of the condition

Trabeculectomy is a well‐established, commonly performed surgery that was introduced in 1968 and is the preferred initial surgical option for the treatment of glaucoma (Cairns 1968; Vinod 2017). Success rates are high, with reports of up to 88% of patients achieving success 20 years after having a trabeculectomy (Landers 2012). The procedure is performed by creating a small fistula in the corneoscleral junction which is guarded by a partial‐thickness scleral flap, much like a hole is covered by a trapdoor. This trapdoor forms the main resistance for the new outflow of fluid out of the eye. It drains out through the new pathway into the sub‐Tenon's space to form a bleb (a pool of aqueous humour under the conjunctiva and tenons). The aqueous humour in the bleb is drained away slowly by the episcleral and conjunctival blood vessels. The tightness of the trapdoor guarding the fistula is modifiable by stitches placed at the time of surgery.

One of the main causes of failure of a trabeculectomy operation occurs when the body's natural wound‐healing process causes excessive scarring in the subconjunctival space, hence increasing the resistance of the fluid outflow. The aggressive healing process is multifactorial and differs depending on race, previous prolonged use of topical medications, age, and with African‐Caribbean and Asian ethnicity being a risk factor for failure due to a vigorous innate healing response (Broadway 2001; Husain 2005).

The risk of cataract formation following a trabeculectomy has been reported as between 20% to 52% up to seven years after surgery (Mathew 2011). In the Collaborative Initial Glaucoma Treatment Study (CIGTS), the likelihood of cataract extraction after initial trabeculectomy was eight times greater in the initial surgery group (Musch 2006). Indeed, cataract has been reported to be the main cause of visual acuity reduction after trabeculectomy surgery (Costa 1993). Furthermore, cataract formation is increased when trabeculectomy surgery is augmented with mitomycin C (Wilkins 2005), which is now common practice. In order to restore good visual acuity in these individuals, cataract surgery needs to be performed; however, it comes with a risk of bleb scarring and consequent IOP rise, hence worsening glaucoma control.

Cataract surgery causes significant anterior chamber inflammation and leads to an increased risk of bleb scarring. The inflammatory reaction can be measured by laser flare photometry and has been shown to persist for up to six months after phacoemulsification cataract extraction (Siriwardena 2000). Hence, it is not surprising that the timing of cataract extraction relative to the trabeculectomy is significantly associated with risk of bleb scarring and trabeculectomy failure: the shorter the interval between the two operations, the higher the risk for bleb scarring (Husain 2012). It is clear that although visual acuity can be successfully recovered following cataract surgery in these individuals, the continued success of a trabeculectomy in controlling IOP and glaucoma needs to be addressed.

Combining cataract and trabeculectomy surgery has been assessed in a Cochrane Review, with the evidence supporting this approach being weak (Zhang 2015). However, based on the limited available evidence, trabeculectomy in isolation rather than as combined surgery offers a better chance of longer‐term bleb survival.

A 2014 Cochrane Review assessed the adjunctive use of antimetabolites such as 5‐fluorouracil (5‐FU) or mitomycin C (MMC) during or after cataract operations to reduce the risk of trabeculectomy failure, but found no trials to support their use (Thomas 2014). Our review aimed to supersede Thomas 2014 by encompassing all adjunctive wound modulation therapies used during cataract surgery, including an update of any antimetabolite use and anti‐vascular endothelial growth factor (anti‐VEGF) therapy studied to promote the survival of a pre‐existing functioning trabeculectomy.

Description of the intervention

Any adjunctive wound modulation therapy (antimetabolites such as 5‐FU and MMC, beta radiation, or anti‐VEGF) administered at the time of cataract surgery to reduce the risk of bleb scarring and promote the survival of a functioning trabeculectomy.

Mitomycin C is an alkaloid produced by the bacterium Streptomyces caespitosus. It has a direct cytotoxic effect through inhibition of DNA‐dependent ribonucleic acid (RNA) synthesis and has been shown to cause apoptosis of human Tenon fibroblasts (Crowston 2002). 5‐fluorouracil is a pyrimidine analogue and inhibits thymidine incorporation into DNA, interfering with RNA and ribosomal RNA synthesis. It also induces apoptosis of fibroblasts in Tenon's, but is less potent in comparison to MMC (Crowston 2002). Both therapies have been widely used as an adjunct to trabeculectomy surgery to reduce scarring, as well as during postoperative bleb needling where subsequent formation of scar tissue is broken down with a needle.

Beta radiation application has been shown to have antiproliferative effects on human Tenon's fibroblasts in vitro (Constable 1998). These irradiated fibroblasts showed long‐term growth arrest, suggesting that the effects may be prolonged (Constable 1998). Beta radiation has been applied as an adjunct during trabeculectomy surgery to improve bleb survival. This is performed using a radioactive applicator which emits beta rays, often strontium‐90. In trials people who received beta‐irradiation as an adjunct during trabeculectomy had a lower risk of surgical failure compared to those who underwent trabeculectomy alone (Kirwan 2012).

Vascular endothelial growth factor is a cytokine that has been shown to stimulate wound healing by vascularisation and fibrosis of tissues, and can also cause an increase in proliferation of fibroblasts in Tenon's (Li 2009). Blocking this family of molecules modulates wound healing, and has been investigated in recent years. Anti‐VEGF therapies such as bevacizumab and ranibizumab are monoclonal antibodies against VEGF‐A that have been shown to reduce fibroblast proliferation and scarring when used as an adjunct after trabeculectomy (Grewal 2008).

How the intervention might work

Wound healing consists of a cascade of interactions between inflammatory cells, cytokines, and growth factors leading to the activation, proliferation, and migration of fibroblasts, angiogenesis, and collagen bundle formation, resulting in scar tissue formation (Skuta 1987). Modulating wound healing would ideally moderate the process such that there is a balance between optimum conjunctival healing, whilst suppressing the aggressive healing response within the subconjunctival space. This balance when suppressed excessively can lead to non‐healing and ischaemia, which can result in bleb leaks and low pressure. It is therefore imperative to identify the right balance of wound modulation.

Why it is important to do this review

The successful management of glaucoma with trabeculectomy is often impacted by decreased vision from the development of cataract. Cataract surgery can improve vision, but this comes at a cost of increasing the risk of trabeculectomy failure. There is a need for therapy to help prolong trabeculectomy survival after cataract extraction. This review aimed to answer the question of whether adjunctive therapies used at the time of cataract surgery can improve trabeculectomy survival rates.

Objectives

To investigate the effect of the adjunctive modulation of wound healing during cataract surgery on the survival of a previously functioning trabeculectomy.

Methods

Criteria for considering studies for this review

Types of studies

We planned to include all randomised controlled trials (RCTs) meeting our inclusion criteria with no date or language restrictions.

Types of participants

We planned to include trials in which participants with a functioning trabeculectomy underwent cataract surgery, using as our definition people with good glaucoma control without the use of any glaucoma medication.

We planned to include trials in which participants had one of the following: primary open‐angle glaucoma, primary angle‐closure glaucoma, pseudoexfoliative glaucoma, normal tension glaucoma, pigmentary glaucoma, uveitic glaucoma, or neovascular glaucoma.

We excluded participants who had undergone more than one previous trabeculectomy, bleb revisions, and minimally invasive glaucoma devices.

Types of interventions

Intervention

Use of any adjunctive therapy that can modulate wound healing such as antimetabolites 5‐FU and MMC, radiation, and anti‐VEGFs including bevacizumab, ranibizumab, pegaptanib, or aflibercept, by intracameral, subconjunctival, or intravitreal injection at any time point including during surgery and up to six months after surgery.

Comparator

Cataract surgery with no adjuvant therapy other than routine intracameral or subconjunctival antibiotics.

Types of outcome measures

Primary outcomes

• Trabeculectomy failure at 6 months and 12 months after cataract surgery, defined as failure of the bleb needing further surgery/intervention or the need for the use of additional medications to control IOP.

Secondary outcomes

• Mean IOP difference from pre‐cataract surgery baseline to 6 to 18 months post‐cataract surgery.

• Number of medications required to control eye pressure compared to before cataract surgery.

• Bleb appearance as measured by a summation score of the Moorfields bleb grading system or other equivalent numerical grading systems.

• Visual field progression measured by difference in mean deviation from baseline.

Adverse effects

• Surgical complications, especially hypotony with clinical sequelae, wound leak, infection, corneal toxicity, need for further surgery, and loss of vision to perception of light.

We planned to include studies irrespective of whether outcome data were reported.

Search methods for identification of studies

Electronic searches

The Cochrane Eyes and Vision Information Specialist searched the following databases for randomised controlled trials and controlled clinical trials. There were no restrictions to language or year of publication. The date of the search was 14 April 2021.

• Cochrane Central Register of Controlled Trials (CENTRAL; 2021, issue 4) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (Appendix 1).

• MEDLINE Ovid (1946 to 14 April 2021) (Appendix 2).

• Embase Ovid (1980 to 14 April 2021) (Appendix 3).

• ISRCTN registry (www.isrctn.com/editAdvancedSearch; searched 14 April 2021) (Appendix 4).

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 14 April 2021) (Appendix 5).

• World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp; searched 14 April 2021) (Appendix 6).

Searching other resources

We planned to search the reference lists of included studies to identify any further relevant studies not found by the electronic searches.

We planned to use Science Citation Index to locate studies that have cited the individual trials. We planned to contact relevant pharmaceutical companies for any clinical trials information that has not been released for publication.

Data collection and analysis

Selection of studies

Both review authors independently screened the titles and abstracts identified by the searches using web‐based software (Covidence). We assessed the search results against the inclusion criteria (see Criteria for considering studies for this review). Any disagreements were resolved by discussion. No studies meeting the inclusion criteria were identified, but if studies had been identified, the following additional steps were planned.

We planned to correspond with investigators to clarify study eligibility, as appropriate. We planned to list all studies excluded after full‐text examination and provide a brief justification for their exclusion.

For any potentially eligible studies identified on the trial registers, we planned to do the following.

• If the study had a completion date of more than two years previously, we searched for publications of the trial and contacted the investigators if necessary to obtain any published or unpublished data. If eligible, the study was included in the review irrespective of whether a publication could be identified.

• If the study had a completion date of within two years, or in the future, we documented the study in the ongoing studies section.

• Eligible studies were included irrespective of whether outcomes were reported.

Data extraction and management

We planned that both review authors would independently extract data using web‐based online review management software (Covidence). Any discrepancies would be resolved by discussion. We planned to contact trial investigators for missing data. We planned to import all data directly into RevMan Web (RevMan Web 2021), with one review author checking the accuracy of the imported data.

We planned to extract the following data from each included study for intervention and comparator groups separately (see Appendix 7).

• Demographics of cohort (country of study, age, gender, ethnicity, comorbidities).

• Number of participants in control and interventional groups.

• Number of participants with trabeculectomy failure at 6 to 18 months after cataract surgery.

• Mean difference in IOP at 6 to 18 months after cataract surgery compared to before surgery.

• Number of medications required to control IOP at 6 to 18 months after cataract surgery compared to before surgery.

• Surgery: trabeculectomy technique, cataract extraction technique (clear cornea, conjunctival/scleral, temporal, superior).

• Wound modulator dosage, delivery method (intracameral, intravitreal, subconjunctival) and frequency (intraoperative, postoperative, monthly).

Assessment of risk of bias in included studies

We planned that both review authors would independently assess the risk of bias in each included study using Cochrane's risk of bias tool, as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). Any disagreements would be resolved by discussion.

We planned to specifically consider and report on the following sources of bias.

• Selection bias (random sequence generation, allocation concealment): was the sequence of allocation generated using a random procedure, and was the allocation concealed to people recruiting/enrolling participants as well as to participants?

• Performance bias (masking of participants and researchers): were the recipients of care unaware of their assigned intervention? Were the individuals providing care unaware of the assigned intervention?

• Detection bias (masking of outcome assessors): were the individuals evaluating outcomes unaware of the assigned intervention?

• Attrition bias: were the rates of follow‐up and compliance similar between groups? Was the analysis by intention‐to‐treat, and were there any postrandomisation exclusions?

• Reporting bias: is there any evidence that outcomes that had been measured were not reported?

We planned to grade each domain as low risk of bias, high risk of bias, or unclear (lack of information or uncertainty of the potential for bias). We planned to contact trial investigators for clarification of parameters graded as 'unclear'.

Measures of treatment effect

We planned to calculate the risk ratio for the dichotomous outcome of trabeculectomy failure. We planned to calculate the mean difference for the following continuous outcomes: IOP difference from preoperative baseline in mmHg, and number of medications required to control eye pressure compared to before cataract surgery.

Hazard ratio for trabeculectomy failure after cataract surgery has been reported to be as high as 3 (Husain 2012), and it has been reported that 10% to 61% of trabeculectomies fail at 12 to 36 months post‐cataract surgery (Mathew 2011). We would consider studies reporting a reduction in rates of trabeculectomy failure after cataract surgery of more than 20% or a hazard ratio of less than 3 to be a clinically significant effect.

Where possible, we would check for the skewness of continuous data (Altman 1996).

Unit of analysis issues

Trials may randomise one or both eyes to the intervention or comparator. If participants were randomly allocated to treatment, but only one eye per participant was included in the trial, then there would be no unit of analysis issue. In such cases we would document how the eye was selected. If participants were randomly allocated to treatment, but both eyes were included and reported, we would analyse as clustered data, that is adjusted for within‐person correlation; to do this it may be necessary to contact the trial investigators for further information. If the study is a within‐person study, that is one eye is randomly allocated to the intervention, and the other eye receives the comparator, then we would analyse as paired data; to do this it may be necessary to contact the trial investigators for further information.

In the case of multi‐arm studies, we would analyse multiple intervention groups in an appropriate way that avoids arbitrary omission of relevant groups and double‐counting of participants.

Dealing with missing data

We planned to conduct an intention‐to‐treat analysis where possible. We would use imputed data if computed by the trial investigators using an appropriate method, but would not impute missing data ourselves.

If intention‐to‐treat data were not available, we would perform an available‐case analysis, which assumes that data are missing at random. We would assess whether this assumption was reasonable by collecting data on the number of participants excluded or lost to follow‐up and the reasons for loss to follow‐up by treatment group from each included trial, if reported.

Assessment of heterogeneity

We planned to examine the overall characteristics of the studies, in particular the type of participants and types of interventions, in order to assess the extent to which the studies were similar enough for pooling of results to make sense.

We planned to look at the forest plots of study results to determine how consistent the results of the studies were, in particular evaluating the size and direction of effects.

We would calculate the I² statistic, which is the percentage of variability in effect estimates that is due to heterogeneity rather than to sampling error (chance) (Higgins 2002). We would consider I² values over 50% as indicative of substantial inconsistency, but would also consider Chi² testP value. As this may have low power in the case of few studies, we would consider P < 0.1 as indicating statistical significance of the Chi² test.

Assessment of reporting biases

We planned to use the risk of bias tool to determine whether there was selective or incomplete reporting. See Assessment of risk of bias in included studies.

If there were 10 or more trials included in a meta‐analysis, we would construct funnel plots and considered tests for asymmetry to assess publication bias, according to the methods described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019).

Data synthesis

We planned to pool data using a random‐effects model in RevMan Web. If there were fewer than three trials in a given comparison, we would use a fixed‐effect model.

If there was inconsistency between individual study results such that a pooled result may not be a good summary of the individual trial results (e.g. the effects are in different directions, or I² > 50% and P < 0.1), we would not pool the data but would describe the pattern of the individual study results.

If there was statistical heterogeneity, but all the effect estimates were in the same direction such that a pooled estimate would seem to provide a good summary of the individual trial results, data would be pooled.

When meta‐analysis was not possible, we would use structured reporting of the available effects, employing tables and visual displays, according to Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2019).

Subgroup analysis and investigation of heterogeneity

If there were sufficient trials, we would compare the effect of treatment in the following subgroups. We would perform the following subgroup analyses on outcomes including trabeculectomy failure and mean IOP difference from baseline.

• Participants with secondary glaucoma versus participants with primary open‐angle glaucoma, i.e. neovascular glaucoma and uveitic glaucoma. Individuals with secondary glaucoma often have a higher inflammatory drive and a higher rate of failure.

• Participants over 65 years of age versus participants aged 30 years to 65 years. Older participants tend to have less aggressive wound‐healing responses and may respond better to wound modulation therapies.

• White participants versus non‐white participants including Indian, African/Caribbean, and Chinese participants. Non‐white participants with brown irides have a higher propensity for inflammation after cataract surgery.

• 5‐FU versus MMC, 5‐FU versus anti‐VEGF, and MMC versus anti‐VEGF. Mitomycin C is thought to have a stronger effect on wound healing compared to other types of wound‐modulating agents.

Sensitivity analysis

We would perform the following sensitivity analyses on trabeculectomy failure post‐cataract surgery.

• Excluding studies at high risk of bias in one or more domains.

• Excluding industry‐funded studies.

Summary of findings and assessment of the certainty of the evidence

We found no RCTs that met our inclusion criteria. However, for future updates of this review, we will prepare a summary of findings table presenting relative and absolute risks. Two review authors will independently assess the overall quality of the evidence for each outcome using the GRADE classification (GRADEpro GDT).

Results

Description of studies

We did not identify any RCTs of adjunctive wound healing modulation during cataract surgery to promote survival of a functioning trabeculectomy.

Results of the search

The electronic searches identified 948 references (Figure 1). After removal of 261 duplicates, the Cochrane Information Specialist screened the remaining 687 records and removed 673 references that were not relevant to the scope of this review. We screened the remaining 14 reports, and based on the information in the abstract excluded them as they did not address our review question.

1.

Study flow diagram.

Included studies

We did not identify any RCTs that met the inclusion criteria of this review.

Excluded studies

We did not exclude any RCTs after full‐text review.

Risk of bias in included studies

We did not identify any RCTs that met the inclusion criteria of this review.

Effects of interventions

We did not identify any RCTs that met the inclusion criteria of this review.

Discussion

We found no RCTs that investigated the role of adjuvant wound modulating therapy at the time of cataract surgery to promote survival of a functioning trabeculectomy.

Summary of main results

No RCTs were available that investigated the role of adjuvant wound modulating therapy at the time of cataract surgery to promote survival of a functioning trabeculectomy.

Overall completeness and applicability of evidence

We found only three studies that attempted to answer the research question of this review (Lascaratos 2015; Shahid 2010; Sharma 2007); however, as none were RCTs, there is no strong evidence to guide clinicians on the role of adjuvant wound modulating therapy use at the time of cataract surgery to promote survival of a functioning trabeculectomy.

Potential biases in the review process

There were no limitations of date or language in the searches. The Cochrane Information Specialist reviewed the titles and abstracts, and both review authors independently assessed the 14 article abstracts.

Agreements and disagreements with other studies or reviews

Although we did not find any RCTs that met our inclusion criteria, we did identify two retrospective studies with small numbers of participants (less than 30 per study arm) evaluating subconjunctival 5‐FU bleb injections, which are discussed below (Shahid 2010; Sharma 2007).

Sharma 2007 reported a retrospective comparative study evaluating 5‐FU subconjunctival bleb injection after cataract surgery (n = 22) compared to control (n = 25). The study reported mean IOP as comparable between groups over 12 months, and that 13.6% of 5‐FU participants needed an increase in medication compared to 36.4% in the control group (P = 0.03).

Shahid and colleagues also performed a retrospective comparative study evaluating a series of 5‐milligram 5‐FU subconjunctival bleb injections at 2, 4, and 12 weeks after cataract surgery (n = 25) compared to control (n = 24) (Shahid 2010). They reported no difference in mean IOP at two‐year follow‐up between 5‐FU (15.1 mmHg standard deviation 3.1) and control (15.3 mmHg standard deviation 3.3) (P = 0.3). Trabeculectomy failure defined as IOP > 21 mmHg at any time point was lower in the 5‐FU group (4%) compared with the control group (16.7%), but this was not statistically significant (P = 0.78).

Authors' conclusions

Implications for practice.

There are no randomised controlled trials to guide clinicians on the choice or use of adjunctive wound healing modulators during cataract surgery to promote survival of a functioning trabeculectomy bleb in patients.

Implications for research.

A randomised controlled trial is needed to investigate the role of adjuvant wound modulating therapy at the time of cataract surgery to promote survival of a functioning trabeculectomy. The definition of a functioning trabeculectomy needs to be predetermined, and could include patients on medications to mimic a real‐life setting and improve recruitment. Participants can be identified and enrolled from glaucoma clinics, with randomisation of the intervention applied at the end of a routine, uncomplicated cataract extraction. In the retrospective studies identified, numbers of participants were small, suggesting that a multicentred approach should be employed to increase recruitment numbers. There is the potential for future studies to perform triple‐masking within the study due to the nature of the operation being under local anaesthetic so that the participant is masked. Furthermore, the surgeon administering the intervention can be blinded through masking of vials, as well as the data collector due to the similarity in appearance of eyes postintervention in comparison to controls. The primary outcome measure should be trabeculectomy failure, which could be defined by glaucoma medications, intraocular pressure, or further surgical interventions. Secondary outcomes and any subgroup analysis could be as recommended in this review.

History

Protocol first published: Issue 7, 2020

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Cataract Extraction] explode all trees
#2 cataract* near/4 (extract* or aspirat* or operat* or remov* or surg* or excis* or implant*)
#3 lens* near/4 (extract* or aspirat* or operat* or remov* or surg* or excis* or implant*)
#4 phacoemulsif* or capsulorhexis or lensectomy
#5 #1 or #2 or #3 or #4
#6 MeSH descriptor: [Mitomycin] explode all trees
#7 mitomycin*
#8 mytomycin*
#9 mitomicin*
#10 mytomicin*
#11 MeSH descriptor: [Fluorouracil] explode all trees
#12 fluorouracil*
#13 flourouracil*
#14 fluoro uracil*
#15 5FU*
#16 5 FU*
#17 MeSH descriptor: [Angiogenesis Inhibitors] explode all trees
#18 MeSH descriptor: [Angiogenesis Inducing Agents] this term only
#19 MeSH descriptor: [Endothelial Growth Factors] this term only
#20 anti near/2 VEGF*
#21 anti near/1 angiogen*
#22 endothelial near/2 growth near/2 factor*
#23 (macugen* or pegaptanib* or lucentis* or rhufab* or ranibizumab* or bevacizumab* or avastin* or aflibercept* or conbercept* or OPT 302 or Opthea* or RTH258 or Brolucizumab* or abicipar pegol)
#24 VEGF TRAP*
#25 #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24
#26 MeSH descriptor: [Trabeculectomy] this term only
#27 trabeculectom*
#28 #26 or #27
#29 #5 and #25 and #28

Appendix 2. MEDLINE Ovid search strategy

1. randomized controlled trial.pt.
2. (randomized or randomised).ab,ti.
3. placebo.ab,ti.
4. dt.fs.
5. randomly.ab,ti.
6. trial.ab,ti.
7. groups.ab,ti.
8. or/1‐7
9. exp animals/
10. exp humans/
11. 9 not (9 and 10)
12. 8 not 11
13. exp cataract extraction/
14. ((extract$ or aspirat$ or operat$ or remov$ or surg$ or excis$ or implant$) adj3 cataract$).tw.
15. ((extract$ or aspirat$ or operat$ or remov$ or surg$ or excis$ or implant$) adj3 lens$).tw.
16. (pha?oemulsif$ or capsulorhexis or lensectomy).tw.
17. or/13‐16
18. exp mitomycin/
19. mitomycin$.tw.
20. mytomycin$.tw.
21. mitomicin$.tw.
22. mytomicin$.tw.
23. exp fluorouracil/
24. fluorouracil$.tw.
25. flourouracil$.tw.
26. fluoro uracil$.tw.
27. 5FU$.tw.
28. 5 FU$.tw.
29. exp angiogenesis inhibitors/
30. angiogenesis inducing agents/
31. endothelial growth factors/
32. exp vascular endothelial growth factors/
33. (anti adj2 VEGF$).tw.
34. (endothelial adj2 growth adj2 factor$).tw.
35. (anti adj1 angiogen$).tw.
36. (macugen$ or pegaptanib$ or lucentis$ or rhufab$ or ranibizumab$ or bevacizumab$ or avastin or aflibercept$ or conbercept$ or OPT 302 or Opthea$ or RTH258 or Brolucizumab$ or abicipar pegol).tw.
37. VEGF TRAP$.tw.
38. or/18‐37
39. trabeculectomy/
40. trabeculectom$.tw.
41. or/39‐40
42. 17 and 38 and 41
43. 12 and 42

The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville 2006.

Appendix 3. Embase Ovid search strategy

1. exp randomized controlled trial/
2. exp randomization/
3. exp double blind procedure/
4. exp single blind procedure/
5. random$.tw.
6. or/1‐5
7. (animal or animal experiment).sh.
8. human.sh.
9. 7 and 8
10. 7 not 9
11. 6 not 10
12. exp clinical trial/
13. (clin$ adj3 trial$).tw.
14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
15. exp placebo/
16. placebo$.tw.
17. random$.tw.
18. exp experimental design/
19. exp crossover procedure/
20. exp control group/
21. exp latin square design/
22. or/12‐21
23. 22 not 10
24. 23 not 11
25. exp comparative study/
26. exp evaluation/
27. exp prospective study/
28. (control$ or prospectiv$ or volunteer$).tw.
29. or/25‐28
30. 29 not 10
31. 30 not (11 or 23)
32. 11 or 24 or 31
33. exp cataract extraction/
34. ((extract$ or aspirat$ or operat$ or remov$ or surg$ or excis$ or implant$) adj3 cataract$).tw.
35. ((extract$ or aspirat$ or operat$ or remov$ or surg$ or excis$ or implant$) adj3 lens$).tw.
36. (pha?oemulsif$ or capsulorhexis or lensectomy).tw.
37. or/33‐36
38. mitomycin/
39. mitomycin c/
40. mitomycin$.tw.
41. mytomycin$.tw.
42. mitomicin$.tw.
43. mytomicin$.tw.
44. fluorouracil/
45. fluorouracil.tw.
46. flourouracil.tw.
47. fluoro uracil.tw.
48. 5FU$.tw.
49. 5 FU$.tw.
50. angiogenesis/
51. exp angiogenesis inhibitors/
52. angiogenic factor/
53. endothelial cell growth factor/
54. monoclonal antibody/
55. vasculotropin/
56. (anti adj2 VEGF$).tw.
57. (endothelial adj2 growth adj2 factor$).tw.
58. (anti adj1 angiogen$).tw.
59. (macugen$ or pegaptanib$ or lucentis$ or rhufab$ or ranibizumab$ or bevacizumab$ or avastin or aflibercept$ or conbercept$ or OPT 302 or Opthea$ or RTH258 or Brolucizumab$ or abicipar pegol).tw.
60. VEGF TRAP$.tw.
61. or/38‐60
62. trabeculectomy/
63. trabeculectom$.tw.
64. or/62‐63
65. 37 and 61 and 64
66. 32 and 65

Appendix 4. ISRCTN search strategy

(antimetabolite OR mitomycin OR fluorouracil OR bevacizumab OR ranibizumab) AND cataract AND trabeculectomy

Appendix 5. ClinicalTrials.gov search strategy

(antimetabolite OR mitomycin OR fluorouracil OR bevacizumab OR ranibizumab) AND cataract AND trabeculectomy

Appendix 6. WHO ICTRP search strategy

cataract = Condtion AND trabeculectomy = Intervention

Appendix 7. Data on study characteristics

Mandatory items		Optional items
Methods
Study design	Parallel‐group RCT   Within‐person RCT	Exclusions after randomisation   Losses to follow‐up   Number randomised/analysed   How were missing data handled? e.g. available‐case analysis, imputation methods   Reported power calculation (Y/N), if yes, sample size and power   Unusual study design/issues
Eyes or   Unit of randomisation/unit of analysis
Participants
Country		Ethnicity (participants of Asian or Afro‐Caribbean origin with brown irides)   Participants with neovascular glaucoma
Total number of participants
Number (%) of men and women
Average age and age range
Inclusion criteria
Exclusion criteria
Interventions 5‐fluorouracil, mitomycin C, and anti‐vascular endothelial growth factors including bevacizumab, ranibizumab, pegaptanib, or aflibercept by intracameral, subconjunctival, or intravitreal injection at any time point including during surgery and up to 6 months after surgery
Intervention: 5‐fluorouracil (n = ) mitomycin C (n = ) bevacizumab (n = ) ranibizumab (n = ) pegaptanib (n = ) aflibercept (n = )   Comparator (n = )	· Number of people randomised to this group · Dose · Frequency · Route of administration intracameral, subconjunctival, or intravitreal injection
Outcomes
Primary and secondary outcomes as defined in study reports	Primary outcome: Trabeculectomy failure at 6 months and 12 months after cataract surgery defined as failure of the bleb needing further surgery or uncontrolled IOP requiring medications.   Secondary outcomes: Mean IOP difference from pre‐cataract surgery baseline to 6 to 18 months post‐cataract surgery Number of medications required to control eye pressure compared to before cataract surgery Bleb appearance (Moorfields bleb grading system) Visual field progression (mean deviation from baseline)   Adverse events reported (Y/N)   Length of follow‐up and intervals at which outcomes assessed:	Planned/actual length of follow‐up
Notes
Date conducted	Specify dates of recruitment of participants mm/yr to mm/yr	Full study name: (if applicable) Reported subgroup analyses (Y/N) Were trial investigators contacted?
Sources of funding
Declaration of interest
Included on trials registry	Y/N including registration number if available

Differences between protocol and review

None.

Contributions of authors

WSN and HJ screened studies for inclusion.

WSN and HJ drafted the text of the review and will be responsible for review updates.

Sources of support

Internal sources

• No sources of support provided

External sources

• National Institute for Health Research (NIHR), UK

  • Richard Wormald, the former Co‐ordinating Editor for Cochrane Eyes and Vision (CEV), received financial support for his CEV research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.

  • Up to March 2021, this review was supported by the NIHR, via Cochrane Infrastructure funding to the CEV UK editorial base.

  The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS, or the Department of Health.

• Public Health Agency, UK

  As of April 2021, the completion of this review was supported by the HSC Research and Development (R&D) Division of the Public Health Agency which funds the Cochrane Eyes and Vision editorial base at Queen's University Belfast.

• Queen's University Belfast, UK

  Gianni Virgili, Co‐ordinating Editor for Cochrane Eyes and Vision’s work is funded by the Centre for Public Health, Queen’s University of Belfast, Northern Ireland.

Declarations of interest

WSN has no competing interests associated with this work, but has received travel support from Allergan and payment for a lecture at an anterior segment meeting from Thea Pharmaceuticals.

HJ has no competing interests associated with this work. He currently co‐mentors a group of 20 young international glaucoma specialists (International Glaucoma Panel) with Professor Jonathan Crowston (Singapore). This is a three‐year educational programme funded by Allergan; however, HJ and Prof Crowston have sole responsibility for organising the educational content of the programme. HJ has given lectures for Allergan, Laboratoires Thea, and Santen on content unrelated to the scope of this review. He has also worked as a consultant for Allergan.

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