Anti-inammatory Therapy after Selective

Laser Trabeculoplasty
A Randomized, Double-Masked, Placebo-Controlled
Clinical Trial
Delan Jinapriya, MD,1 Mark DSouza, MD,1 Hussein Hollands, MD, MSc,1 Sherif R. El-Defrawy, MD, PhD,1
Isabella Irrcher, PhD,1 Donald Smallman, MD,1 James P. Farmer, MD,1 John Cheung, MD,1 Todd Urton, MD,1,2
Andrew Day, MSc,2 Xiaoquin Sun, MSc,2 Robert J. Campbell, MD, MSc1,3

Purpose: To investigate the effect of anti-inammatory therapy on selective laser trabeculoplasty (SLT)
outcomes.
Design: Randomized, double-masked, placebo-controlled trial.
Participants: Patients with primary open-angle or pseudo-exfoliation glaucoma.
Methods: Patients undergoing SLT were randomized to receive placebo (articial tears), prednisolone
acetate 1%, or ketorolac tromethamine 0.5% eye drops 4 times per day for 5 days commencing immediately
after SLT.
Main Outcome Measures: Change in intraocular pressure (IOP) from baseline to the 1-month post-SLT visit.
Results: Mean change in IOP at the 1-month primary outcome time point, as well as all other time points, was
not signicantly different among groups (P 0.99). Likewise, a repeated-measures, mixed-effects model did not
nd signicant differences in IOP outcome at the 1-month time point (P 0.95). The IOP was reduced in all
groups at the 1-month post-SLT time point and all other time points, and no signicant differences were found
between groups using separate unadjusted cross-sectional analyses of variance (P > 0.15 for analyses at all time
points). Treatment failure rates were not different among groups (P 0.75), and at 1 year after SLT, the per-
centage of patients maintaining a 20% IOP reduction ranged from 18% to 22% in the 3 study groups.
Conclusions: Anti-inammatory therapy after SLT does not seem to substantially inuence the IOP-lowering
effect of SLT. In this study of patients with low baseline IOP, SLT showed limited efcacy in achieving a sustained
reduction in IOP. Ophthalmology 2014;121:2356-2361 2014 by the American Academy of Ophthalmology.

Selective laser trabeculoplasty (SLT) effectively lowers
intraocular pressure (IOP) with minimal risk of complica-
tions and is a widely used and effective treatment for
glaucoma.1e5 Despite its widespread use, the mechanisms
by which SLT induces an IOP-lowering effect remain only
partially understood.1,3e8
The IOP-lowering effect of SLT is premised on selective
photothermolysis, in which laser interacts with pigmented
components of trabecular meshwork cells to facilitate aqueous
outow.9 In particular, SLT induces the release of chemotactic
and vasoactive agents, including the inammatory mediators
interleukin-1a, interleukin-1b, and tumor necrosis factor-a.1
These mediators have numerous effects, including macro-
phage recruitment, matrix metalloproteinaseeinduced extra-
cellular matrix remodeling, and improved permeability of
Schlemms canal endothelial cells.1,8,10
Many studies of SLT have described the routine use of anti-
inammatory ophthalmic medications for a short period after
laser treatment.1,4e7 However, the utility of this practice has
not been validated. Although high levels of intraocular
inammation over extended periods of time can cause
complications, the degree of inammation seen after SLT is
minimal. In light of the likelihood that inammatory mediators
are important in the positive clinical effect of SLT, high-level
evidence is needed to inform the use of anti-inammatory
medication after SLT.1,6,8 However, to date, only limited data
have been reported from randomized trials and observational
studies have been inconclusive.3,6,7,11,12 Indeed, a recent
American Academy of Ophthalmology Ophthalmic Tech-
nology Assessment identied the need for research into
pharmacologic methods that could enhance the response to
trabeculoplasty.13 Thus, we conducted a randomized, double-
masked, placebo-controlled trial to determine whether post-
laser anti-inammatory therapy modies the effect of SLT.
Methods
Study Design and Overview
This randomized, double-masked, placebo-controlled trial was
conducted at the Hotel Dieu Hospital in Kingston, Ontario,
Canada, and adhered to the tenets of the Declaration of Helsinki.

2356  2014 by the American Academy of Ophthalmology http://dx.doi.org/10.1016/j.ophtha.2014.07.017

Published by Elsevier Inc. ISSN 0161-6420/14
 Jinapriya et al 
Anti-inammatory Therapy after SLT
Enrollment
Tears
(placebo)
Allocation Received allocated
intervention (n = 38)
Not available for 1 month
Follow-Up at 1
follow-up (n = 1)
Month
Total included in primary
Analysis
outcome end point
(n = 37)
Figure 1. Consolidated Standards of Reporting Trials diagram. NSAID nonsteroidal anti-inammatory drug.
All patients provided written, informed consent before any study-
related procedures. The Queens University and Afliated Teach-
ing Hospitals Health Sciences Research Ethics Board approved the
study before enrolling study participants. The study is listed on
ClinicalTrials.gov, under the identier NCT00485108.
Study Population and Inclusion/Exclusion Criteria
Patients were recruited from study ophthalmologists practices
within the Department of Ophthalmology at Queens University,
Kingston, Ontario, Canada. Eligible patients were aged 18 years or
older with a diagnosis of primary open-angle glaucoma (POAG) or
pseudo-exfoliation glaucoma (PEXG), without previous laser tra-
beculoplasty. Patients receiving SLT as initial glaucoma therapy or
as an adjunctive therapy were included. In addition, to be eligible,
patients had to be capable of providing consent and returning for
follow-up visits. Only 1 eye per patient was enrolled in the study.
Patients were excluded if they had a history of uveitis or previous
incisional glaucoma surgery.
Random Treatment Assignment
Patients undergoing SLT were assigned to 1 of 3 post-laser treat-
ment arms in blocks of 6 to maintain balanced groups: (1) car-
boxymethyl cellulose sodium 1.5% articial tears (placebo group)
1 drop 4 times daily for 5 days after SLT; (2) prednisolone acetate
1% (steroid group) 1 drop 4 times daily for 5 days after SLT; or (3)
ketorolac tromethamine 0.5% (nonsteroidal anti-inammatory drug
[NSAID] group) 1 drop 4 times daily for 5 days after SLT (Fig 1).
Randomization was stratied by (1) surgeon; (2) glaucoma subtype
(POAG or PEXG); and (3) whether SLT was the initial glaucoma
therapy or an adjunctive treatment.
Sequentially numbered sealed envelopes, prepared by an
unmasked study coordinator who was not involved with treatment
Randomized (n = 125)
Prednisolone acetate Ketorolac tromethamine
(steroid) (NSAID)
Received allocated Received allocated
intervention (n = 46) intervention (n = 41)
Not available for 1 month Not available for 1 month
follow-up (n = 3) follow-up (n = 4)
Total included in primary Total included in primary
outcome end point outcome end point
(n = 43) (n = 37)
or data acquisition, were used to assign patients to treatment arms
and to assign 1 eye to be enrolled if both eyes were undergoing
laser treatment. Commercially available medication bottles were
covered with opaque labels over the entire bottle and labeled only
with instructions on how often to administer drops.
Selective Laser Trabeculoplasty Treatment
Procedure, Baseline Examinations, and Follow-Up
In all cases, the SLT procedure consisted of 50 pulses to the
inferior 180 of the trabecular meshwork. Power was initially set at
0.8 mJ and titrated to produce occasional small bubbles. All
patients were treated with a single brimonidine drop before laser.
Patients were assessed twice on separate days before SLT and
follow-up examinations scheduled at 1 hour, 1 day, 1 week, 1
month, 3 months, 6 months, and 1 year after SLT.
Examination Procedures
The IOP measurement protocol followed the methods described
in the Ocular Hypertension Treatment Study, and calibrated
tonometers were used throughout the study.10 Measurements at
all study time points were taken by an ophthalmologist or a
senior resident involved with the study. All follow-up IOP
measures were the average of 2 measurements taken
sequentially at each visit. Baseline IOP was dened as the
average of the 4 measurements taken on 2 separate days before
laser treatment.
Anterior chamber inammation was graded by a study
ophthalmologist or study senior resident. Assessments were made
on the basis of the Standardization of Uveitis Nomenclature
working group grading scheme for anterior chamber cells.14
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 Ophthalmology Volume 121, Number 12, December 2014
Table 1. Patient Demographics and Baseline Characteristics
Articial Tears (Placebo)
n [ 38
Age (yrs) 71.911.5
Female sex (%) 50
Baseline IOP (mmHg) 19.14.6
Study eye diagnosis (%)
POAG 87
PEXG 13
No. of medications at baseline 1.41.4
Timing of SLT (%)
Initial therapy 34
Adjunctive therapy 66
IOP intraocular pressure; NSAID nonsteroidal anti-inammatory drug; PEXG pseudoexfoliation glaucoma; POAG primary open-angle glaucoma;
SLT selective laser trabeculoplasty.
Data are reported as mean  standard deviation unless otherwise specied.
Outcome Measures
The primary study outcome was the absolute change in IOP from
baseline to the 1-month time point after SLT. Additional therapies
were not permitted before this follow-up time point. In a secondary
analysis, IOP changes from baseline at other time points also were
compared between treatment arms.
Time to treatment failure, dened as not maintaining a 20% IOP
reduction from baseline or requiring additional glaucoma therapy
(at the treating ophthalmologists discretion), was assessed as a
secondary outcome. Finally, anterior chamber inammation was
graded according to the Standardization of Uveitis Nomenclature
grading scheme.14
Sample Determination and Power
By assuming that our primary outcome (absolute change in IOP
from baseline to the 1-month post-laser assessment) had a within-
group standard deviation of 4 mmHg, using the F-test from anal-
ysis of variance (ANOVA), 40 patients per arm provide at least
85% power at alpha 0.05 (2-sided) to reject the null hypothesis
that all 3 arms had the same mean change if the actual change in
IOP differed by at least 3 mmHg between the 2 most extreme arms.
Statistical Analysis
The difference between arms in IOP change from baseline to
follow-up time points was estimated by a linear mixed-effects
model for longitudinal data.15 The model included the baseline IOP
measurement and the trials 3 stratication factors (physician,
diagnosis, and initial vs. adjunctive treatment) as xed covariates.
The estimated adjusted between-group differences were then
plotted with 95% condence intervals (CIs). The TukeyeKramer
adjustment was applied to the CIs to account for the 3 pairwise
between-group comparisons at each time point.16 The model used
an unstructured covariance to account for within-subject correla-
tion between the 5 post-baseline assessments.17 The conclusions
were conrmed by a simple unadjusted cross-sectional analysis
comparing the mean and variance between arms separately at each
time by a 1-way ANOVA with Levenes test for homogeneity
variance. The ManteleHaenszel mean test score was used to
compare our secondary outcome, anterior chamber inammation,
between arms at 1 hour, 2 days, and 1 month after SLT.
In the secondary analysis examining time to treatment failure,
failure was dened a priori as (1) an IOP at month 1, 3, 6, or 12 that
2358
Prednisolone Acetate (Steroid) Ketorolac Tromethamine (NSAID)
n [ 46 n [ 41
69.310.1 70.611.6
50 63
19.64.6 18.53.5
70 83
30 17
1.51.3 1.61.3
43 26
57 73
was not at least 20% below baseline or (2) requiring additional
IOP-lowering therapy. Cause-specic failure rates were estimated
by the life table method. The log-rank test was then used to test for
differences in all-cause treatment failure rates. All statistical ana-
lyses were carried out using SAS version 9.2 (SAS Inc., Cary, NC).
Results
In total, 125 patients were randomized to placebo (n 38), steroid
(n 46), or NSAID (n 41). The Consolidated Standards of
Reporting Trials ow diagram illustrating patient allocation to
groups is presented in Figure 1. Baseline patient characteristics
were well balanced (Table 1). Mean age across all 3 groups was
70.5 years (standard deviation, 11 years). Mean baseline IOP
across all groups was 19.1 mmHg (standard deviation, 4.3 mmHg).
Intraocular Pressure
Mean change in IOP at the 1-month visit, the primary outcome,
was not signicantly different among groups (P 0.99). At all
other time points, mean change in IOP was not signicantly
different among groups (P > 0.1). The adjusted between-arm
differences in IOP lowering from baseline are shown in Figure 2.
After adjusting for baseline IOP and the study stratication factors
(physician, diagnosis, and SLT as initial vs. adjunctive treatment),
the repeated measures mixed-effects model did not show any sig-
nicant differences between groups at any time point. An analysis
based on percentage of IOP reduction from baseline showed
analogous results (not shown). Boxplots of raw IOP measurements
from each group over time are shown in Figure 3. These data show
that IOP was reduced in all groups at the 1-month post-SLT time
point and all other time points, with no signicant differences
between groups found with separate unadjusted cross-sectional
ANOVA analyses (P > 0.15 for analyses at all time points).
Time to Treatment Failure
The cumulative survival plot for treatment success is shown in
Figure 4. The treatment failure rates were not signicantly different
between treatment arms (P 0.75). At the primary end point of 1
month, the treatment failure rates in the placebo, steroid, and
NSAID arms were 59% (95% CI, 44e75), 44% (95% CI, 31e60),
and 51% (95% CI, 37e67), respectively. One patient who failed
required trabeculectomy surgery during follow-up (NSAID group).
 Jinapriya et al 
Anti-inammatory Therapy after SLT

Figure 2. Adjusted between-arm differences in intraocular pressure (IOP) reduction from baseline. The expected mean difference is represented by the
diamond. The boxes represent nominal 95% condence interval (CI). The whiskers extend to the TukeyeKramer adjusted simultaneous 95% CI accounting
for the 3 between-arm pairwise comparisons. P values (p) represent the between-group comparisons at each time point. D2 day 2 after selective laser
trabeculoplasty (SLT); H1 hour 1 after SLT; M1 month 1 after SLT; M3 month 3 after SLT; M6 month 6 after SLT; NSAID nonsteroidal anti-
inammatory drug; Y1 year 1 after SLT.

Anterior Chamber Inammation
Mean anterior chamber inammation scores at 1 hour, 2 days, and
1 month after SLT treatment were not signicantly different be-
tween any of the treatment arms (P > 0.2 for all comparisons). By
1 month after SLT, anterior chamber inammation was observed in
only 1 patient.
Discussion
Despite the widespread use of anti-inammatory medication
after SLT, high-level data supporting this practice have been
lacking. In this randomized clinical trial, we found that the
use of anti-inammatory therapy after SLT did not inuence
the IOP-lowering effect of SLT when compared with pla-
cebo. This nding was consistent among patients with both
POAG and PEXG and among patients receiving SLT as
initial or adjunctive glaucoma therapy.
Although previous observational studies that included
groups receiving different post-laser anti-inammatory ther-
apy were not designed to address the question of efcacy, they
do provide some information.1,3,6,12 In particular, McIlraith
et al6 found no difference in IOP reduction between patients
receiving ketorolac and prednisone after SLT. Realini et al11
randomized eyes of patients undergoing bilateral SLT to
prednisolone acetate versus no therapy. Although this study
did not detect differences in outcome between treated and
untreated eyes, the study included only 25 patients.6,7,10
In our study, SLT had a smaller IOP-lowering effect than
that observed in some previous reports.3,7,18e20 Moreover,
initial reductions in IOP were often not sustained. Conse-
quently, by the 1-year post-SLT time point, approximately
80% of patients in all groups had failed to maintain a 20%
reduction in IOP. This low success rate may be a result of
the low baseline IOP in our study, which strongly inuences
SLT success.4,12 Indeed, the efcacy of SLT in our study
was similar to that observed by Song et al,21 who also
studied a population with relatively low baseline IOPs.
Nevertheless, baseline IOP effects were nondifferential and
would not be expected to inuence our comparisons be-
tween groups.
Study Limitations
To our knowledge, our study is the largest double-masked,
placebo-controlled trial to evaluate this clinically important
question. The use of a clinically relevant primary outcome
chosen a priori is an important strength of our study. Stratied
randomization and standardized examination and assessment
procedures were additional strengths. Our study has limitations
that warrant mention. First, a larger study could provide more
precise measures of effect. Second, although subgroup results
suggest that our ndings apply to both POAG and PEXG, and
to SLT as an initial and adjunctive therapy, the subgroup data
should be interpreted with caution because of the limited power
of our study to detect clinically important differences in

2359
 Ophthalmology Volume 121, Number 12, December 2014

Figure 3. The intraocular pressure (IOP) (mmHg) over time by treatment arm. Boxes represent the interquartile range (i.e., middle half) of the data.
Lines and diamonds inside the boxes represent the median and mean, respectively. Whiskers extend to the most extreme values up to 1.5 times the
interquartile range beyond the interquartile range. Circles are used to plot values beyond whiskers. P values (p) are based on separate unadjusted 1-way
analyses of variance comparing means at each time point. B1 baseline 1; B2 baseline 2; D2 day 2 after selective laser trabeculoplasty (SLT); H1
hour 1 after SLT; M1 month 1 after SLT; M3 month 3 after SLT; M6 month 6 after SLT; NSAID nonsteroidal anti-inammatory drug; Y1
year 1 after SLT.

subgroup analyses. Third, it is possible that patients could
determine the medication received from the cap color or
medication consistency. However, few patients would be ex-
pected to be aware of the specic differences. Of note, study
evaluators did not see the medication bottles at follow-up visits.
However, some patients may have had their follow-up visit
1
0.8
Proportion Surviving
assessment carried out by an investigator who had been present
at the initial SLT. Thus, it is possible that the investigator could
have recalled the treatment assignment. Finally, in our study
we evaluated 180 SLT treatments only, and the generaliz-
ability to 360 treatments is not known.
In conclusion, our ndings suggest that the therapeutic
mechanism of SLT may be less dependent on inammatory
mediators than some studies have postulated.1,8 However,
although we studied commonly used doses of widely used
anti-inammatory medication, our results may not be
generalizable to other drugs and alternative doses. This
should be the focus of future research. Further studies will
be needed to assess the impact of anti-inammatory treat-
ment on SLT responses in subtypes of glaucoma other than

0.6

Placebo
POAG and PEXG, such as pigment dispersion glaucoma.
Steroid The results of this randomized, double-masked, placebo-
0.4 NSAID controlled study suggest that the IOP-lowering effect of SLT
is not substantially inuenced by the use of post-laser anti-
inammatory medications.
0.2

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Footnotes and Financial Disclosures
Originally received: November 30, 2013.
Final revision: February 3, 2014.
Accepted: July 9, 2014.
Available online: September 15, 2014. Manuscript no. 2013-1972.
1
Department of Ophthalmology, Queens University and Hotel Dieu
Hospital, Kingston, Ontario, Canada.
2 Abbreviations and Acronyms:
Clinical Evaluation Research Unit, Kingston General Hospital, Kingston,
Ontario, Canada.
3
Institute for Clinical Evaluative Sciences, Ontario, Canada.
Financial Disclosure(s):
The author(s) have made the following disclosure(s): D.J.: received
payment for CME talks for Allergan, Alcon, and Pzer. H.H.: received
payment for the development of educational presentations from Novartis.
D.S.: consultant to Tear Science.
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This study was funded by the Glaucoma Research Society of Canada. The
sponsors of this study had no role in the design and conduct of the study;
collection, management, analysis, and interpretation of the data; prepara-
tion, review, or approval of the manuscript; and the decision to submit for
publication. The opinions, results, and conclusions reported in this article
are those of the authors and are independent from the funding sources.
ANOVA analysis of variance; CI condence interval;
IOP intraocular pressure; NSAID nonsteroidal anti-inammatory
drug; PEXG pseudo-exfoliation glaucoma; POAG primary open-
angle glaucoma; SLT selective laser trabeculoplasty.
Correspondence:
Robert J. Campbell, MD, MSc, Department of Ophthalmology, Hotel Dieu
Hospital, 166 Brock Street, Kingston, Ontario, Canada, K7L 5G2. E-mail:
rob.campbell@queensu.ca.
2361