429

ARTICLE

European multicenter trial of the

prevention of cystoid macular edema after
cataract surgery in nondiabetics:
ESCRS PREMED study report 1
Laura H.P. Wielders, MD, Jan S.A.G. Schouten, MD, PhD, Bjorn Winkens, PhD,
Frank J.H.M. van den Biggelaar, PhD, Claudette A. Veldhuizen, MD, Oliver Findl, MD, PhD,
Joaquim C.N. Murta, MD, PhD, Willem R.O. Goslings, MD, PhD, Marie-Jos
e Tassignon, MD, PhD,
Maurits V. Joosse, MD, PhD, Ype P. Henry, MD, Alexander H.F. Rulo, MD, Jos
e L. G€
uell, MD, PhD,
Michael Amon, MD, PhD, Thomas Kohnen, MD, PhD, Rudy M.M.A. Nuijts, MD, PhD,
on behalf of the ESCRS PREMED Study Group

Purpose: To compare the efficacy of a topical nonsteroidal antiin- and clinically significant macular edema (CSME) within 6 weeks
flammatory drug, topical corticosteroid, and a combination of both and 12 weeks postoperatively.
drugs to prevent the occurrence of cystoid macular edema (CME)
after cataract surgery in nondiabetic patients. Results: This study comprised 914 patients. Six weeks postoper-
atively, the central subfield mean macular thickness was 288.3 mm,
Setting: Twelve European study centers. 296.0 mm, and 284.5 mm in the bromfenac group, dexamethasone
group, and combination treatment group, respectively (overall
Design: Randomized clinical trial. P Z .006). The incidence of clinically significant macular edema
within 12 weeks postoperatively was 3.6%, 5.1%, and 1.5%,
Methods: Nondiabetic patients having uneventful cataract sur- respectively (overall P Z .043).
gery were included in this study. Patients were randomized to
receive topical bromfenac 0.09% twice daily for 2 weeks or dexa- Conclusion: Patients treated with a combination of topical brom-
methasone 0.1% 4 times daily with 1 drop less per day every fenac 0.09% and dexamethasone 0.1% had a lower risk for devel-
following week, or a combination of both. The primary outcome oping CSME after cataract surgery than patients treated with a
was the difference in central subfield mean macular thickness single drug.
6 weeks postoperatively. Secondary outcome measures included J Cataract Refract Surg 2018; 44:429–439 Q 2018 ASCRS and ESCRS
corrected distance visual acuity as well as the incidence of CME Supplemental material available at www.jcrsjournal.org.

with mild to severe visual impairment and is considered

W
orldwide, cataract is the leading cause of pre-
one of the most cost-effective of all healthcare interven-
ventable and treatable blindness.1 Cataract sur-
tions.2 Even though improvements in modern cataract
gery can improve visual acuity in many patients

Submitted: December 3, 2017 | Final revision submitted: January 19, 2018 | Accepted: January 19, 2018
From University Eye Clinic Maastricht UMCC (Wielders, Schouten, van den Biggelaar, Veldhuizen, Nuijts), Maastricht University Medical CenterC, and Maastricht
University (Winkens), Care and Public Health Research Institute (CAPHRI), Department of Methodology & Statistics, Maastricht, Zuyderland Medical Center (Wielders,
Schouten, Nuijts), Department of Ophthalmology, Heerlen, Elisabeth-TweeSteden Hospital (Goslings), Department of Ophthalmology, Tilburg, Haaglanden Medical
Center (Joosse), Department of Ophthalmology, The Hague, VU University Medical Center (Henry), Department of Ophthalmology, Amsterdam, and Eye Hospital
Zonnestraal (Rulo), Hilversum, the Netherlands; Vienna Institute for Research in Ocular Surgery (Findl), Hanusch Hospital, Vienna, Austria; Centro Hospitalar

rio Coimbra (Murta), Department of Ophthalmology, and Association for Innovation and Biomedical Research on Light (AIBILI), Coimbra, Portugal; Antwerp
Universita
€ell), Barcelona, Spain;
University Hospital and University of Antwerp (Tassignon), Department of Ophthalmology, Antwerp, Belgium; Instituto Microcirugia Ocular (Gu
Hospital of the Brothers of St. John of God (Amon), Department of Ophthalmology, Vienna, Austria; Goethe University (Kohnen), Department of Ophthalmology,
Frankfurt am Main, Germany.
Supported by the European Society of Cataract and Refractive Surgeons (ESCRS), Blackrock, Co Dublin, Ireland. The ESCRS was not involved in any part of the study
design, data analysis, and interpretation; writing of the report; or the decision to submit the article for publication. Bausch & Lomb France SAS supplied the Yellox
eyedrops free of charge.
Presented at the XXXV Congress of the European Society of Cataract and Refractive Surgeons, Lisbon, Portugal, October 2017.
Corresponding author: Laura H.P. Wielders, MD, University Eye Clinic Maastricht UMC, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, the
Netherlands. Email: [email protected].

Q 2018 ASCRS and ESCRS 0886-3350/$ - see frontmatter

Published by Elsevier Inc. https://doi.org/10.1016/j.jcrs.2018.01.029
430 ESCRS PREMED STUDY REPORT 1

surgery techniques have significantly decreased the inci- tenets of the Declaration of Helsinki. The study protocol can be
dence of postoperative complications, cystoid macular found on the U.S. National Institutes of Health Clinical Trials
site.A A data safety monitoring board (members reported in
edema (CME) remains one of the most important causes Appendix S1, available at http://jcrsjournal.org) evaluated the
of suboptimum visual acuity after otherwise uneventful safety of trial participants.
surgery.3,4
Cystoid macular edema after cataract surgery, also known Patient Enrolment
as the Irvine-Gass syndrome, was first reported by Irvine in Patient recruitment started in Maastricht, the Netherlands, in July
19535 and discussed by Gass and Norton in 1966.6 Since 2013. Final inclusion took place at study centers in the
then, ophthalmologists have aimed to prevent CME using Netherlands after a decision was made to stop recruitment on
perioperative topical corticosteroids and/or nonsteroidal anti- February 8, 2016. The trial included nondiabetic patients 21 years
inflammatory drugs (NSAIDs), albeit current practice varies or older who required regular phacoemulsification cataract sur-
gery in at least 1 eye. Patients were included in 1 of 12 study centers
between organizations and countries.3,7 As yet, the optimum involved in the ESCRS PREMED study located in Austria (Hospi-
approach in routine cataract surgery cases remains debatable tal of the Brothers of St. John of God and Vienna Institute for
because of the high societal costs involved with routine pre- Research in Ocular Surgery, Vienna), Belgium (Antwerp Univer-
scription of topical NSAIDs in some countries, such as the sity Hospital, Antwerp), Germany (Goethe University Hospital,
United States of America.8 An Ophthalmic Technology Frankfurt am Main), Portugal (Centro Hospitalar Universit
ario
Coimbra, Coimbra), Spain (Institute of Ocular Microsurgery, Bar-
Assessment of the American Academy of Ophthalmology3 celona), and the Netherlands (VU University Medical Center,
does not support the use of topical NSAIDs because of insuf- Amsterdam; Zuyderland Medical Center, Heerlen; Eye Hospital
ficient high-quality evidence with regard to its long-term Zonnestraal, Hilversum; University Eye Clinic Maastricht UMC,
benefit to prevent vision loss from CME 3 months or more af- Maastricht; Haaglanden Medical Center, The Hague; and
ter cataract surgery. The Cataract Clinical Committee of the Elisabeth-TweeSteden Hospital, Tilburg). All patients signed writ-
ten informed consent before inclusion.
American Society of Cataract and Refractive Surgery, on the Only 1 eye per patient was included in the study, and patients
other hand, recently published a report on topical NSAIDs were excluded if they had sustained moderate to severe visual
as an important adjunctive tool for surgeons performing impairment in the other eye according to the definition of the In-
routine and complicated cataract surgery and emphasized ternational Statistical Classification of Diseases and Related
the compelling effectiveness of NSAIDs to reduce pain, pre- Health Problems 10th revision.13 Patients were excluded if they
had previous CME, any macular pathology that could influence vi-
vent intraoperative miosis, modulate postoperative inflamma- sual acuity, previous intraocular inflammation or uveitis, retinal
tion, and reduce the incidence of CME.7 Two recent vein occlusion, posttraumatic cataract, progressive glaucoma,
systematic reviews of the Cochrane Collaboration and 2 inde- intraocular pressure (IOP) of 25 mm Hg or higher, previous
pendent European metaanalyses suggest that topical NSAIDs steroid-induced IOP elevation, pseudoexfoliation syndrome, or
reduce the risk for developing CME after cataract surgery, Fuchs endothelial dystrophy in the study eye. Furthermore, pa-
tients were excluded if they had intraocular surgery in the study
although none of them found a clinically relevant effect on eye. Patients who used topical NSAIDs, corticosteroids, antiglau-
mean visual acuity.9–12 comatous medication, or high-dose systemic corticosteroids at
To further investigate this important clinical question, the time of screening were excluded, as were patients who received
many ophthalmologists have studied the efficacy of various
NSAIDs and corticosteroids to prevent CME after cataract
surgery. Most studies compared the efficacy of topical
NSAIDs or combination treatment versus corticosteroids
alone; however, few studies directly compared the efficacy
of combination treatment versus topical NSAIDs.9 More-
over, the low a priori incidence of CME demands large sam-
ples to detect small, yet clinically important, differences.
The PREvention of Macular EDema after cataract sur-
gery (PREMED) study was a randomized controlled clinical
multicenter trial designed to directly compare the efficacy
of a topical NSAID, a topical corticosteroid, and the combi-
nation of both in nondiabetic patients. The study was
funded by the European Society of Cataract and Refractive
Surgeons (ESCRS). The aim of the ESCRS PREMED study
was to provide evidence-based recommendations that
could serve as a basis for clinical guidelines on the preven-
tion of CME after cataract surgery.
Figure 1. The ETDRS retinal thickness map. A: Mean central subfield
macular thickness in the central 1.0 mm area. B: Parafoveal thick-
PATIENTS AND METHODS ness in a concentric ring located 1.0 to 3.0 mm around the fovea.
The ESCRS PREMED study was a randomized controlled trial C: Perifoveal thickness in a concentric ring located 3.0 to 6.0 mm
(RCT). The study protocol was approved by the local ethics com- around the fovea. A to C: Total macular volume is calculated for
mittees and national authorities of all participating study centers. the central 6.0 mm area (ETDRS Z Early Treatment Diabetic Reti-
The study procedures were performed in accordance with the nopathy Study).

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 ESCRS PREMED STUDY REPORT 1 431

Figure 2. Consort flow diagram

showing the number of partici-
pants who were screened, ran-
domized, and analyzed.

an intravitreal injection of bevacizumab or ranibizumab in the and 2 weeks postoperatively. Patients in the dexamethasone group
study eye in the previous 6 weeks, an intravitreal injection of afli- received dexamethasone disodium phosphate 0.1% eyedrops 4
bercept in the previous 10 weeks, or an intraocular or periocular times daily for 2 days preoperatively and 1 week postoperatively,
corticosteroid injection in the previous 4 months. Finally, patients with 1 drop less per day every following week. Patients in the com-
were excluded if there was a contraindication to the use of any bination treatment group received topical bromfenac and dexa-
investigation drug. methasone in the above-mentioned doses. Topical treatments
started 2 days before cataract surgery because previous studies14,15
found a lower incidence of CME in patients who started antiin-
Surgical Technique, Patient Allocation, and Treatment flammatory treatment preoperatively. No other ocular corticoste-
All patients had regular phacoemulsification cataract surgery with roids or NSAIDs were allowed to be used during the course of the
intraocular lens (IOL) implantation in the posterior segment and study.
received perioperative and/or postoperative antibiotics according
to the standard of care in the participating study center.
Patients were randomly allocated to 1 of 3 treatment groups in a Outcomes Assessment
1:1:1 ratio. Stratified block randomization was performed per study An extensive ophthalmologic examination, including slitlamp
center by a local investigator using concealed online softwareB evaluation, IOP measurement, and fundoscopy of both eyes, was
(ALEA, version 3.0, Formsvision BV) and a block size of 15 pa- performed at baseline. Cataract was graded according to the
tients. Trial participants were unblinded for the allocated treat- Lens Opacities Classification System II,16 and the presence of
ment. Patients in the bromfenac group received bromfenac aqueous cells and flare was graded according to the Standardiza-
0.09% eyedrops (Yellox) twice daily for 2 days preoperatively tion of Uveitis Nomenclature (SUN) classification.17 Subjective

Table 1. Main baseline characteristics.

Overall Bromfenac Dexamethasone Combination
Parameter (N Z 914) (n Z 307) (n Z 304) (n Z 303)
Mean age (y) G SD 70.45 G 8.87 69.70 G 8.94 71.23 G 8.73 70.41 G 8.91
Right eye, n (%) 504/914 (55.1) 182/307 (59.3) 157/304 (51.6) 165/303 (54.5)
Female sex, n (%) 478/914 (52.3) 166/307 (54.1) 163/304 (53.6) 149/303 (49.2)
White race, n (%) 897/914 (98.1) 300/307 (97.7) 301/304 (99.0) 296/303 (97.7)
CME in contralateral eye, n (%) 4/912 (0.4) 0/307 (0.0) 3/302 (1.0) 1/303 (0.3)
Previous anti-VEGF, n (%) 2/909 (0.2) 0/306 (0.0) 1/300 (0.3) 1/303 (0.3)
Type of cataract, n (%)
Nuclear 777/903 (86.0) 267/304 (87.8) 260/299 (87.0) 250/300 (83.3)
Cortical 610/903 (67.6) 211/304 (69.4) 203/299 (67.9) 196/300 (65.3)
Subcapsular 199/903 (22.0) 72/304 (23.7) 61/299 (20.4) 66/300 (22.0)

CME Z cystoid macular edema; VEGF Z vascular endothelial growth factor

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432 ESCRS PREMED STUDY REPORT 1

Table 2. Differences in macular thickness, TMV, and CDVA (intention-to-treat analysis).

Mean ± SD (Patients)

Parameter Bromfenac Dexamethasone Combination

CSMT (mm)
Baseline 274.18 G 25.48 (294) 275.18 G 27.16 (293) 273.20 G 24.67 (298)
6 wk 288.28 G 46.78 (270) 296.04 G 52.46 (265) 284.51 G 36.40 (267)
12 wk 283.30 G 28.03 (264) 283.96 G 28.64 (263) 283.30 G 27.38 (262)
Parafoveal thickness (mm)
Baseline 325.17 G 19.53 (295) 326.44 G 20.47 (298) 326.84 G 21.75 (298)
6 wk 336.50 G 26.95 (270) 342.40 G 25.43 (266) 337.54 G 21.89 (267)
12 wk 334.32 G 21.60 (265) 336.87 G 21.10 (263) 336.40 G 21.33 (263)
Perifoveal thickness (mm)
Baseline 282.31 G 16.45 (280) 282.48 G 17.22 (288) 282.44 G 18.07 (285)
6 wk 290.79 G 21.77 (258) 294.85 G 18.13 (254) 291.19 G 18.44 (257)
12 wk 288.57 G 17.48 (256) 291.11 G 17.73 (254) 291.02 G 17.19 (255)
TMV (mm3)
Baseline 8.29 G 0.53 (278) 8.29 G 0.53 (282) 8.28 G 0.51 (277)
6 wk 8.52 G 0.70 (256) 8.67 G 0.58 (249) 8.51 G 0.61 (256)
12 wk 8.47 G 0.58 (256) 8.55 G 0.55 (250) 8.51 G 0.60 (255)
CDVA (logMAR)
Baseline 0.29 G 0.23 (299) 0.29 G 0.21 (298) 0.29 G 0.22 (300)
6 wk 0.01 G 0.12 (276) 0.02 G 0.14 (274) 0.01 G 0.12 (274)
12 wk 0.02 G 0.10 (270) 0.01 G 0.11 (267) 0.01 G 0.11 (271)
CDVA Z corrected distance visual acuity; CI Z confidence interval; CSMT Z central subfield mean macular thickness; logMAR Z logarithm of the minimal
angle of resolution; TMV Z total macular volume
*Treatment effect after correction for center, sex, age, and cystoid macular edema in the fellow eye
†
Overall effect at that timepoint over all 3 groups

refraction and corrected distance visual acuity (CDVA) were Therefore, the primary outcome of this study was the difference in
measured using Early Treatment Diabetic Retinopathy Study central subfield mean macular thickness 6 weeks postoperatively
(ETDRS) charts. If patients were unable to read any letter on the compared with the baseline value. Secondary outcomes were the
ETDRS chart, hand motion or finger counting at a given distance difference in central subfield mean macular thickness 12 weeks
were converted to the logarithm of the minimum angle of resolu- postoperatively, the incidence of CME and clinically significant
tion (logMAR) equivalent.18 macular edema (CSME) within 6 to 12 weeks postoperatively,
A baseline optical coherence tomography (OCT) was per- and CDVA, total macular volume, and parafoveal and perifoveal
formed within 3 months preoperatively using spectral-domain thickness 6 weeks and 12 weeks postoperatively. Furthermore,
OCT (SD-OCT) devices (3D OCT, Topcon Corp.; Cirrus HD- all adverse events were reported.
OCT, Carl Zeiss Meditec AG; OCT-HS100, Canon, Inc.; Cystoid macular edema was defined as an increase in central
RTVue-100 Optovue, Inc.; or Spectralis, Heidelberg Engineering, subfield mean macular thickness of 10% or more over baseline,
Inc.). Each study center used only 1 type of SD-OCT device for with cystic changes on SD-OCT. Cystoid changes and other retinal
all preoperative and postoperative measurements. Retinal thick- pathology were identified by 2 independent and masked retina
ness was measured in accordance with the ETDRS retinal thick- specialists of the University Eye Clinic Maastricht UMC
ness map (Figure 1), which includes the central subfield mean (Appendix S1, available at http://jcrsjournal.org). CSME was
macular thickness in the central 1.0 mm area, parafoveal thickness defined as CME with less than a 0.2 logMAR CDVA
in a concentric ring located 1.0 to 3.0 mm around the fovea, peri- improvement compared with the preoperative baseline.
foveal thickness in a concentric ring located 3.0 to 6.0 mm around
the fovea, and total macular volume in the central 6.0 mm area.19 If
the preoperative OCT was of insufficient quality (eg, because of
dense cataract), an alternative baseline measurement was per-
formed at 1 day postoperatively because previous studies have Escape Treatment
shown no significant differences between preoperative and 1-day Small studies have shown that a combination of topical corticoste-
postoperative retinal thickness measurements.20 roids and NSAIDs is more effective than single-drug treatment in
Postoperative visits were performed 6 weeks and 12 weeks post- patients with acute CSME after cataract surgery.22 Patients who
operatively and included a full ophthalmologic examination of the developed CSME during the course of this study were therefore
study eye, as reported above. Postoperative CDVA measurements treated with bromfenac 0.09% eyedrops twice daily and dexameth-
and SD-OCT assessments were performed by a local investigator asone 0.1% eyedrops 4 times daily for 4 weeks. If CSME resolved
who was masked to the allocated study treatment. within these 4 weeks, bromfenac was stopped and dexamethasone
eyedrops were reduced with 1 drop per day every following week.
If CSME persisted after 4 weeks of topical treatment, patients
Study Outcomes received 1 intravitreal injection of 0.05 mL (1.25 mg) bevacizumab.
Cystoid macular edema usually occurs within 3 months postoper- From 12 weeks postoperatively, CSME was treated in accordance
atively, with a peak incidence 4 to 6 weeks after cataract surgery.21 with the standard of care at each participating study center.

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 ESCRS PREMED STUDY REPORT 1 433

Table 2. (Cont.)
Treatment Effect* (95% CI); P Value

Overall Dexamethasone Bromfenac Vs Dexamethasone Vs

Parameter P Value† Vs Bromfenac Combination Combination
CSMT (mm)
Baseline
6 wk .006 6.91 (0.81, 13.01); .026 2.72 ( 3.36, 8.80); .380 9.63 (3.52, 15.74); .002
12 wk .299 1.47 ( 0.67, 3.61); .178 1.46 ( 3.60, 0.67); .178 0.004 ( 2.13, 2.14); .997
Parafoveal thickness (mm)
Baseline
6 wk .002 3.72 (1.08, 6.35); .006 0.86 ( 1.77, 3.49); 0.520 4.58 (1.94, 7.21); .001
12 wk .136 1.80 ( 0.02, 3.61); .053 0.52 ( 2.34, 1.30); .574 1.28 ( 0.54, 3.09); .167
Perifoveal thickness (mm)
Baseline
6 wk .012 2.63 (0.58, 4.67); .012 0.15 ( 1.89, 2.19); 0.883 2.78 (0.73, 4.82); .008
12 wk .008 2.11 (0.69, 3.53); .004 1.78 ( 3.19, 0.36); .014 0.33 ( 1.08, 1.75); .645
TMV (mm3)
Baseline
6 wk !.001 0.12 (0.07, 0.18); !.001 0.01 ( 0.06, 0.05); 0.763 0.12 (0.06, 0.17); !.001
12 wk .002 0.07 (0.03, 0.11); .001 0.04 ( 0.08, 0.001); .045 0.03 ( 0.01, 0.07); .139
CDVA (logMAR)
Baseline
6 wk .327 0.01 ( 0.01, 0.03); 0.186 0.001 ( 0.02, 0.02); .953 0.01 ( 0.01, 0.03); .206
12 wk .309 0.01 ( 0.004; 0.03); 0.128 0.01 ( 0.02, 0.01); .546 0.01 ( 0.01, 0.03); .355

Moreover, a stepwise treatment approach was used if patients trauma. Other perioperative complications, such as intraoperative
developed severe postoperative inflammation, defined as at least floppy-iris syndrome without iris trauma, IOL damage, and
2C cells according to the SUN classification. corneal erosions, were thought not to influence the risk for devel-
oping CME. These cases were not excluded from the final analyses.
Sample Size Categorical data were presented as number of patients (and per-
centage) and numerical data as means G SD. Differences between
The sample-size calculation for this study was based on the pri-
treatment groups in the occurrence of perioperative complica-
mary outcomedthe difference in central subfield mean macular
tions, adverse events, dropout, and reasons for dropout between
thickness at 6 weeks postoperatively. Sample size was recalculated,
treatment groups in were assessed using the chi-square test or
masked for treatment allocation, based on overall nuisance param-
Fisher exact test, where appropriate.
eters obtained from the first 159 patients included in the study;
Postoperative data analyses were performed with masking for
that is, a standard deviation (SD) of a postoperative central sub-
the treatment groups. Because of the Bonferroni adjustment for
field mean macular thickness of 42.25 mm and a correlation be-
multiple testing, a P value less than 0.0167 was considered statis-
tween the mean preoperative and postoperative central subfield
tically significant. Linear mixed-model analyses using restricted
macular thickness of 0.62. With a total sample size of 741, a
maximum likelihood were used for numerical outcomes that
mean difference of 10 mm between treatment groups could be de-
were measured repeatedly, including the primary outcome of the
tected with 80% power at a Bonferroni-corrected significance level
study. Linear mixed models account for the correlation between
of 0.0167, where 40 patients were added to correct for center, cen-
repeated measurements within a patient and also include data
ter with treatment interactions, and other covariates. To compen-
from patients who dropped out of the study. No data were
sate for a maximum dropout rate of 20%, the total calculated
imputed. A likelihood-based approach was used for missing
sample size for this study was 926 patients.
outcome data, including SD-OCT data, for which data were
assumed to be missing at random. No missing data were expected
Statistical Analysis for the fixed factors included in the model, such as study center,
No interim analyses were performed during the course of the timing of study visits, and the interaction term treatment
study. Data were collected in a web-based database (Macro, group  timing of the study visit. Logistic regression analysis
version 4.4C) and were subsequently exported to SPSS Statistics was used to check whether missing outcome data were signifi-
for Windows software (version 23.0, IBM Corp.) for analysis. cantly related to certain patient characteristics. Variables signifi-
Generalized logistic mixed-model analyses were performed using cantly related to missing outcome data were added to the model
the GLMER function within RD (version 3.3.1, The R Foundation to ensure missing at random. In addition, baseline patient charac-
for Statistical Computing). teristics that are known to be related to the primary outcome, such
Data were excluded from the final analyses if patients developed as sex, age, and the presence of CME in the fellow eye, were
a perioperative complication that was expected to increase the risk included, while the model without these patient characteristics
for developing CME.4,23 These included patients with a posterior was used as a sensitivity analysis.4,23 A second sensitivity analysis
capsule rupture with or without vitreous loss, zonulysis, or iris was performed with study center included as a random instead of a

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434 ESCRS PREMED STUDY REPORT 1

fixed factor. A 3-way interaction term treatment group  timing

of the study visit  study center (plus their 2-way interaction
terms) was applied to verify whether treatment effect depended
significantly on study center. If this 3-way interaction term proved
significant, the treatment effect was reported for each center sepa-
rately. If the 3-way interaction term was not significant, it was
removed from the model and only the overall treatment effect
over all centers was reported.
Generalized logistic mixed-model analyses were used for binary
outcomes, in which a random intercept on center level was
included to account for the nesting of patients within a center.
Adaptive Gauss-Hermite approximation (10 quadrate points) Figure 3. Observed mean central subfield macular thickness with
was used for estimating the log-likelihood. Odds ratios (ORs) 95% CIs (CIs Z confidence intervals) (CSMT Z central subfield
and 95% confidence intervals (CIs) were reported for pairwise macular thickness).
comparisons.
Because the sample size within a center might be small, the
above-mentioned analyses were also performed after combining was dropped from the study when CSME was diagnosed;
study centers based on location and center type (ie, academic cen- however, primary outcome data were available. One patient
ters in the Netherlands, nonacademic centers in the Netherlands, in the dexamethasone group discontinued participation af-
other West European centers, Central European centers, and ter developing lymphatic metastases of a preexisting rectal
South European centers). This was included as a sensitivity
carcinoma, and another patient died after developing a ce-
analysis.
Finally, per-protocol analyses were performed and compared rebrovascular infarction. No patient in the combination
with the intention-to-treat analyses. Data were excluded from treatment group dropped out because of adverse events.
the per-protocol analyses if deviations from the allocated treat-
ment intervention occurred (eg, patients who received additional Macular Thickness and Volume
NSAID or corticosteroid eyedrops).
Patients treated with a combination of bromfenac and
dexamethasone eyedrops had the lowest postoperative
RESULTS macular thickness after correction for baseline measure-
Population ments. (Table 2 and Figure 3). Six weeks postoperatively,
Figure 2 shows a flow diagram showing the number of par- the mean central subfield macular thickness was
ticipants who were screened, randomized, and analyzed in 288.3 mm, 296.0 mm, and 284.5 mm in the bromfenac group,
the study. Baseline characteristics of the participants are dexamethasone group, and combination treatment group,
shown in Table 1 and Appendix S2 (available at http:// respectively (overall P Z .006). After correction for the
jcrsjournal.org). mean baseline central subfield macular thickness and other
Twenty-seven patients (3.1%) developed a perioperative covariables, the mean central subfield macular thickness
complication (Appendix S3, available at http://jcrsjournal. was 9.6 mm higher in the dexamethasone group than in
org). There were no significant differences in the number the combination treatment group (P Z .002). It was
of perioperative complications between treatment groups 6.9 mm higher in the dexamethasone group than in brom-
(P Z .668). Data of 8 patients (0.9%) were not included fenac group, although the difference between the 2 treat-
in the final analyses because the reported perioperative ment groups was not statistically significant (P Z .026).
complications have been related to an increased risk for The mean central subfield mean macular thickness was
developing CME after cataract surgery. 2.7 mm higher in the bromfenac group than in the combina-
Although the study included only 914 instead of 926 pa- tion treatment group (P Z .380). The mean central subfield
tients, the final dropout rate was substantially lower than mean macular thickness was comparable in all treatment
the accounted for maximum rate of 20%. Of 906 patients groups 12 weeks after cataract surgery (overall P Z .299).
suitable for inclusion in the final data analyses, 86 patients Figure 4 shows the parafoveal thickness, perifoveal thick-
(9.5%) (26 in bromfenac group, 33 in dexamethasone ness, total macular volume, and CDVA by group over time.
group, and 27 in combination treatment group) were drop- Patients treated with topical dexamethasone had a signifi-
outs. There were no statistically significant differences be- cantly higher parafoveal thickness at 6 weeks than patients
tween treatment groups in the number of patients who treated with bromfenac (P Z .006) or with a combination
dropped from the study (P Z .560) or reasons for dropout of bromfenac and dexamethasone (P Z .001). The parafo-
(P Z .227). Four patients voluntarily postponed cataract veal thickness was comparable in the bromfenac group and
surgery and 40 patients withdrew from study participation combination treatment group (P Z .520). At 12 weeks, the
before the day of cataract surgery. The 2 patients in the parafoveal thickness was comparable between all treatment
bromfenac group who discontinued participation because groups (overall P Z .136).
of adverse events considered not related to topical NSAID The postoperative perifoveal thickness was also highest in
treatment had increased IOP and cerebral metastases of a the dexamethasone treatment group. At 6 weeks, the peri-
preexisting lung carcinoma, respectively. Of the 6 patients foveal thickness was significantly higher in patients treated
in the dexamethasone group considered dropouts because with topical dexamethasone than in patients treated
of adverse events, 2 patients had red eyes and 1 developed with bromfenac or with bromfenac and dexamethasone
a corneal erosion. One patient in the dexamethasone group (P Z .012 and P Z .008, respectively). There were no

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 ESCRS PREMED STUDY REPORT 1 435

Figure 4. Secondary outcome measures: observed means with 95% CIs. A: Parafoveal thickness. B: Perifoveal thickness. C: Total macular
volume. D: Corrected distance visual acuity (CDVA Z Corrected distance visual acuity; CIs Z confidence intervals; logMAR Z logarithm of
the minimal angle of resolution; TMV Z total macular volume).

significant differences in perifoveal thickness between the eyedrops than in patients in the combination group; how-
bromfenac group and combination group (P Z .883). At ever, a pairwise comparison did not reach statistical signif-
12 weeks, the perifoveal thickness was lowest in the brom- icance (OR, 2.2; 95% CI, 0.8-6.5; P Z .144). A similar
fenac treatment group. The mean perifoveal thickness was pattern was seen 12 weeks postoperatively (Table 3).
2.1 mm higher in the dexamethasone group and 1.8 mm Although the incidence of CSME remained highest in the
higher in the combination treatment group (P Z .004 dexamethasone treatment group during the course of the
and P Z .014, respectively). study (Table 3), the differences were statistically significant
Finally, the mean total macular volume was significantly at 6 weeks only (overall P Z .006 and P Z .043 within
higher in the dexamethasone treatment group than in the 6 weeks and 12 weeks, respectively).
other treatment groups 6 weeks postoperatively Sensitivity and per-protocol analyses showed comparable
(P ! .001). Up to the end of the study, the total macular results, and the effects were not significantly different be-
volume remained significantly lower in the bromfenac tween study centers.
treatment group than in the dexamethasone group
(P Z .001). After Bonferroni correction, there were no sta- Visual Acuity
tistically significant differences between the bromfenac There were no significant differences in CDVA 6 and
group and combination group (P Z .045). 12 weeks postoperatively between groups (overall P Z .327
Only overall treatment effects are reported because the and P Z .309, respectively) (Table 2). The mean final visual
effects were not significantly different between study cen- acuity was 0.02 logMAR (21/20 Snellen) in the bromfenac
ters for any postoperative outcome. Sensitivity analyses treatment group and 0.01 logMAR (20/20 Snellen) in the
showed similar results with respect to total macular volume other treatment groups.
and macular thickness measurements. Per-protocol ana- In patients with CSME, the maximum decline in CDVA
lyses showed comparable results (Appendix S4, available was up to 0.54 logMAR (20/70 Snellen). The median CDVA
at http://jcrsjournal.org). decreased to 0.20 logMAR (20/32 Snellen) but improved to
0.07 logMAR (20/26 Snellen) 12 weeks postoperatively.
Incidence of Cystoid Macular Edema and Clinically
Significant Macular Edema Adverse Events
Most cases of CME developed within 6 weeks postopera- All adverse events and serious adverse events are shown in
tively (Table 3). There were clinically important and statis- Appendices S5 and S6 (available at http://jcrsjournal.org).
tically significant differences in the incidence of CME No treatment-related serious adverse events were reported
within 6 and 12 weeks postoperatively between treatment during the course of this study. Adverse events occurred in
groups (overall P Z .002 and P Z .003, respectively). 310 patients. These events were reported in 104 patients
The odds of developing CME were significantly higher in (34.3%), 120 patients (39.9%), and 86 patients (28.5%) in
the dexamethasone treatment group than in the combina- the bromfenac group, dexamethasone group, and combina-
tion group (OR, 4.7; 95% CI, 1.7-12.5; P Z .002). The tion treatment group, respectively (overall P Z .013).
odds were also higher in patients treated with bromfenac Frequently reported adverse events were mild pain or

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436 ESCRS PREMED STUDY REPORT 1

Table 3. Incidence of CME and CSME (intention-to-treat analysis).

Incidence, n/N (%)

Parameter Bromfenac Dexamethasone Combination

CME within 6 wk 11/269 (4.1) 22/270 (8.1) 5/266 (1.9)
CME within 12 wk 11/269 (4.1) 23/270 (8.5) 6/266 (2.3)
CSME within 6 wk 10/274 (3.6) 14/273 (5.1) 2/275 (0.7)
CSME within 12 wk 10/274 (3.6) 14/273 (5.1) 4/275 (1.5)
CI Z confidence interval; CME Z cystoid macular edema; CSME Z clinically significant macular edema
*Overall effect at that timepoint over all 3 groups

foreign-body sensation, dry eyes, tearing, and posterior vit- The overall incidence of CSME in this study was 3.4%,
reous detachment. while previous studies have reported a lower incidence of
Six weeks postoperatively, the presence of cells on slit- 1.2% to 2.0% in patients with no risk factors for developing
lamp examination was reported in 11 (4.0%) of 272 patients CSME after cataract surgery.4,23 However, a fair comparison
in the bromfenac group, 12 (4.4%) of 271 patients in the of incidence rates between studies requires standardization
dexamethasone group, and in 15 (5.5%) of 273 patients in of the applied definitions.9,21 The ESCRS PREMED study
the combination treatment group. Flare was reported in 1 definition for CME is very sensitive because of a very low
patient in the combination treatment group. At 12 weeks, cutoff value with respect to macular thickening; that is, at
anterior chamber cells were reported in 1 (0.4%) of 268 pa- least a 10% increase in the mean central subfield macular
tients in both the bromfenac and combination treatment thickness compared with the preoperative baseline. More-
groups and in 5 (1.9%) of 264 patients in the dexametha- over, SD-OCT allows detection of very small cystoid
sone group. No patient presented with anterior chamber changes, and some of them might not be clinically relevant.
flare at 12 weeks. No patient had 2C or more cells accord- Clinically significant macular edema was defined as the
ing to the SUN classification 6 or 12 weeks postoperatively. occurrence of CME on OCT and less than 0.2 logMAR
The mean IOP decreased from 16.1 G 3.3 mm Hg at improvement in CDVA compared with the preoperative
baseline to 13.4 G 2.9 mm Hg 12 weeks after cataract sur- baseline. This definition assumes that modern phacoemulsi-
gery. There were no statistically significant differences in fication cataract surgery leads to at least 2 lines of improve-
the mean IOP between treatment groups at 6 or 12 weeks ment in CDVA. However, the current study also included
(overall P Z .707 and P Z .877, respectively). One patient patients with a preoperative CDVA of 20/25 Snellen or
in the bromfenac group developed severely increased IOP better who had cataract surgery for decreased quality of
and was hospitalized to receive intravenous medication. vision (eg, glare or decreased contrast sensitivity) because
Four patients in the dexamethasone group and 2 patients many national guidelines report that a reduced visual acuity
in the combination treatment group received topical treat- is not the only indication for cataract surgery. Therefore, the
ment to reduce IOP; however, none received a prosta- PREMED study definition for CSME might have caused a
glandin analog. Two patients in the dexamethasone group surplus of CME cases to be considered clinically significant.
and 1 patient in the combination treatment group received Previous studies have assed the efficacy of topical antiin-
additional oral acetazolamide. flammatory treatments to prevent vision loss resulting
from CME after cataract surgery.3 The ESCRS PREMED
DISCUSSION study could not identify a statistically significant difference
Modern phacoemulsification cataract surgery techniques in the mean postoperative CDVA between treatment groups.
have substantially decreased the incidence of CME after Although the CDVA decreased to 20/70 Snellen in patients
cataract surgery. However, because phacoemulsification is with CSME, those outliers did not cause significant differ-
one of the most frequently performed surgical procedures ences with respect to the mean CDVA 6 weeks and 12 weeks
worldwide, even small improvements in perioperative postoperatively. Nevertheless, individual patients will benefit
care can be clinically important. Many studies have evalu- most from optimum prevention of visually significant CME.
ated the optimum treatment to prevent CME after cataract The odds ratio of developing CSME within 12 weeks
surgery; however, most were insufficiently powered to postoperatively was 2.6 in patients treated with topical
detect small, yet clinically relevant differences between bromfenac and 3.7 in patients treated with topical dexa-
treatment groups. Moreover, most studies did not compare methasone compared with the combination treatment
the efficacy of an NSAID only versus combination treat- group. The incidence of CSME within 12 weeks postopera-
ment with a topical corticosteroid. The ESCRS PREMED tively was 3.6%, 5.1%, and 1.5% in the bromfenac group,
study included 914 nondiabetic patients and at present is dexamethasone group, and combination treatment group,
the largest multicenter study directly comparing the effi- respectively. Although these differences were not statisti-
cacy of a topical NSAID, corticosteroid, and combination cally significant after Bonferroni correction (P Z .043),
treatment to prevent CME after cataract surgery. the rates clearly indicate benefit from the use of both

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 ESCRS PREMED STUDY REPORT 1 437

Table 3. (Cont.)
Odds Ratios (95% CI); P Value

Dexamethasone Vs Bromfenac Vs Dexamethasone Vs

Parameter Overall P Value* Bromfenac Combination Combination
CME within 6 wk .002 2.08 (0.99, 4.40); .053 2.22 (0.76, 6.50); .144 4.65 (1.73, 12.48); .002
CME within 12 wk .003 2.19 (1.05, 4.60); .038 1.85 (0.67, 5.07); .234 4.05 (1.62, 10.12); .003
CSME within 6 wk .004 1.43 (0.62, 3.30); .398 5.22 (1.13, 24.12); .034 7.48 (1.68, 33.36); .008
CSME within 12 wk .043 1.43 (0.62, 3.30); .397 2.58 (0.80, 8.36); .114 3.70 (1.20, 11.44); .023

bromfenac and dexamethasone eyedrops to prevent CSME statistically significant or clinically relevant differences in
after uneventful cataract surgery. the mean macular thickness and total macular volume
Various topical NSAID preparations are available; howev- 6 weeks postoperatively between the bromfenac group
er, the U.S. Food and Drug Administration has not approved and combination group. The odds ratio for developing
any for the prevention of CME after cataract surgery.3 The CSME within 12 weeks postoperatively was 2.6 in patients
European Medicines Agency (EMA) approved nepafenac treated with topical bromfenac when compared to patients
for prevention of inflammation and macular edema after receiving combination treatment; however, the differences
cataract surgery in diabetic patients, whereas bromfenac is were not statistically significant. In this study, topical brom-
only approved for prevention of postoperative inflammation. fenac was used twice daily for 2 weeks postoperatively, as
Despite this, many ophthalmologists continue to use bromfe- per the EMA Summary of Product Characteristics 2011.29
nac and other topical NSAIDs to prevent CME after cataract Although the EMA recommends topical bromfenac treat-
surgery because CME is likely a result of an overall postoper- ment for 2 weeks postoperatively, ophthalmologists have
ative inflammatory response.3,21 At the initiation of this Eu- studied its use for up to 2 months after cataract surgery.
ropean multicenter trial in 2012, the ESCRS PREMED Study One small study of 72 patients30 compared the efficacy of
Group decided to use bromfenac 0.09% because previous topical bromfenac for 2 months postoperatively versus a
studies7,24 indicated better penetration into ocular tissues, combination treatment with a corticosteroid. The study
extended duration of antiinflammatory activity, and found no significant differences in postoperative inflamma-
enhanced inhibitory effect on cyclooxygenase 2. The results tory response and reported no cases of CME in the bromfe-
of an indirect network comparison and several small RCTs nac group or the combination treatment group. However,
suggest some differences between NSAID preparations in the sample size in this study might have been too small
their efficacy to reduce inflammation after cataract surgery.25 and the study might have had insufficient power to detect
The quality of evidence, however, is low to moderate, in part clinically relevant differences. Another study31 reported
because of the small samples in the available studies. Previous no added value of using bromfenac eyedrops for more
studies did not indicate significant differences between than 1 month postoperatively. Nevertheless, future RCTs
various NSAIDs in their efficacy to prevent macular thick- are needed to compare the efficacy of topical bromfenac
ening.25,26 More recently, reformulated once-daily NSAID for 1 month postoperatively versus combination treatment
preparations have been shown to be effective in preventing with a corticosteroid to prevent the occurrence of CME and
inflammation and CME after cataract surgery.4,27 Therefore, CSME after cataract surgery.
healthcare costs and patient comfort could be taken into ac- This European RCT has limitations that are related to its
count when choosing the optimal NSAID to be used as a stan- study design and the multinational setting. First, macular
dard of care in clinical practice.2,28 thickness and total macular volume were measured using
In the ESCRS PREMED study, the efficacy of bromfenac 5 different SD-OCT devices. Where some OCT devices
eyedrops was compared with that of dexamethasone 0.1%. measure retinal thickness from the internal limiting mem-
Dexamethasone was the corticosteroid of choice because brane to the retinal pigment epithelium (RPE), others use
this preparation was used at 8 of 9 PREMED study centers Bruch membrane as the outer retinal boundary. These dif-
that included a topical corticosteroid in their standard of ferences are most relevant in pathologies that affect the
care. A previous metaanalysis10 showed that both potent RPE–Bruch membrane complex.32 Because CME is caused
steroids and weaker steroids are less effective than topical by an accumulation of fluid in the inner nuclear and outer
NSAIDs in preventing CME after cataract surgery. plexiform layers of the retina, all OCT devices will detect
The primary outcome of the ESCRS PREMED study was postoperative changes in macular thickness and total mac-
the difference in the mean postoperative central subfield ular volume. Each study center used only 1 type of SD-OCT
macular thickness. The results suggest that topical bromfe- device for all preoperative and postoperative measure-
nac 0.09% is more effective than topical dexamethasone ments. Furthermore, differences between treatment groups
0.1% in preventing retinal thickening after cataract surgery. reported in this study were corrected for baseline measure-
These results are in line with the conclusions of previous ments. Second, the current study had a follow-up of
systematic reviews.9–11 The PREMED study found no 3 months postoperatively. The currently available literature

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438 ESCRS PREMED STUDY REPORT 1

does not provide clear evidence with regard to the long- in patients treated with topical bromfenac 0.09% than in pa-
term efficacy of topical NSAIDs and/or corticosteroids on tients treated with topical dexamethasone 0.1%. A combi-
CDVA more than 3 months after regular cataract surgery, nation treatment of dexamethasone and bromfenac
although some studies provide long-term results in high- eyedrops could not further reduce postoperative macular
risk patients (eg, patients with diabetes mellitus or uve- thickness, total macular volume, or CDVA compared
itis).11 The current study has shown a benefit to using a with topical bromfenac alone. However, the odds of devel-
combination of topical bromfenac and dexamethasone oping CSME within 12 weeks postoperatively were lowest
eyedrops up to 3 months postoperatively. Considering in the combination treatment group.
that most cases of CME develop within 4 to 6 weeks after
cataract surgery, preventive treatments should be optimized
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