cochrane database of systematic reviews (reviews) || non-steroidal anti-inflammatory agents for...

Non-steroidal anti-inflammatory agents for treating cystoid

macular oedema following cataract surgery (Review)

Sivaprasad S, Bunce C, Crosby-Nwaobi R

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2012, Issue 2

http://www.thecochranelibrary.com

Non-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.


T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 NSAID versus placebo in chronic CMO, Outcome 1 Visual acuity improvement at end of

treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Analysis 1.2. Comparison 1 NSAID versus placebo in chronic CMO, Outcome 2 Visual acuity improvement one month

post treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

19ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iNon-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery (Review)


[Intervention Review]

Non-steroidal anti-inflammatory agents for treating cystoidmacular oedema following cataract surgery

Sobha Sivaprasad1 , Catey Bunce2, Roxanne Crosby-Nwaobi3

1Normanby Building, King’s College Hospital, London, UK. 2Research and Development Department, Moorfields Eye Hospital NHS

Foundation Trust, London, UK. 3The Florence Nightingale School of Nursing and Midwifery, King’s College London, London, UK

Contact address: Sobha Sivaprasad, Normanby Building, King’s College Hospital, Denmark Hill, London, SE5 9RS, UK.

[email protected].

Editorial group: Cochrane Eyes and Vision Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 2, 2012.

Review content assessed as up-to-date: 5 August 2011.

Citation: Sivaprasad S, Bunce C, Crosby-Nwaobi R. Non-steroidal anti-inflammatory agents for treating cystoid macu-

lar oedema following cataract surgery. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD004239. DOI:

10.1002/14651858.CD004239.pub3.


A B S T R A C T

Background

Cystoid macular oedema (CMO) is the accumulation of fluid in the central retina (the macula) due to leakage from dilated capillaries.

It is the most common cause of poor visual outcome following cataract surgery. The exact cause is unclear. Acute CMO, defined as

oedema of less than four months duration, often resolve spontaneously. CMO that persists for four months or more is termed chronic

CMO. Different types of non-steroidal anti-inflammatory agents (NSAIDs) are used in the treatment of CMO which may be delivered

topically or systemically.

Objectives

To examine the effectiveness of NSAIDs in the treatment of CMO following cataract surgery.

Search methods

We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 7),

MEDLINE (January 1950 to August 2011), EMBASE (January 1980 to August 2011), Latin American and Caribbean Health Sciences

Literature Database (LILACS) (January 1982 to August 2011), the metaRegister of Controlled Trials (mRCT) (www.controlled-

trials.com) (August 2011) and ClinicalTrials.gov (www.clinicaltrials.gov) (August 2011). We searched the reference lists of identified

trials. We searched conference abstracts (sessions related to cataract) in The Association for Research in Vision and Ophthalmology

(ARVO) 1975 to 2011. We contacted experts in the field and NSAIDs manufacturers for details on published and unpublished

trials.There were no language or date restrictions in the search for trials. The electronic databases were last searched on 5 August 2011.

Selection criteria

We included randomised controlled trials evaluating the effects of NSAIDs in the treatment of CMO following cataract surgery.

Data collection and analysis

Two review authors independently extracted data. Since considerable heterogeneity was observed between studies we did not conduct

meta-analyses.

1Non-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery (Review)


mailto:[email protected]

http://www.controlled-trials.com/


http://www.clinicaltrials.gov

Main results

Seven trials involving a total of 266 participants were included. Four trials studied the effects of NSAIDs in chronic CMO while

the other three examined the effect of NSAIDs in acute CMO. Of the studies examining chronic CMO, one study enrolled 120

participants, but the remainder had 34 or fewer participants. Four different NSAIDs were used and administered in different ways.

Indomethacin was used orally and was found to be ineffective for chronic CMO in one trial. Topical fenoprofen appeared effective

but not statistically significantly so for chronic CMO in another small trial. Treatment with topical 0.5% ketorolac for chronic CMO

was found to be effective in two trials. Three trials examined the effect of topical NSAIDs on acute CMO. The comparisons among

these studies were of an NSAID to placebo, prednisolone or another NSAID. The study design differed between the studies in other

important aspects thus they could not be combined in a meta-analysis.

Authors’ conclusions

This review found two trials which showed that topical NSAID (0.5% ketorolac tromethamine ophthalmic solution) has a positive

effect on chronic CMO and two trials which revealed no significant difference between comparative groups. As such, the effects of

NSAIDs in acute and chronic CMO remain unclear and needs further investigation.

P L A I N L A N G U A G E S U M M A R Y

Non-steroidal anti-inflammatory drugs for treating fluid accumulation in the macula after cataract surgery

Cystoid macular oedema (CMO) is the accumulation of fluid in the macula (central retina) due to leakage from capillaries. Clinically

significant CMO following cataract surgery is a complication of unknown cause. Acute CMO, defined as oedema of less than four months

duration, often gets better spontaneously. This review included seven randomised controlled trials with a total of 266 participants. Four

trials studied the effects of non-steroidal anti-inflammatory agents (NSAIDs) in chronic CMO while the other three examined the effect

of NSAIDs in acute CMO. This review found two trials which showed that topical NSAID (0.5% ketorolac tromethamine ophthalmic

solution) has a positive effect on chronic CMO and a third trial which was supportive of this finding (albeit not statistically significantly

so). One study suggested no effect and our review suggests further work is needed for a more conclusive decision regarding use of

NSAIDS in chronic CMO. Similarly, the effects of NSAIDs in acute CMO remain unclear and this too needs further investigation.

B A C K G R O U N D

Cystoid macular oedema (CMO) is the accumulation of extra-

cellular fluid between the layers of the neurosensory retina and

retinal pigment epithelium in the central retina (the macula) due

to leakage from dilated capillaries. Cystoid macular oedema fol-

lowing cataract surgery was first reported in 1953 (Irvine 1953).

Since then techniques of cataract surgery have become much more

sophisticated yet CMO is still recognised as one of the most com-

mon causes of poor visual outcome in patients following cataract

surgery with or without intraocular lens implantation (Drolsum

1995).

Description of the condition

Cystoid macular oedema can be classified into two types. Angio-

graphic CMO is diagnosed on fundus fluorescein angiography

(FFA) and may not be associated with visual impairment. It has

been reported to occur in 3% to 70% of people at four to 16 weeks

after cataract surgery. Clinical CMO is characterised by reduced

visual acuity accompanied by ophthalmoscopic and angiographic

findings and this accounts for 0.1% to 12 % of cases (Rossetti

2000). This wide variation in the reported incidence of CMO is

due mainly to the different surgical techniques and methods used

for diagnosis, although there are thought to be many other so far

unidentified risk factors (Flach 1998).

Presentation and diagnosis

Cystoid macular oedema may be asymptomatic but may present

with decreased and/or distorted vision. Slit-lamp biomicroscopy

may not show any abnormalities in 5% to 10% of eyes (Desai

1993). In others, the findings may vary from an altered foveal reflex

to a honeycomb appearance at the macula. Many patients have co-



existent inflammatory signs. Fundus fluorescein angiography is the

diagnostic procedure of choice in case of doubtful clinical CMO.

Findings may vary from a mild leakage to a full-fledged flower petal

appearance at the macula. The macular findings are associated

with leakage from the optic disc. Visual function does not correlate

well with the severity of clinical or angiographic changes (Spaide

1993).

Description of the intervention

The exact cause of CMO remains unclear. Irvine 1953 attributed

it to the incarceration of vitreous in the anterior segment and

consequent vitreo-macular traction. This has led investigators to

manage CMO with pars plana vitrectomy or neodymium yttrium-

aluminum-garnet (YAG) vitreolysis. The use of acetazolamide and

hyperbaric oxygen are based on the theory that CMO may be the

result of disruption of the blood-retinal barrier.

Most investigators agree that inflammation is the major aetio-

logical factor. The pharmacologic agents used to combat the in-

flammation and CMO are topical and periocular corticosteroids

and non-steroidal anti-inflammatory drugs (NSAIDs). Topical

NSAIDs have been used since the 1970s both pre- and postoper-

atively to prevent and treat CMO following cataract surgery.

How the intervention might work

One of the postulations for pseudophakic CMO is inflammation

with adjunct increased synthesis of prostaglandins.

Why it is important to do this review

A systematic review on the medical prophylaxis and treatment

of CMO after cataract surgery was published in 1998 (Rossetti

1998). The review concluded that when numerous small studies

are combined, there was an indication of an effect of NSAIDs both

in the prevention and treatment of CMO. However, no conclusion

could be safely drawn since the authors commented that many of

the trials were of poor quality and may additionally be regarded

as too heterogeneous to include in one meta-analysis. Therefore,

uncertainty of the effectiveness of NSAIDs in the treatment of

CMO persists. A Cochrane review is needed to address this ques-

tion alone and to update what is currently known using rigorous

quality control and conducting meta-analysis only when sufficient

homogeneity of studies allows. A separate Cochrane review on

NSAID prophylaxis for post-cataract surgery CMO is underway

(Abeysiri 2011).

O B J E C T I V E S

The aim of this review was to examine the effectiveness of non-

steroidal anti-inflammatory drugs in the treatment of cystoid mac-

ular oedema following cataract surgery.

M E T H O D S

Criteria for considering studies for this review

Types of studies

This review included randomised controlled trials.

Types of participants

Participants in the trials were adults who developed cystoid mac-

ular oedema (CMO) following cataract surgery in an eye with no

history of ocular inflammatory disease, trauma or previous intraoc-

ular surgery. Since surgery and the postoperative course of cataract

are different in children and adults, children were excluded from

the review.

Cystoid macular oedema was classified into two groups - acute

CMO defined as therapeutic intervention within four months

of onset of CMO and chronic CMO defined as persistence of

clinical CMO four months after cataract surgery and treatment

commenced after four months.

Types of interventions

We included trials in which non-steroidal anti-inflammatory

agents (NSAIDs) in any form or dosage were compared to placebo,

no treatment or to another treatment modality with the aim of

treating CMO following cataract surgery. There was no minimum

or maximum limit on the duration of treatment.

Types of outcome measures

Primary outcomes

The primary outcome measures were:

1. an improvement of 2 or more lines in Snellen visual acuity

or equivalent at end of treatment;

2. persistence of improvement of vision one month after

discontinuation of treatment.



Secondary outcomes

Secondary outcome measures were:

1. proportion of participants with improvement in leakage on

fundus fluorescein angiography (FFA);

2. proportion of participants with improved contrast

sensitivity;

3. quality of life.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Tri-

als (CENTRAL) 2011, Issue 7, part of The Cochrane Library.

www.thecochranelibrary.com (accessed 5 August 2011), MED-

LINE (January 1950 to August 2011), EMBASE (January 1980

to August 2011), Latin American and Caribbean Health Sci-

ences Literature Database (LILACS) (January 1982 to Au-

gust 2011), the metaRegister of Controlled Trials (mRCT) (

www.controlled-trials.com) (August 2011) and ClinicalTrials.gov

(www.clinicaltrials.gov) (August 2011). There were no language

or date restrictions in the search for trials. The electronic databases

were last searched on 5 August 2011.

See: Appendices for details of search strategies for CENTRAL

(Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix

3), LILACS (Appendix 4), mRCT (Appendix 5) and ClinicalTri-

als.gov (Appendix 6).

Searching other resources

Reference lists of all identified trials and previous reviews were

searched for additional trials. Key authors were identified and

asked to identify additional published or unpublished trials. Addi-

tionally, manufacturers of NSAIDs (Allergan, Inc. and Novartis,

Inc. (Basel, Switzerland)) were contacted in order to retrieve infor-

mation on relevant published or unpublished trials. We searched

conference abstracts (sessions related to cataract) in The Associa-

tion for Research in Vision and Ophthalmology (ARVO) 1975 to

2011 for mention of trials. Manual searches of journals were not

done specifically for this review.

Data collection and analysis

Selection of studies

Two review authors independently scanned the titles, abstracts and

keywords of every record retrieved in the searches. Full articles were

obtained of any report referring to definitely or possibly relevant

trials. If there was any doubt regarding these criteria from the

information given in the title and abstract, we retrieved the full

article for clarification. We assessed these full copies according

to the definitions in the ’Criteria for considering studies for this

review’ section. Only trials meeting these criteria were assessed for

methodological quality. The review authors were unmasked to the

report authors, institution and trial results during the assessment.

All discrepancies were resolved by discussion.

Data extraction and management

We used a standard data extraction form which included at least

the following items.

1. Method: duration, randomisation technique, allocation con-

cealment method, masking (participants, provider, outcome as-

sessors), country, setting.

2. Participants: sampling (random/convenience), number in com-

parison groups, age, sex, similarity of groups at baseline, with-

drawals/losses to follow-up (reason), subgroups.

3. Interventions: placebo included, interventions (dose, route, du-

ration), comparison interventions (dose, route, duration), co-med-

ications (dose, route, duration).

4. Outcomes: outcomes specified above, any other outcomes as-

sessed, other events, times of assessment, length of follow up.

5. Notes: general information such as published/unpublished, ti-

tle, authors, source, contact address, language of publication, year

of publication, funding sources.

All three review authors independently extracted outcome data

onto paper data collection forms developed by the Cochrane Eyes

and Vision Group. One review author entered the data into Re-

view Manager 5 and the other two authors checked for errors and

inconsistencies. Differences in data extraction were resolved by

consensus, referring to the original article.

Assessment of risk of bias in included studies

Two review authors independently assessed the quality of each trial

and any disagreement was resolved by discussion. We assessed trial

quality according to methods set out in Chapter 8 in the Cochrane

Handbook for Systematic Reviews of Interventions (Higgins 2011).

In particular, the following parameters were assessed.

1. Selection bias: was the randomisation procedure and the allo-

cation concealment adequate?

2. Performance bias: were the participants and people administer-

ing the treatment masked to the intervention?

3. Attrition bias: a) were withdrawals and dropouts completely

described? b) was the analysis by intention-to-treat or ’available

case’ analysis?

4. Detection bias: were outcome assessors masked to the interven-

tion?

We graded trials as low risk of bias, high risk of bias or unclear risk

of bias. Trials graded as low risk of bias or unclear risk of bias were

included in the review and high risk of bias trials were excluded.






http://www.clinicaltrials.gov

http://clinicaltrials.gov%29.

Data synthesis

We were unable to conduct any meta-analyses on acute CMO be-

cause of the clinical heterogeneity observed between studies. Dif-

ferent interventions, time points for outcome measures etc. meant

that although a forest plot was presented for the effectiveness of

NSAID on chronic CMO at the end of treatment and at one

month after cessation of treatment, summary effects were not es-

timated. The two Flach studies (Flach 1987; Flach 1991) could

perhaps be combined but this would add little to the overall con-

clusions of the review.

If additional trials become available in future we will analyse them

as follows. We will calculate relative risks for dichotomous out-

comes. If appropriate, we will combine data in a meta-analysis us-

ing the random-effects model. If there are fewer than three studies

and results appear homogeneous, we will use a fixed-effect model.

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 also examine

the I2 value and its confidence interval.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

Results of the search

The electronic searches found a total of 382 reports of studies. We

obtained the full copy of 16 reports of trials that appeared to meet

the inclusion criteria. We excluded nine of these (Ahluwalia 1988;

Azzolini 1986; IDSG 1997; Jampol 1994; Kraff 1985; Miyake

1995; Rossetti 1996; Singal 2004; Stark 1984) (see ’Characteristics

of excluded studies’). In particular, all trials that used non-steroidal

anti-inflammatory drugs (NSAIDs) for prophylaxis of cystoid

macular oedema (CMO) were excluded. We included seven trials

involving a total of 266 participants (Burnett 1983; Flach 1987;

Flach 1991; Flach 1998a; Heier 2000; Rho 2003; Yannuzzi 1977).

A summary of the included studies is given below. Further details

can be found in the ’Characteristics of included studies’ .

Updated searches

An updated search done in September 2006 identified 138 reports

of trials. After initial assessment by the Trials Search Co-ordinator,

134 references were excluded as they were deemed not relevant

to the scope of the review and four reports were subsequently

forwarded on to the authors. The authors looked at the titles and

abstracts for these four reports and rejected them.

Another update search was run in September 2008. After dedupli-

cation the search identified a total of 56 references. Two authors

independently screened the abstracts but found no relevant reports

of studies.

A third update search was conducted in August 2011. After dedu-

plication the search identified a total of 77 references. The Tri-

als Search Co-ordinator scanned the search results and removed

70 references which were not relevant to the scope of the review.

Two of the authors independently screened the remaining seven

abstracts but none of these new studies met the inclusion criteria

for this review.

Included studies

Types of participants and settings

The seven included trials can be divided into two groups: three

trials were on the effect of NSAIDs on acute CMO following

cataract surgery (treatment commenced within four months) (

Flach 1998a; Heier 2000; Rho 2003) and four trials used NSAIDs

in the treatment of chronic CMO (persisting for four months or

more) (Burnett 1983; Flach 1987; Flach 1991; Yannuzzi 1977).

Five trials were small (sample size less than 30) (Burnett 1983;

Flach 1987; Flach 1998a; Heier 2000; Yannuzzi 1977), one study

had 34 participants (Rho 2003) and one was a multi-centre trial

of 120 participants (Flach 1991). All studies were conducted in

the USA.

Types of interventions

One study compared the effect of oral indomethacin with placebo

in chronic CMO (Yannuzzi 1977). One trial compared the use of

topical fenoprofen with placebo in chronic CMO (Burnett 1983).

Five trials examined the effect of topical ketorolac tromethamine,

two with placebo in chronic CMO (Flach 1987; Flach 1991),

one with placebo in acute CMO (Flach 1998a). One trial com-

pared ketorolac with prednisolone and a combination of ketoro-

lac with prednisolone for acute CMO (Heier 2000) and another

study compared ketorolac with topical diclofenac sodium for acute

CMO (Rho 2003).

Outcomes

A 2 line improvement in Snellen visual acuity at the end of treat-

ment was recorded in four studies (Flach 1987; Flach 1991; Flach

1998a; Yannuzzi 1977). A 2 line improvement at one month fol-

lowing cessation of treatment was done in four studies (Flach 1987;

Flach 1991; Flach 1998a; Yannuzzi 1977). The follow-up period

in one study is unclear (Burnett 1983). Flach 1998a also reviewed

the participants at one year. Heier 2000 and Rho 2003 recorded

the mean time taken to improve visual acuity by 2 lines.

Fundus fluorescein angiography (FFA) was done as a diagnostic

measure in all six trials. Decreased leakage on fluorescein angiogra-

phy was used as an outcome measure in four trials (Burnett 1983;



Flach 1987; Flach 1998a; Heier 2000). Contrast sensitivity was

assessed in one study (Heier 2000).

Risk of bias in included studies

Allocation

Three trials used computer generated randomisation (Flach 1987;

Flach 1991; Flach 1998a). One trial used centralised randomisa-

tion by pharmacy (Heier 2000).The method of treatment assign-

ment in the other three trials was unclear, although they stated that

the groups were randomly allocated (Burnett 1983; Rho 2003;

Yannuzzi 1977).

Blinding

All the trials except Rho 2003 were double-masked, that is, par-

ticipants and people giving the treatment were unaware of the in-

tervention given.

Incomplete outcome data

Documentation of exclusions

There were no exclusions after treatment in two trials (Burnett

1983; Yannuzzi 1977). Exclusions are clearly documented in the

other five trials (Flach 1987; Flach 1991; Flach 1998a; Heier 2000;

Rho 2003). In Flach 1987, four participants were excluded, and

an available case analysis conducted, due to poor compliance, my-

ocardial infarction, ocular allergy and lost to follow-up. In Flach

1991 the reasons for exclusion included systemic illness, missed

hospital appointment, poor compliance or lost to follow-up. These

participants were excluded from data analysis at the relevant point

of examination and an available case analysis conducted as well.

Ninety-five of the original 120 randomised participants were in-

cluded. There was no serious imbalance of lost to follow up be-

tween the two arms. In Heier 2000, two participants were excluded

due to the development of other posterior segment pathology and

they were excluded from the data analyses. In Rho 2003, there

were no dropouts and so all participants were included in the data

analyses.

Completeness of follow up

All trials followed up participants for at least one month following

cessation of treatment. Burnett 1983 followed up participants until

the end of the study but the period of study is not clear. Visual

outcome at one year was done in only one study (Flach 1998a).

The follow-up rates were good.

Selective reporting

None of the included studies demonstrated selective reporting.

Other potential sources of bias

Intention-to-treat analysis

All trials analysed all participants who completed follow up in the

group to which they were randomised. True intent-to-treat analy-

ses were not conducted as there were patients for whom outcome

data were not available and the authors did not conduct any form

of imputation for missing data.

Handling of data for two eyes

One trial had two participants with both eyes involved (Yannuzzi

1977). In each case, both eyes received the same treatment. A pa-

tient-based approach (whereby there was no cross-over in treat-

ment for participant with both eyes involved in the study but if a

person had both eyes involved, both eyes were either in the treat-

ment group or the placebo group) was used in this case.

Effects of interventions

1. Acute cystoid macular oedema

Three trials studied acute cystoid macular oedema (CMO), de-

fined as treatment of CMO within four months of cataract surgery

(Flach 1998; Heier 2000; Rho 2003).

Heier 2000: An improvement of 2 or more lines in Snellen visual

acuity was achieved at the end of one month in 6/9 (67%) of the

ketorolac group compared to 4/8 (50%) of the prednisolone group

and 8/9 (89%) in the combination of ketorolac and prednisolone

group.

The proportion of participants with an improvement of contrast

sensitivity one month after discontinuation of medications was

noted in this study. The results mirrored the visual improvement

i.e. 4/8 (50%) in the prednisolone group, 5/9 (89%) in the com-

bination group but 5/9 (55%) in the ketorolac group.

The proportion with decreased leakage on fluorescein angiogra-

phy was 4/8 (50%) in the prednisolone group, 5/9 (55%) in the

ketorolac group and 7/9 (77%) in the combination group.

Rho 2003: The mean time taken for a 2 line improvement in

Snellen visual acuity and resolution of CMO was compared and

found to be equally effective for the 0.1% diclofenac sodium and

0.5% ketorolac tromethamine groups. Reduced CMO was noted

within 26 weeks in 16/18 (89%) of the diclofenac group and 14/

16 (88%) in the ketorolac group. Complete resolution of clinical



CMO within 26 weeks was seen in 14/18 (78%) of the diclofenac

group and 12/16 (75%) of the ketorolac group.

Flach 1998: A cross-over study in which 4/11(36%) of the ke-

torolac group achieved a 2 line improvement while 2/11(18%)

of the placebo group demonstrated a 2 line improvement at the

end of one month of treatment. After one month the treatment

was switched over for a subsequent one month. Following cross-

over of treatment, 3/11(27%) in the treatment group improved

from baseline of the second period of the cross-over (that is one

more patient improved when the placebo group switched to treat-

ment group) and 2/11(18%) in the placebo group achieved a 2

line improvement from baseline of the second period of the cross-

over. When this group had the treatment for one month, four par-

ticipants improved while only two maintained the improvement

while using the placebo.

The study did not report angiographic response to treatment. Con-

trast sensitivity was not analysed. Quality of life was not assessed

although it is mentioned that the visual acuity improved in 20 of

22 participants in the trial seven years after completion of the trial.

Adverse effects: In all the trials, only one case of ocular allergy

has been reported and the patient discontinued the treatment. No

other mention of adverse effects was found.

2. Chronic cystoid macular oedema

Oral indomethacin

Yannuzzi 1977 compared 25 mg oral indomethacin three times

daily for six weeks with placebo for the treatment of chronic CMO.

Two lines or more visual improvement was obtained in 1/10 (10%)

in the indomethacin group and 3/10 (30%) in the placebo group

at the end of treatment (relative risk (RR) 0.33, 95% confidence

interval (CI) 0.04 to 2.69) (Table 1). The numbers increased to

2/10 (20%) in the indomethacin group and 4/10 (40%) in the

placebo group one month after cessation of treatment (Table 2). All

participants had four fluorescein angiograms following treatment

and all angiograms showed evidence of CMO.

Contrast sensitivity was not assessed in this study.

Topical fenoprofen

Burnett 1983 studied the effect of topical 1% fenoprofen sodium

one drop applied four times daily for eight weeks compared to

placebo. Two lines or more visual improvement at the end of the

study (length not specified) was achieved by 3/6 (50%) in the

fenoprofen group and 3/8 (38%) in the placebo group (RR 1.33,

95% CI 0.40 to 4.43) (Table 1).

The fundus angiography results did not correlate to visual outcome

with 2/6 (33%) in the fenoprofen group and 2/8 (25%) in the

placebo group showing decreased leakage at the end of study.

Contrast sensitivity was not analysed in this study.

Topical ketorolac

Two trials examined the effect of 0.5% ketorolac tromethamine

four times daily for chronic CMO (Flach 1987; Flach 1991).

Flach 1987 used ketorolac for two months while the other study

continued treatment for three months.

Flach 1987: 8/13 (62%) participants treated with ketorolac had

2 lines or more visual improvement at the end of treatment com-

pared to 1/13 (8%) in the placebo group (RR 8.0, 95% CI 1.16

to 55.20) (Table 1). One month after cessation of therapy, a 2 line

improvement was seen in 5/13 (38%) of the ketorolac group and

2/13 (15%)in the placebo group (Table 2). Fluorescein leakage

was less in 2/13 (15%) participants on ketorolac but the response

in the placebo group was not mentioned.

Flach 1991: 22/46 (48%) participants treated with ketorolac had 2

lines or more improvement at the end of three months of treatment

compared to 10/49 (20%) in the placebo group (RR 2.34, 95%

CI 1.25 to 4.40) (Table 1). One month later, 21/41 (51%) of

the ketorolac group maintained improvement compared to 7/46

(15%) in the placebo group (Table 2).

The angiographic response and contrast sensitivity assessment was

not done in this study.

None of the trials assessed quality of life.

No reports of adverse effects were found.

D I S C U S S I O N

This review of non-steroidal anti-inflammatory drugs (NSAIDs)

for the treatment of cystoid macular oedema (CMO) following

cataract surgery classified CMO into acute CMO (duration of

CMO of less than four months) and chronic CMO (more than

four months).

Acute CMO

All three randomised controlled trials assessing the effect of

NSAIDs in the treatment of acute CMO were small (Flach 1998;

Heier 2000; Rho 2003) and insufficiently powered to detect any-

thing but major effects. Spontaneous resolution and drug effect in

acute CMO are hard to distinguish in these studies. Outcomes at

seven years in Flach 1998 suggest the natural history of CMO is

spontaneous resolution. Flach 1998 showed no benefit of NSAIDs

alone in the treatment of acute CMO. However, Heier 2000 found

that the combination of topical prednisolone and ketorolac to be

synergistic and beneficial. Rho 2003 noted significant reduction

in CMO and improvement of visual acuity with either topical ke-

torolac or diclofenac sodium.

While Heier 2000 and Rho 2003 showed a statistically significant

positive response of acute CMO with combined treatment of ke-

torolac and steroids, Flach 1998 did not show a significant effect

of ketorolac alone in acute CMO. This difference in effect can be

explained by the following facts:



1. All three trials used 0.5% topical ketorolac tromethamine as

the NSAID. Flach 1998 compared the effect of ketorolac with

placebo while Heier 2000 compared ketorolac alone with pred-

nisolone alone and a combination of ketorolac and prednisolone

and Rho 2003 compared ketorolac to diclofenac sodium. Heier

2000 treated participants for three months while Flach 1998 did

a cross-over study of one month of ketorolac and one month of

placebo. Rho 2003 treated participants for 26 weeks.

2. The duration of CMO was less than 45 days in Rho 2003, 45

to 49 days in Heier 2000 and 60 to 90 days in Flach 1998.

3. The cataract surgery was different in the three trials. The par-

ticipants in Heier 2000 and Rho 2003 underwent uncomplicated

phacoemulsification and intraocular lens implantation while Flach

1998 used extracapsular cataract surgery and intraocular lens im-

plantation including complicated cases.

4. In Heier 2000, 50% of the participants in the ketorolac group

were already on topical steroids at the time of enrolment, so some

of the positive effect noted in this study might be attributed to the

combination of NSAIDs and steroids.

We could not conduct a meta-analysis because of the heterogene-

ity in study design. Heier 2000 suggested that a combination of

topical ketorolac and steroids is beneficial in acute CMO while

Rho 2003 concluded that both ketorolac and diclofenac sodium

are equally effective in reducing CMO and improving visual acu-

ity.

Chronic CMO

The four trials on NSAIDs for chronic CMO showed a broad range

of therapeutic effects (Burnett 1983; Flach 1987; Flach 1991;

Yannuzzi 1977). One trial showed a negative but not statistically

significant effect of NSAIDs in chronic CMO (Yannuzzi 1977).

It used an oral NSAID which raises doubts about the role of oral

NSAIDs in ocular disease; one study found a positive but not

significant effect (Burnett 1983) and the other two studies found

a statistically significant benefit (Flach 1987; Flach 1991).

The two older studies with negative results included only apha-

kic eyes (intracapsular cataract surgery) while the newer studies

included both aphakic and pseudophakic eyes (intracapsular and

extracapsular cataract surgery with intraocular lens implantation).

The different surgical techniques and associated inflammation and

the light transmission characteristics of the various intraocular

lenses may be important variables that affected the results. The

variability in results can also be explained by the fact that different

NSAIDs were used in the various trials. Oral indomethacin was

found to be ineffective in the treatment of clinical chronic CMO

(Yannuzzi 1977). Topical fenoprofen was not shown to be effective

(Burnett 1983). The only NSAID found to be effective is topical

0.5% ketorolac tromethamine (Flach 1987; Flach 1991).

Another factor is the small sample size in three of the four studies (

Burnett 1983 -14 participants, Flach 1987 - 26 and Yannuzzi 1977

- 23). These sample sizes are too small to allow subgroup analysis of

the duration of decreased visual acuity and the resultant structural

changes at the macula that can influence the initial vision, response

to treatment and final outcome.

Comparison of duration of treatment

Duration of treatment differed between the two trials which

showed some benefit of NSAIDs (topical ketorolac) for chronic

CMO. The treatment lasted for two months in Flach 1987 and

for three months in Flach 1991. Three months duration showed

better therapeutic response but the study samples were different

(30 versus 120 participants respectively).

All studies used angiographic evidence as one of the criteria to con-

firm clinically significant CMO. Angiographic response to treat-

ment was also an outcome measure in two trials (Burnett 1983;

Flach 1987). Improvement in vision did not correlate with angio-

graphic changes, so angiography is of doubtful value as an out-

come in future studies.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

For acute cystoid macular oedema (CMO), the evidence is insuf-

ficient to clearly inform practice. Three small studies which could

not be combined indicated that there may be therapeutic benefit

especially when used in combination with topical steroids.

In chronic disease, the findings of the two trials by Flach suggest

topical NSAID (0.5% ketorolac tromethamine) is effective and

that duration of treatment for three months provides a more per-

sistent benefit than two months. One trial reported a negative ef-

fect and because the trials are small, we still recommend further

work in this area for a conclusive result.

Implications for research

More research is needed to better understand the cause of this con-

dition and its patho-physiology. Risk factors require elucidation

so that those at risk can be identified.

The therapeutic effect of non-steroidal anti-inflammatory agents

(NSAIDs) on acute CMO needs to be assessed by larger trials with

longer follow up. Further studies are needed to compare various

available topical NSAIDs to find the most effective NSAID in the

treatment of chronic clinical CMO following cataract surgery. In

addition, the optimum duration of treatment cannot be deter-

mined at present as the existing trials used different time scales.

The most relevant and pragmatic outcome measure is probably

best corrected visual acuity of the affected eye at different time

points after initiation of treatment. Contrast sensitivity may be of



value but was only looked at in one of the included trials. Mea-

sures of retinal thickness using the optical coherence tomography

(OCT) may also be of use though the extent to which this corre-

lates with function has so far not been described in randomised

controlled trials. Fluorescein angiography may be of value in con-

firming diagnosis but OCT is probably safer and simpler. As an

outcome measure to assess therapeutic response, it is not likely

to be justified. Other aspects of visual function and vision related

quality of life should be considered.

Given that CMO, though not that common a complication of

cataract surgery, affects many thousands of people since cataract

surgery is one of the most frequently performed surgical proce-

dures, it is astonishing that there is so little good quality research

to answer questions about its treatment. There is clearly an urgent

need for this gap in the evidence base to be filled.

A C K N O W L E D G E M E N T S

We thank the Cochrane Eyes and Vision Group for their help and

advice and for preparing the electronic searches. We also thank

Bruce Gaynes, Roberta Scherer and Suzanne Brodney-Folse for

their peer review comments. We thank Nishal Patel and Sreedhar

Jyothi for their contributions to earlier versions of this review. We

acknowledge Adriaan van Sorge for registering the title for this

Cochrane review.

Richard Wormald (Co-ordinating Editor for CEVG) acknowl-

edges financial support for his CEVG 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 Spe-

cialist Biomedical Research Centre for Ophthalmology. The views

expressed in this publication are those of the authors and not nec-

essarily those of the Department of Health.

R E F E R E N C E S

References to studies included in this review

Burnett 1983 {published data only}

Burnett J, Tessler H, Isenberg S, Tso MO. Double-masked

trial of fenoprofen sodium: treatment of chronic aphakic

cystoid macular edema. Ophthalmic Surgery 1983;14(2):

150–2.

Flach 1987 {published data only}

Flach AJ, Dolan BJ, Irvine AR. Effectiveness of ketorolac

tromethamine 0.5% ophthalmic solution for chronic

aphakic and pseudophakic cystoid macular edema.

American Journal of Ophthalmology 1987;103(4):479–86.

Flach 1991 {published data only}

Flach AJ, Jampol LM, Weinberg D, Kraff MC, Yannuzzi

LA, Campo RV, et al.Improvement in visual acuity in

chronic aphakic and pseudophakic cystoid macular edema

after treatment with topical 0.5% Ketorolac tromethamine.

American Journal of Ophthalmology 1991;112(5):514–9.

Flach 1998 {published and unpublished data}

Flach AJ. The incidence, pathogenesis and treatment

of cystoid macular edema following cataract surgery.

Transactions of the American Ophthalmological Society 1998;

96:557–634.

Heier 2000 {published data only}

Heier JS, Topping TM, Baumann W, Dirks MS, Chern S,

Flach AJ. Ketorolac versus prednisolone versus combination

therapy in the treatment of acute pseudophakic cystoid

macular edema. Ophthalmology 2000;107(11):2034–9.

Rho 2003 {published data only}

Rho DS. Treatment of acute pseudophakic cystoid macular

edema: diclofenac versus ketorolac. Journal of Cataract and

Refractive Surgery 2003;29(12):2378–84.

Yannuzzi 1977 {published data only}

Yannuzzi LA, Klein RM, Wallyn RH, Cohen N, Katiz I.

Ineffectiveness of indomethacin in the treatment of chronic

cystoid macular edema. American Journal of Ophthalmology

1977;84(4):517–9.

References to studies excluded from this review

Ahluwalia 1988 {published data only}

Ahluwalia BK, Kalra SC, Parmar IPS, Khurana AK. A

comparative study of the effect of antiprostaglandins and

steroids on aphakic cystoid macular oedema. Indian Journal

of Ophthalmology 1988;36(4):176–8.

Asano 2008 {published data only}

Asano S, Miyake K, Ota I, Sugita G, Kimura W,

Sakka Y, et al.Reducing angiographic cystoid macular

edema and blood-aqueous barrier disruption after small

incision phacoemusification and foldable intraocular

lens implantation: multicenter prospective randomized

comparison of topical diclofenac 0.1% and bethamethasone

0.1%. Journal of Cataract and Refractive Surgery 2008;34

(1):57–63.

Azzolini 1986 {published data only}

Azzolini C, Bressan P, Dorigo MT. Medical treatment of

cystoid macular oedema in aphakia patients. Minerva

Oftalmologica 1986;28(1):15–20.

IDSG 1997 {published data only}

Italian Diclofenac Study Group. Efficacy of diclofenac

eyedrops in preventing postoperative inflammation and

long-term cystoid macular edema. Journal of Cataract and

Refractive Surgery 1997;23(8):1183–9.



Jampol 1994 {published data only}

Jampol LM, Jain S, Pudzisz B, Weinreb RN. Nonsteroidal

anti-inflammatory drugs and cataract surgery. Archives of

Ophthalmology 1994;112(7):891–4.

Kraff 1985 {published data only}

Kraff MC, Sanders DR, Jampol LM, Lieberman HL.

Factors affecting pseudophakic cystoid mascular edema: five

randomized trials. Journal American Intra-Ocular Implant

Society 1985;11:380–5.

Mathys 2010 {published data only}

Mathys KC, Cohen KL. Impact of nepafenac 0.1% on

macular thickness and postoperative visual acuity after

cataract surgery in patients at low risk for cystoid macular

oedema. Eye 2010;24(1):90-6.

Miyake 1995 {published data only}

Miyake K. Nonsteroidal anti-inflammatory agents in

cataract intraocular lens surgery. Current Opinion of

Ophthalmology 1995;6(1):62–5.

Miyake 2007 {published data only}

Miyake K, Nishimura K, Harino S, Ota I, Asano S, Kondo

N, et al.The effect of topical diclofenac on choroidal

blood flow in early postoperative pseudophakias with

regard to cystoid macular edema formation. Investigative

Ophthalmology and Visual Science 2007;48(12):5647-52.

Rossetti 1996 {published data only}

Rossetti L, Bujtar E, Castoldi D, Torrazza C, Orzalesi

N. Effectiveness of diclofenac eyedrops in reducing

inflammation and the incidence of cystoid macular edema

after cataract surgery. Journal of Cataract and Refractive

Surgery 1996;22 Suppl 1:794–9.

Singal 2004 {published data only}

Singal N, Hopkins J. Pseudophakic cystoid macular edema:

ketorolac alone vs. ketorolac plus prednisolone. Canadian

Journal of Ophthalmology 2004;39(3):245–50.

Stark 1984 {published data only}

Stark Jr WJ, Maumenee AE, Fagadau W, Datiles M,

Baker CC, Worthen D, et al.Cystoid macular edema in

pseudophakia. Survey of Ophthalmology 1984;28(Suppl):

442–51.

Warren 2010 {published data only}

Warren KA, Bahrani H, Fox JE. NSAIDS in combination

therapy for the chronic pseudophakic cystoid macular

edema. Retina 2010;30(2):260-6.

Additional references

Abeysiri 2011

Abeysiri P, Wormald R, Bunce C. Prophylactic non-steroidal

anti-inflammatory agents for the prevention of cystoid

macular oedema after cataract surgery. Cochrane Database

of Systematic Reviews 2011, Issue 6. [DOI: 10.1002/

14651858.CD006683.pub2]

Desai 1993

Desai P. The National Cataract Surgery Survey: II. Clinical

outcomes. Eye 1993;7(Pt 4):489–94.

Drolsum 1995

Drolsum L, Haaskjold E. Causes of decreased visual acuity

after cataract extraction. Journal of Cataract and Refractive

Surgery 1995;21(1):59–63.

Flach 1998a

Flach AJ. The incidence, pathogenesis and treatment

of cystoid macular edema following cataract surgery.

Transactions of the American Ophthalmological Society 1998;

96:557–634.

Glanville 2006

Glanville JM, Lefebvre C, Miles JN, Camosso-Stefinovic J.

How to identify randomized controlled trials in MEDLINE:

ten years on. Journal of the Medical Library Association 2006;

94(2):130–6.

Higgins 2011

Higgins JPT, Altman DG, Sterne JAC (editors). Chapter

8: Assessing risk of bias in included studies. In: Higgins

JPT, Green S (editors). Cochrane Handbook for Systematic

Reviews of Interventions Version 5.1.0 (updated March

2011). The Cochrane Collaboration, 2011. Available from

www.cochrane-handbook.org.

Irvine 1953

Irvine SR. A newly defined vitreous syndrome following

cataract surgery. American Journal of Ophthalmology 1953;

36(5):599–619.

Rossetti 1998

Rossetti L, Chaudhari J, Dickersin K. Medical prophylaxis

and treatment of cystoid macular edema after cataract

surgery. The results of a meta-analysis. Ophthalmology

1998;105(3):397–405.

Rossetti 2000

Rossetti L, Autelitano A. Cystoid macular edema following

cataract surgery. Current Opinion in Ophthalmology 2000;

11(1):65–72.

Spaide 1993

Spaide RF, Yannuzzi LA. Cystoid macular edema after

cataract surgery. Seminars in Ophthalmology 1993;8:121–9.

References to other published versions of this review

Sivaprasad 2004

Sivaprasad S, Bunce C, Jyothi S. Non-steroidal anti-

inflammatory agents for treating cystoid macular

oedema following cataract surgery. Cochrane Database


14651858.CD004239.pub2]

Sivaprasad 2009

Sivaprasad S, Bunce C, Jyothi S. Non-steroidal anti-

inflammatory agents for treating cystoid macular

oedema following cataract surgery. Cochrane Database


14651858.CD004239.pub2]∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Burnett 1983

Methods Randomised double-masked

Participants Number randomised: 14 (6 fenoprofen sodium, 8 placebo)

Inclusion criteria: chronic aphakic CMO of four months or more with angiographic

evidence

Interventions Topical 1% fenoprofen sodium versus placebo four times daily for eight weeks

Outcomes Visual acuity at unstated time point post treatment; FFA; Iris angiography

Notes Aphakic chronic CMO

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk “Once then existence of cystoid macular oedema was

documented, the patients were randomly assigned to

treatment with either fenoprofen or placebo, methylcel-

lulose.”

Blinding (performance bias and detection

bias)

All outcomes

Low risk “The examiner was masked as to whether the patient had

fenoprofen or placebo.”

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk “Patients were willing to be placed in either the treatment

or placebo group without prior knowledge as to which

they belong”.“The examiner was masked as to whether

the patient had fenoprofen or placebo.”

Incomplete outcome data (attrition bias)

All outcomes

Low risk All participants completed the study. Table shows final

vision data for n=14 participants

Selective reporting (reporting bias) Low risk None detected

Flach 1987


Participants Number randomised: 30

Outcome on 26 patients (13 treatment, 13 placebo)

Inclusion criteria: aphakic and pseudophakic

Inclusion criteria: chronic aphakic and pseudophakic CMO of four months or more



Flach 1987 (Continued)

with angiographic evidence

Interventions Topical 0.5% ketorolac tromethamine versus placebo four times daily for eight weeks

Outcomes Visual acuity at 60 days (end of treatment) and at 90 days (one month post-treatment);

FFA

Notes Aphakic and pseudophakic eyes with chronic CMO

Risk of bias


Allocation concealment (selection bias) Low risk “.....as part of a computer-generated pre-determined ran-

domization schedule”


bias)

All outcomes

Low risk “The investigator was unaware of what treatment the

patients received and of changes in angiography patterns

or slit lamp ocular examinations.”


(performance bias)

All outcomes

Low risk “Each patient included in the study had a 60-day treat-

ment period with either ketorolac ophthalmic solution

0.5% or a vehicle of the same pH and tonicity packaged

in an identical container....”


All outcomes

Low risk “Four patients failed to complete this study...Because

these patients did not complete the two-month treat-

ment regimen they are not discussed in this study.”


Flach 1991

Methods Randomised double-masked multicentre study

Participants Number randomised: 120 (61 to active treatment, 59 to placebo)

Inclusion criteria: aphakic and pseudophakic

Inclusion criteria: chronic aphakic and pseudophakic CMO of four months or more

with angiographic evidence

Interventions Topical 0.5% ketorolac tromethamine versus placebo four times daily for twelve weeks

Outcomes Visual acuity improvement at 90 days (end of treatment) for 95 patients and at 120 days

(one month post treatment) for 87 patients

Notes Aphakic and pseudophakic eyes with chronic CMO

Risk of bias





Allocation concealment (selection bias) Low risk “Treatment was assigned by a computer-

generated, pre-determined randomisation

schedule”


bias)

All outcomes

Low risk “Visual acuity determination was the pri-

mary task of one person. This person was

unaware of the treatments, angiograms,and

details of the clinical examination.”


(performance bias)

All outcomes

Low risk “...ketorolac tromethamine 0.5% oph-

thalmic solution or placebo solution of the

same pH an tonicity packaged in identical

containers.”


All outcomes

Low risk “From this initial enrolment, 113 patients

were examined at 30 days of treatment, 106

were examined at 60 days of treatment, 95

were examined at 90 days of treatment, and

87 were examined at 120 days of treatment

after not having been treated for 30 days.”


Flach 1998

Methods Randomised double-masked crossover study

Participants Number randomised: 24, 22 followed up to 2 months

Inclusion criteria: acute aphakic CMO of four months or less with angiographic evidence

Interventions Topical 0.5% ketorolac tromethamine versus placebo four times daily for four weeks

Outcomes Visual acuity improvement at end of each treatment for each treatment period

Notes Aphakic and pseudophakic eyes with acute CMO

Risk of bias


Allocation concealment (selection bias) Low risk “...either 0.5% ketorolac ophthalmic solu-

tion or vehicle solution of the same pH and

tonicity packaged in an identical container.

....and distributed with a computer-gener-

ated pre-determined randomization sched-

ule in a double masked fashion.”





bias)

All outcomes

Low risk “All refractions were performed by the same

examiner using the same examination lane.

This investigator was unaware of the treat-

ment regimen.”


(performance bias)

All outcomes

Low risk “All refractions were performed by the same

examiner using the same examination lane.

This investigator was unaware of the treat-

ment regimen. Furthermore, this examiner

was unaware of results of fluorescein an-

giograms and slit-lamp observations.”


All outcomes

Low risk “From the group of patients enrolled dur-

ing the 18-month period, 22 patients com-

pleted the 2-month study. The 2 patients

eliminated from the study during the first

10 days consisted of 1 drug-treated patient

(lost medication) and 1 vehicle-treated pa-

tient (moved to a different state). These pa-

tients are not included in this report.”


Heier 2000


Participants Number randomised: 28, 26 completed the study

Inclusion criteria: acute aphakic CMO of four months or less with angiographic evidence

Interventions One drop topical 0.5% ketorolac tromethamine & artificial tears versus prednisolone

acetate & artificial tears versus combination (no tears) four times daily for a maximum

of twelve weeks. Treatment tapered earlier if CMO resolved

Outcomes Visual acuity at one month post treatment; Contrast sensitivity; FFA

Notes Aphakic and pseudophakic eyes with acute CMO

Risk of bias


Allocation concealment (selection bias) Low risk “The randomisation was performed by the pharmacy

that supplied by the premasked medication.”


bias)

Low risk “Two retinal specialists read all fluorescein angiograms

in a masked fashion.”



Heier 2000 (Continued)

All outcomes


(performance bias)

All outcomes

Low risk “The study medication were masked to both patients and

examiners.”


All outcomes

Low risk “Twenty-eight patients were enrolled in the study.

Twenty six completed the study.”


Rho 2003

Methods Randomised, unmasked

Participants Number randomised: 34

Inclusion criteria: pseudophakic cystoid macular oedema of less than 4 months confirmed

by fluorescein angiography

Interventions Topical 0.5% ketorolac tromethamine versus topical 0.1% diclofenac sodium 1 drop 4

times daily

Outcomes Visual acuity post treatment; time to reduce CMO

Notes Pseudophakic eyes with acute CMO

Risk of bias


Allocation concealment (selection bias) Unclear risk “Patients were randomized to receive 1 drop 4 times a day....

.”


bias)

All outcomes

Unclear risk No statement found as to masking of examiners


(performance bias)

All outcomes

Unclear risk No statement found as to masking of participants or person-

nel


All outcomes

Low risk “All patients were followed for 26 weeks....Data of all patients

presenting with CME......were included for analysis.”




Yannuzzi 1977


Participants Number randomised: 20 (23 eyes). 10 eyes in indomethacin, 13 on placebo

Inclusion criteria: chronic aphakic CMO of four months or more with angiographic

evidence

Interventions Oral indomethacin 25 mg vs placebo three times a day for six weeks

Outcomes Visual acuity at 42 days (end of treatment) and 70 days (one month post treatment)

Notes Aphakic chronic CMO

Risk of bias


Allocation concealment (selection bias) Unclear risk “Twenty patients with reduced vision and clinical and

fluorescein angiographic evidence of cystoid macular

edema four months or more after cataract surgery were

randomly assigned to the indomethacin or the placebo

group.”


bias)

All outcomes

Unclear risk No statement for the masking of personnel


(performance bias)

All outcomes

Unclear risk “Informed consent was obtained from each patient; the

dangers and limitations of therapy as well as the possibil-

ity that a placebo might be used were explained carefully.

” No statement for the masking of personnel


All outcomes

Low risk “Ten eyes of ten patients were in the indomethacin group;

13 eyes in ten patients were in the placebo group.”


CME:CMO: cystoid macular oedema

FFA: fundus fluorescein angiography

vs: versus



Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Ahluwalia 1988 Prophylactic use of NSAIDs in CMO

Asano 2008 Prophylactic use of NSAIDs and steroids in CMO

Azzolini 1986 Prophylactic use of NSAIDs in CMO

IDSG 1997 Prophylaxis of CMO using NSAIDs

Jampol 1994 Review article

Kraff 1985 Prophylactic use of NSAIDs in CMO

Mathys 2010 Prophylactic use of NSAIDs in CMO

Miyake 1995 Review article. No RCT on treatment of CMO with NSAIDs

Miyake 2007 Prophylactic use of NSAIDs and steroids in CMO

Rossetti 1996 Prophylactic use of NSAIDs in CMO

Singal 2004 The efficacy of steroids in the treatment of CMO is compared on 2 groups of patients on ketorolac

Stark 1984 Prophylactic use of NSAIDs in CMO

Warren 2010 The efficacy of NSAIDS in the treatment of CMO in patients who have had previous treatment (intravitreal

triamcinolone and bevacizumab)

CMO: cystoid macular oedema

NSAIDS: non-steroidal anti-inflammatory drugs



D A T A A N D A N A L Y S E S

Comparison 1. NSAID versus placebo in chronic CMO

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Visual acuity improvement at

end of treatment

4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

2 Visual acuity improvement one

month post treatment

3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

Analysis 1.1. Comparison 1 NSAID versus placebo in chronic CMO, Outcome 1 Visual acuity improvement

at end of treatment.

Review: Non-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery

Comparison: 1 NSAID versus placebo in chronic CMO

Outcome: 1 Visual acuity improvement at end of treatment

Study or subgroup NSAID Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Flach 1987 8/13 1/13 8.00 [ 1.16, 55.20 ]

Flach 1991 22/46 10/49 2.34 [ 1.25, 4.40 ]

Yannuzzi 1977 1/10 3/10 0.33 [ 0.04, 2.69 ]

Burnett 1983 3/6 3/8 1.33 [ 0.40, 4.43 ]

Subtotal (95% CI) 0 0 0.0 [ 0.0, 0.0 ]

Total events: 34 (NSAID), 17 (Placebo)

Heterogeneity: Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%

Test for overall effect: Z = 0.0 (P < 0.00001)

Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours placebo Favours NSAID



Analysis 1.2. Comparison 1 NSAID versus placebo in chronic CMO, Outcome 2 Visual acuity improvement

one month post treatment.

Review: Non-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery

Comparison: 1 NSAID versus placebo in chronic CMO

Outcome: 2 Visual acuity improvement one month post treatment

Study or subgroup NSAID placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Flach 1987 5/13 2/13 2.50 [ 0.59, 10.64 ]

Flach 1991 21/41 7/46 3.37 [ 1.60, 7.09 ]

Yannuzzi 1977 2/10 4/10 0.50 [ 0.12, 2.14 ]

Subtotal (95% CI) 0 0 0.0 [ 0.0, 0.0 ]

Total events: 28 (NSAID), 13 (placebo)

Heterogeneity: Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%

Test for overall effect: Z = 0.0 (P < 0.00001)

0.1 0.2 0.5 1 2 5 10

Favours placebo Favours NSAID

A D D I T I O N A L T A B L E S

Table 1. VA improvement at end of treatment period (pd) acute CMO. Flach 1998

Treatment (pd 1) Placebo (pd 1) Treatment (pd 2) Placebo (pd2)

4/11 2/11 3/11 2/11

Table 2. VA improvement one month post treatment acute CMO. Heier 2000

Ketorolac Prednisolone Ketoroloc + Prednisolone

6/9 4/8 8/9



A P P E N D I C E S

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor Macular Edema, Cystoid

#2 (macula*) and (edema or oedema)

#3 (cme or cmo)

#4 (#1 OR #2 OR #3)

#5 MeSH descriptor Anti-Inflammatory Agents, Non-Steroidal

#6 nsaid*

#7 nonsteroidal anti-inflammator*

#8 non-steroidal anti-inflammator*

#9 MeSH descriptor Diclofenac

#10 diclofenac* OR fenoprofen* OR flurbiprofen*

#11 MeSH descriptor Indomethacin

#12 indometacin*

#13 MeSH descriptor Ketoprofen

#14 ketoprofen*

#15 piroxicam*

#16 (#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15)

Appendix 2. MEDLINE 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 macular edema cystoid/

14. exp macula lutea/

15. (macula$ adj3 oedema).tw.

16. (macula$ adj3 edema).tw.

17. (CME or CMO).tw.

18. or/13-17

19. exp anti inflammatory agents non steroidal/

20. nsaid$.tw.

21. nonsteroidal anti-inflammator$.tw.

22. non-steroidal anti-inflammator$.tw.

23. exp diclofenac/

24. diclofenac$.tw.

25. fenoprofen$.tw.

26. flurbiprofen$.tw.

27. exp indometacin/

28. indometacin$.tw.

29. exp ketoprofen/

30. ketoprofen$.tw.



31. piroxicam$.tw.

32. or/19-31

33. 18 and 32

34. 12 and 33

The search filter for trials at the beginning of the strategy is from the published paper by Glanville et al (Glanville 2006).

Appendix 3. EMBASE 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 propspectiv$ 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 retina macula cystoid edema/

34. exp eye edema/

35. exp retina macula lutea/

36. (macula$ adj3 oedema).tw.

37. (macula$ adj3 edema).tw.

38. (CME or CMO).tw.

39. or/33-38

40. exp nonsteroidal antiinflammatory agent/

41. nsaid$.tw.

42. nonsteroidal anti-inflammator$.tw.

43. non-steroidal anti-inflammator$.tw.

44. exp diclofenac/



45. diclofenac$.tw.

46. fenoprofen$.tw.

47. flurbiprofen$.tw.

48. exp indometacin/

49. indometacin$.tw.

50. exp ketoprofen/

51. ketoprofen$.tw.

52. exp piroxicam/

53. piroxicam$.tw.

54. or/40-53

55. 39 and 54

56. 32 and 55

Appendix 4. LILACS search strategy

cystoid macula$ or cmo or cme and nsaid$

Appendix 5. metaRegister of Controlled Trials search strategy

cystoid macular oedema

Appendix 6. ClinicalTrials.gov search strategy

Cystoid Macular Oedema AND NSAID

W H A T ’ S N E W

Last assessed as up-to-date: 5 August 2011.

Date Event Description

9 January 2012 New search has been performed Issue 2 2012: Update searches yielded no new studies for

inclusion in the review

9 January 2012 New citation required but conclusions have not changed A new co-author has joined the review team. The review

has been amended to include new Cochrane method-

ology including completion of risk of bias tables for all

included studies



H I S T O R Y

Protocol first published: Issue 2, 2003

Review first published: Issue 1, 2005

Date Event Description

4 November 2008 New search has been performed Issue 1 2009: Updated searches yielded no new trials.

21 August 2008 Amended Converted to new review format.

C O N T R I B U T I O N S O F A U T H O R S

SS came up with the review question,co-ordinated the review, wrote to authors of papers for more information, obtained and screened

data on unpublished studies, collected data and wrote the review.

SS and Nishal Patel screened search results, appraised quality of papers and managed data.

SS, CB and Nishal Patel abstracted data from papers, entered data into RevMan.

SS and CB analysed and interpreted data.

SS and Sreedhar Jyoti updated the first two updates.

SS, RC-N and CB updated the 2012 version.

SS and RC-N screened search results, appraised quality of papers and extracted data.

SS, RC-N and CB entered data into RevMan.

SS and CB analysed and interpreted data.

D E C L A R A T I O N S O F I N T E R E S T

SS has received travel grants, research grants and sat on advisory boards of Pfizer, Novartis, Allergan, Alimera and Bayer.

S O U R C E S O F S U P P O R T

Internal sources

• NIHR, UK.

Catey Bunce acknowledges financial support 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. The views expressed in this publication are those of the authors and not necessarily those of the

Department of Health.



External sources

• No sources of support supplied

I N D E X T E R M S

Medical Subject Headings (MeSH)

Acute Disease; Anti-Inflammatory Agents, Non-Steroidal [∗therapeutic use]; Cataract Extraction [∗adverse effects]; Chronic Disease;

Fenoprofen [therapeutic use]; Indomethacin [therapeutic use]; Ketorolac [therapeutic use]; Macular Edema [∗drug therapy; etiology];

Randomized Controlled Trials as Topic

MeSH check words

Humans



cochrane database of systematic reviews (reviews) || non-steroidal anti-inflammatory agents for...

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