Prophylactic non‐steroidal anti‐inflammatory agents for the prevention of cystoid macular oedema after cataract surgery
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The aim of this review is to answer the question: is there sufficient evidence to recommend the prophylactic use of topical NSAIDs in addition to topical steroids postoperatively to reduce the incidence of PMO and associated visual morbidity, compared to current standard practice of topical steroids alone?
This review will be confined to addressing the use of NSAIDs in the prophylaxis of pseudophakic CMO. A separate Cochrane Review on treatment of established CMO has already been published (Sivaprasad 2004) but the effectiveness of NSAIDs in treatment remains uncertain. PMO can lead to permanent structural damage in the central retina, therefore a prevention strategy may be more effective than treatment after the damage has been done.
Background
Description of the condition
Cataract is the leading cause of low vision and blindness in the world. The majority of cataract formation occurs with age, as the lens within the eye becomes less translucent with time and is termed age‐related cataract (Wills Eye Hospital 2010). The World Health Organization (WHO) estimates that cataract accounts for 16 million cases of blindness worldwide. In industrialised countries, the prevalence of visually detrimental cataract is difficult to quantify due to wide variability in reporting rates, definitions of what constitutes visual impairment from cataract and different behaviour patterns of local populations in seeking surgical intervention. However, in most industrialised countries, availability of cataract surgery at an early stage of visual impairment in the disease process has led to this procedure being one of the most commonly performed surgical procedures worldwide.
Macular oedema is the accumulation of extracellular fluid in the central retina (the macula) which may present following cataract surgery with lens implantation (pseudophakic macular oedema (PMO)) or without (aphakia ‐ aphakic macular oedema (AMO)) and may give rise to poor visual outcome with reduced visual acuity and distortion of the central vision. The diagnosis of this condition is made both clinically using slit lamp biomicroscopic examination of the macula and with the aid of fundus fluorescein angiography (FFA) or ocular coherence tomography (OCT) (Choi 2005).
The incidence of PMO varies with type of surgery, intraoperative complications and pre‐existing risk factors. Reported risk of PMO varies between 0.9% and 5% for modern uncomplicated phacoemulsification cataract surgery (Spaide 1993), but can be as high as 10% in the presence of surgical complications such as vitreous loss (Blomquist 2002). Vision is not always affected and the incidence of PMO with decrease in visual acuity is reported at 1% (Ahmed 1999) and is associated with increasing retinal thickness (Hee 1995). A recent multicentre audit of 55,567 cataract operations in the UK's National Health Service (NHS) showed a risk of 1.62%, at a median postoperative review time of 31 days (Jaycock 2009). This was based on surgeons' reports rather than systematic examination of the macula and defined as poor visual outcome attributed to PMO.
Other risk factors for PMO include preoperative uveitis and diabetic retinopathy while the use of topical prostaglandin analogue therapy in glaucoma remains a theoretical risk (Nelson 2003). Other factors may include cerebrovascular and cardiovascular disease (Jain 2001).
PMO is often self‐limiting with spontaneous resolution (Ahmed 1999). The small proportion of patients with chronic persistent PMO may be difficult to treat (Yannuzzi 1995) and they may experience permanent reduction in vision from atrophy of the photoreceptor layer of the retina (Ahmed 1999). Chronic oedema may lead to the formation of cystic spaces in the retina termed cystoid macular oedema (CMO).
Description of the intervention
The intervention is the topical use of non‐steroidal anti‐inflammatory agent (NSAID) eyedrops in addition to topical steroid eyedrops after cataract surgery. They may also be used preoperatively primarily to reduce the risk of pupil constriction during surgery but this may potentially also reduce the risk of PMO. Non‐steroidal anti‐inflammatory agents are a group of drugs which are in common use orally as over the counter treatments for the reduction of pain, redness and swelling associated with systemic inflammation. Some of these are also available in eyedrop form as prescription medicines for the reduction of ocular inflammation.
The comparative intervention is the use of topical steroids on the eye after cataract surgery, which is current standard therapy and may in itself reduce the risk of macular oedema. Steroids are a group of prescription‐only drugs which are used systemically to suppress the symptoms, signs and sequelae of inflammation. They are also used in their topical eyedrop form for the reduction of ocular inflammation.
In the last decade or so, several clinical trials have examined the use of topical NSAIDs in the treatment and prevention of postoperative inflammation and PMO, without the adverse effects of topical corticosteroids (Ballonzoli 2010; Carnahan 2000; Heier 1999; Polanski 1992; Solomon 2001). Non‐steroidal anti‐inflammatory agents such as ketorolac and indomethacin are cyclo‐oxygenase inhibitors which suppress breakdown of the blood‐aqueous barrier that may occur in the early postoperative period (Flach 1987; Flach 1988; Miyake 1984; Sanders 1984).
Jain 2001 recommended the use of NSAID prophylaxis in patients with predisposing factors to developing postsurgical PMO irrespective of cause. Other clinical studies suggest that topical NSAIDs may be more effective than topical steroids in re‐establishing the blood‐aqueous barrier postoperatively, suggesting an important role in PMO prevention (Flach 1989; Kraff 1990; Ursell 1999).
Rossetti 1998's meta‐analysis of the use of NSAIDs suggested possible beneficial effects of NSAIDs in both the prophylaxis and treatment of CMO but concluded that the overall quality of the evidence was insufficient to justify recommendation of its widespread use in prophylaxis. A Cochrane systematic review on treatment of PMO following cataract surgery (Sivaprasad 2004) found that two out of seven randomised controlled trials (RCTs) included showed a beneficial effect of NSAIDs on chronic PMO, although problems with trial quality and heterogeneity prevented valid meta‐analysis.
A recent randomised, placebo‐controlled trial looking at the adjunctive effect of topical NSAIDs in addition to intravitreal steroids (triamcinolone) and intravitreal anti‐vascular endothelial growth factor (bevacizumab) in chronic PMO, has found a statistically significant improvement with the use of topical nepafenac in reduction of retinal thickness and improvement in visual acuity at 16 weeks (Warren 2010). NSAIDs have also been used as an alternate treatment for patients with CMO of mixed origin who are steroid responders and therefore cannot have the latter, with good tolerance and efficacy (Warren 2008).
How the intervention might work
NSAIDs are cyclo‐oxygenase inhibitors and may work by reducing the production of pro‐inflammatory prostaglandins. Inflammation within tissue is caused by the production of pro‐inflammatory products by several pathways. NSAIDs act to suppress the cyclo‐oxygenase pathway of inflammation, inhibiting production of prostaglandins (Eisenach 2010).
Why it is important to do this review
As cataract surgery is the second most commonly performed operation worldwide and PMO occurs in between 1% and 10% of all cataract surgeries depending on risk and complications and leads to poor visual outcome, there is a significant volume of visual morbidity which can be potentially prevented if it is found that NSAIDs are effective in its prophylaxis. NSAIDs are relatively inexpensive, easily obtainable and carry the potential to significantly improve the outcome of cataract surgery worldwide.
Despite some evidence in favour of the beneficial effects of NSAIDs in PMO, uncertainty remains about whether it has significant benefit on the prevention of PMO when used perioperatively in addition to steroids, as does widespread variation in clinical practice.
Objectives
The aim of this review is to answer the question: is there sufficient evidence to recommend the prophylactic use of topical NSAIDs in addition to topical steroids postoperatively to reduce the incidence of PMO and associated visual morbidity, compared to current standard practice of topical steroids alone?
This review will be confined to addressing the use of NSAIDs in the prophylaxis of pseudophakic CMO. A separate Cochrane Review on treatment of established CMO has already been published (Sivaprasad 2004) but the effectiveness of NSAIDs in treatment remains uncertain. PMO can lead to permanent structural damage in the central retina, therefore a prevention strategy may be more effective than treatment after the damage has been done.
Methods
Criteria for considering studies for this review
Types of studies
We will include only randomised controlled trials (RCTs) in this review.
Types of participants
We will include trials in which adult participants have undergone standard surgery for age‐related cataract. We will include those participants with a higher baseline risk, such as diabetic and uveitic patients, but will perform subgroup analysis if possible to elucidate whether or not treatment effect differs according to baseline risk. Surgery can include extracapsular (large incision with sutures ‐ ECCE), manual small incision without sutures (MSICS) and mechanised small incision extracapsular extraction (PHACO) and intracapsular procedures when an extracapsular procedure was planned. We will include elective intracapsular procedures but analyse these as a separate subgroup.
Types of interventions
The primary comparison of this review will be the effect of postoperative topical NSAIDs in addition to topical steroids compared to topical steroids alone. If possible, we will also examine the benefit of preoperative topical NSAIDS but the control comparator will remain postoperative topical steroids alone.
We will also try to examine the effect of preoperative NSAIDs alone versus steroids alone postoperatively.
We will not exclude studies if incident PMO is subsequently treated.
Types of outcome measures
Primary outcomes
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The proportion of patients undergoing cataract extraction in one eye (the study eye) with a poor vision outcome (visual acuity not improving to 6/9 (or equivalent with other notations of vision) with best refractive correction ‐ attributed to a diagnosis of PMO (detected clinically, angiographically or on ocular coherence tomography (OCT)) at three months after surgery. This may include participants who develop PMO and require and receive treatment. Such patients would be counted as having a poor vision outcome.
Secondary outcomes
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The proportion of patients undergoing cataract extraction in one eye (the study eye) with a poor visual outcome (visual acuity not improving to 6/9 with best refractive correction) attributed to a diagnosis of PMO (detected clinically, angiographically or on OCT) within one, six and 12 months after surgery.
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Any quality of life measures or patient satisfaction relating to the patient's experience of surgery on the study eye. Patients randomised to have both eyes done with or without NSAIDS could be included here but not those randomised to have NSAIDs in one eye but not the other.
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The mean difference in central retinal thickness within one, three and/or six months as measured by OCT scan.
Adverse effects
We will look at known harms of NSAIDs including respiratory effects and gastrointestinal disturbance, in addition to intolerance of medication and allergic reactions. We will record any other harms such as liver toxicity, as has been reported with some NSAIDs.
Economic evaluation
We will also seek an evaluation of the cost‐effectiveness and cost per quality‐adjusted life year (QALY)/disability‐adjusted life year (DALY) modelling.
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, Latin American and Caribbean Health Sciences Literature Database (LILACS), the metaRegister of Controlled Trials (mRCT) (www.controlled‐trials.com) and ClinicalTrials.gov (www.clinicaltrials.gov). 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), LILACS (Appendix 4), mRCT (Appendix 5) and ClinicalTrials.gov (Appendix 6).
Searching other resources
We will search the reference lists of the studies included in the review. We will use the Science Citation Index to find studies that have cited the individual trials. We will contact certain pharmaceutical companies for any relevant clinical trials information that has not been released for publication. We will not handsearch conference proceedings or journals specifically for the review.
Data collection and analysis
Selection of studies
Two review authors independently will screen the titles and abstracts resulting from the searches. We will obtain full copies of the potentially relevant trials. We will assess the full copies according to the 'Criteria for considering studies for this review.' We will only assess trials meeting these criteria for methodological quality. We will resolve disagreements by discussion.
We will list all studies excluded after evaluation of evidence and include a brief description of the reason for exclusion.
Data extraction and management
Two review authors independently will extract data using a form developed by the Cochrane Eyes and Vision Group. We will resolve discrepancies by discussion. As far as possible, we will extract data for an intention‐to‐treat (ITT) analysis. We will contact trial investigators for missing data. All data will be entered into RevMan 5.1 (RevMan 2011) by one review author after checks by both authors. Both authors will then check data entry for inaccuracies.
Assessment of risk of bias in included studies
We will use the Cochrane Collaboration 'Risk of bias' tool for assessing risk of bias in each included study. Two review authors independently will assess trial quality according to methods set out in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve disagreements by discussion with the third author.
We will specifically consider and report on the following parameters in the review.
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Selection bias (random sequence generation, allocation concealment): was the sequence of allocation of participants to groups concealed until after the interventions were allocated?
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Was the randomisation sequence genuinely random or was it in fact a quasi‐randomised trial?
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Performance bias (masking of participants and researchers): were the recipients of care unaware of their assigned intervention? Were persons providing care unaware of the assigned intervention? Double‐masked studies are feasible and will be assigned low risk of bias.
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Attrition bias: were the rates of follow up and compliance similar in the groups? Was the analysis by intention‐to‐treat and were there any postrandomisation exclusions?
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Selective outcome reporting bias: are there systematic differences between reported and unreported findings?
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Commercial bias: was there a difference in outcome between industry‐funded and independently‐funded studies? Is there any evidence of suppressed or unpublished industry‐funded trials?
We will grade each parameter of trial quality as low risk of bias, high risk of bias or unclear (lack of information or uncertainty of potential for bias). We will contact trial investigators for clarification of parameters graded as 'unclear'.
Measures of treatment effect
We will calculate the risk ratio for outcome measures reported as dichotomous data (for example, poor visual acuity attributed to PMO within three months). We will calculate the mean difference for measures of retinal thickness. We will analyse ordinal outcome data as dichotomous data if an established defensible cut‐off point is available, such as quality of life measures. Alternatively, we may analyse longer ordinal scales in a meta‐analysis as continuous data, such as ocular coherence tomography (OCT) measurements and fundus fluorescein angiography (FFA) data. We do not plan to meta analyse adverse events.
Unit of analysis issues
Trials included may randomise a single eye or both eyes to the intervention. If both eyes have been allocated to the same treatment, we will analyse as "clustered data". We will exclude studies which have allocated different eyes to different treatments as there may be a confounding cross‐over effect due to systemic absorption.
Dealing with missing data
We will assess all included trials for number of participants excluded or lost to follow up. We will seek intention‐to‐treat analysis for included trials but whilst we will use imputed data if computed by the trialists we do not plan to impute missing data on their behalf.
Assessment of heterogeneity
Where heterogeneity is observed between individual study results we will not combine studies but will present a tabulated summary of results. We will not rely on statistical significance of a Chi2 test to indicate heterogeneity but will examine the forest plot of the study results and the overall characteristics of the studies. We will look at the consistency between studies by examining the I2 statistic value. We will consider I2 values over 50% to indicate substantial inconsistency but will consider confidence intervals of the I2 value and the direction of effects.
Assessment of reporting biases
We will use the risk of selective outcome reporting bias assessment tool to look for selective or incomplete reporting. If there are 10 trials or more included in the review, we will construct funnel plots and consider tests for asymmetry for bias assessment, according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Data synthesis
We aim to use a random effects model provided we do not detect substantial inconsistency between results. If there are fewer than three trials in a comparison we may use the fixed‐effect model. Where heterogeneity is observed between studies we will not combine studies but will present a tabulated summary of results.
Subgroup analysis and investigation of heterogeneity
We will consider heterogeneity of individual studies in terms of subgroup analysis or meta‐regression if there are a sufficient numbers of studies under review. We will attempt to analyse subgroups where the baseline risk of PMO is higher and treatment may be less effective, such as patients with diabetes and uveitis.
Sensitivity analysis
We will perform a sensitivity analysis to investigate the influence of studies without masking of allocation, participants and providers on the overall estimates of effect.
