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Purpose: The effectiveness of selective laser trabeculoplasty (SLT) was compared with argon laser trabe-
culoplasty (ALT) in a randomized clinical trial for patients with medically uncontrolled open-angle glaucoma who
have previously received 360 SLT.
Design: An active equivalence parallel armed randomized control trial.
Participants: Patients with open-angle glaucoma including pigmentary dispersion syndrome and pseu-
doexfoliation syndrome were enrolled into the study from 7 different sites across Canada.
Methods: One setting of 180 of either SLT or ALT was assigned randomly and applied to each participant.
Main Outcome Measures: The change in intraocular pressure (IOP) from baseline to 12 months was
compared between the 2 groups.
Results: A total of 132 patients were recruited, 2 of which dropped out early in the study, leaving 130 patients
who completed the study as per protocol. For those, the study’s primary outcome was calculated. The IOP
change at 1 year in comparison to baseline for SLT vs. ALT was found to be different by 0.33 mmHg between the
2 groups (3.16 for SLT and 2.83 for ALT) and was not statistically significant (P ¼ 0.71) Further analysis, though,
showed that SLT had a significantly lower IOP reduction at early time points: 1 week and 1 month, but this effect
was lost by 3 months. Corresponding to this finding was the strong trend for ALT to fail more quickly than SLT.
Although repeatable, the first repeat SLT reduced IOP to only about half compared with initial SLT treatment.
Conclusions: The comparison at 12 months following the laser therapy showed that both modalities lowered
the IOP with approximately 3 mmHg, yet essentially all of the time-to-failure analyses favored SLT over ALT. The
repeat SLT effect was found to be half of the initial treatment. Ophthalmology 2018;-:1e10 Crown
Copyright ª 2018 Published by Elsevier Inc. on behalf of the American Academy of Ophthalmology
Argon laser trabeculoplasty (ALT) was the standard-of-care of the melanin chromophore. The absence of histologic or
method of laser therapy to the trabecular meshwork (TM) architectural change in SLT-treated eyes has the theoret-
for open-angle glaucoma until 2005.1,2 Argon laser trabe- ical advantage of allowing effective repeated laser treat-
culoplasty is effective, but its most significant problem is ments, which was not possible with ALT. Indeed, if correct,
that its effectiveness decreases with retreatment because the this would be a very significant clinical advantage of SLT
tissue it targets (the TM) is changed by the laser, rendering and is the focus of this randomized clinical trial (RCT).
repeat treatments less effective.3 Subsequent to its The first phase 1/2 results from treatment of patients with
introduction in 2005, selective laser trabeculoplasty (SLT) SLT were reported in 1998 and established safety and ef-
has emerged as the more popular trabeculoplasty laser. ficacy of the procedure.4 The first small RCT that studied
There are many potential advantages to SLT, but to date, SLT vs. ALT was published in 1999 by some of our
these advantages are not supported with the best evidence. authors.5 This was a small trial that found and showed
The most important potential clinical advantage of SLT is equivalence in efficacy of the 2 lasers. The definitive RCT
based on the premise that it causes less damage to the confirming efficacy equivalence was published in 2006 by
tissue it targets.1 The nanosecond pulse duration of the the same authors.6 Baseline variables that predict SLT
SLT is a key factor in preventing collateral thermal success also have been published.7 This study found that
damage because it is less than the thermal relaxation time the most important predictor of SLT success was baseline
Crown Copyright ª 2018 Published by Elsevier Inc. on behalf of the American https://doi.org/10.1016/j.ophtha.2018.09.037 1
Academy of Ophthalmology ISSN 0161-6420/18
Ophthalmology Volume -, Number -, Month 2018
intraocular pressure (IOP). The results of SLT treatment eyes with POAG, normal-tension glaucoma, or PXF were
after ALT therapy were published in 2007 by our group.8 included in the study. Intraocular pressure reduced
Prediction rules that estimate the probability of SLT 1.82.2 mmHg and 2.23.7 mmHg at 15 months, which
success were published in 2008 and 2011.9,10 Finally, we was not a significant difference (P ¼ 0.53). One of the
recently published the results of an RCT examining the difficulties in interpreting these case series is that the
efficacy and side effects of SLT vs. ALT in patients with concomitant use of medications for glaucoma cannot be
pseudoexfoliation syndrome (PXF), again demonstrating controlled for in either a randomization methodology or in a
equivalence.11 generalized linear model analysis. Hence, confounding by
Regarding SLT retreatment, in 2009, Hong et al12 first indication permeates these studies and makes interpretation
reported the efficacy of repeat SLT in a case series of 44 difficult.
eyes with open-angle glaucoma. In those patients, IOP In summary, according to most of the available infor-
was controlled successfully for at least 6 months after the mation, repeat SLT is comparable with primary SLT
first 360 SLT treatment, and they underwent a second 360 regarding IOP reduction, although not all studies show the
treatment. The IOP reduction was significantly greater for same IOP-lowering effect from the first and repeat SLT.
the first SLT than the second one during the 1- to 3-month Both IOP spike and inflammation after laser treatment were
follow-up, with an average value of 5 mmHg for the first rare. However, only 1 study was an RCT and had a very
SLT and 2.9 mmHg for the second SLT. Avery et al13 short follow-up. The other studies were all case series car-
conducted a similar case series using 42 eyes with ried out by retrospective chart review. The sample size of
primary open-angle glaucoma (POAG). No significant dif- most of the previous studies was small to moderate.
ference was found between the first and the second treat- Therefore, more studies with better study design for evalu-
ments with an IOP drop of approximately 4 mm Hg. Khouri ating the efficacy of repeat SLT are needed.
et al14 retrospectively reviewed the electronic medical In this trial, all patients had been treated previously with
records from 45 eyes that underwent 2 360 SLT 360 of SLT. Then, they were randomized to either 180 of
treatments with up to 24 months of follow-up. The initial SLT or 180 of ALT treatment. The 1-year IOP change from
SLT yielded a significantly greater IOP reduction than the baseline is the primary outcome. This question and outcome
repeated one at 12 months, but the effect was the same at 1, were chosen to help understand several issues and to
18, and 24 months. In 2014, Ayala15 reported the first RCT examine several clinical scenarios as follows, which are
for evaluating the IOP-lowering effect of repeat SLT. Pa- summarized in Table 1.
tients (n = 80) who had undergone previous 180 SLT were Our studies on previous SLT and ALT work indicate that
allocated randomly to receive another 180 SLT either at the equivalence in lowering IOP is probable.5,6 Thus, we chose
same TM area or the untreated TM area. Intraocular pressure to design an equivalence study. Nevertheless, even with
reduction at 2 hours, 1 month, 3 months, or 6 months after IOP-lowering equivalence between the 2 lasers, SLT has
laser treatment was not significantly different between the theoretical advantages over ALT, but clinical advantages
primary and repeat SLT groups. Recently, Polat et al16 re- remain to be ascertained.
treated patients with 360 of SLT after an initial 360
treatment. Thirty-eight eyes in the study were diagnosed
with POAG, PXF, or pigment dispersion syndrome. The Methods
mean IOP reduction at each time point throughout the 24-
month follow-up ranged from 2.9 to 5.7 mmHg for the Trial Design
initial SLT and 2.3 to 4.4 mmHg for the repeat SLT without We chose an active equivalence parallel-arm RCT based on the
significant difference between the 2 SLT procedures. In results of our earlier clinical trial work with SLT and ALT. We
2016, Durr and Harasymowycz17 reported a case series registered the study at clinicaltrials.gov (identifier, NCT01687465).
evaluating repeat 360 SLT on IOP control. Thirty-eight The study protocol was approved by the Western University
Table 1. Potential Clinical Scenarios and Interpretations of this Randomized Control Trial
ALT ¼ argon laser trabeculoplasty; IOP ¼ intraocular pressure; SLT ¼ selective laser trabeculoplasty.
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Hutnik et al
SLT vs. ALT in Patients with Previous SLT
Research Ethics Board (file no., 103238). This study was con- with either SLT or ALT according to a blocked randomization
ducted in accordance with the ethical standards of the Western schedule, with blocks of 4, 6, or 8 chosen randomly by a computer-
University Research Ethics Board and the 1964 Helsinki declara- generated algorithm, with each block type having an equal chance
tion. The patient was masked to treatment, but the clinician was not of being chosen. Generally, the inferior 180 of the angle was
masked. In keeping with an effectiveness-type clinical trial, we treated. One hundred eighty degrees was chosen conservatively
chose to include a generalizable study population, permissive because the effect of repeat laser had not been studied in this
eligibility criteria, an easily administered treatment protocol, and context and in this type of RCT before. Argon laser trabeculoplasty
outcomes that are relevant to patient care. This effectiveness-type was performed using 50 applications of 50-mM spot size,
RCT maximizes generalizability; that and ethical priorities neces- 0.1-second duration, and an average power ranging from 400 to
sitated that any glaucoma medications used would not be washed 600 mW directed through an antireflective coated Goldman lens to
out in this trial. Substantive glaucoma surgical trial design and produce blanching or occasional bubble formation in the anterior
reporting issues, including IOP measurements, were followed TM. Selective laser trabeculoplasty was performed with the Selecta
based on the World Glaucoma Society consensus 7000 using 50 nonoverlapping applications, with a spot size of
recommendations.18 400 mM (centered on the TM) and pulse duration of 3 nanoseconds.
The initial energy used was 0.8 mJ. The energy was adjusted until
Inclusion Criteria bubble formation appeared and then was decreased by 0.1 mJ for
the remainder of the treatment. Average power during treatment
Inclusion criteria were as follows. All patients were enrolled from ranged from 0.8 to 1.4 mJ. A drop of 1% apraclonidine was
one of the practices participating in this study and were 18 years instilled in all treated eyes after laser treatment.
of age or older. Patients were diagnosed with open-angle glau-
coma, including pigmentary dispersion syndrome and PXF to Frequency and Duration of Follow-up
increase the generalizability of the study. Previous 360 SLT had
failed in all patients based on determining a target pressure for After treatment, patients were sent home with instructions that
each individual patient. This target IOP can be defined as the prednisolone acetate 1% be instilled in the treated eye 4 times daily
upper limit of a stable range of measured IOPs deemed likely to for 5 days. Patients were evaluated at 1 hour, 1 week, and at 1, 3, 6,
retard further optic nerve damage.19,20 In all patients, an IOP and 12 months after surgery. At all follow-up examinations, best-
measurement of more than the target pressure on at least 2 suc- corrected vision, anterior chamber reaction, IOP, and cup-to-disc
cessive occasions separated by 1 month constituted failure in light ratio were recorded. Gonioscopy to assess angle pigmentation
of previous SLT. All patients had 2 sighted eyes, defined as best- and peripheral anterior synechiae was performed at baseline and at
corrected visual acuity of 20/200 or better in the absence of an 12 months after laser treatment. At every postoperative visit, every
advanced visual field defect. attempt was made to keep the topical medication as constant as
possible.
Exclusion Criteria
Primary Outcome and Its Measure
Exclusion criteria were as follows. Patients with any evidence of
secondary open-angle glaucoma (other than pigmentary dispersion The primary outcome was the change in IOP from the baseline visit
syndrome and PXF) or narrow-angle glaucoma (where the anterior to the 12-month visit. The Goldman applanation tonometer was
TM is not visible over 360 ); advanced visual field defect in the used, and it was calibrated weekly. Applanation was performed at
eye being considered for treatment (defined as a scotoma within approximately the same time of day (1 hour) as the original
10 of fixation or split fixation on Humphrey visual field 24-2, full- baseline IOP.
threshold program); previous nonlaser glaucoma surgery in the eye
being considered for treatment; intraocular surgery anticipated in Sample Size
the 12 months after treatment; any corneal disease obscuring
adequate visualization of the anterior chamber TM or reliable The sample size calculation was based on the IOP change from
applanation tonometry; and present treatment with topical or sys- baseline to the 12-month follow-up. Equivalence was defined if the
temic steroids or anticipated treatment with systemic steroids in the 95% confidence interval (CI) of the mean difference between 2
6 months after treatment were excluded. treatment groups was within e3 mmHg and þ3 mmHg. This was
chosen as the equivalence window because the standard deviation
Randomization of normal IOP variation is 2.6 mmHg.21 The margin was decided in
advance by the study group based on the clinically meaningful
Patients were recruited by each center’s participating glaucoma difference along with previous clinical and statistical outcomes
physician(s). Patients were randomized by a randomized block and feasibility. Assuming a 90% chance (power) with type I
design. The randomization was computer generated using the error rate of 0.05 that a 95% CI can exclude a difference of
uniform distribution and was carried out by a centralized clinical more than 3 mmHg, the trial would need to recruit 117 eyes in
trial randomization unit (The London Health Research Kidney total. The process of recruitment, including the assessment,
Research Unit; Dr. Amit Garg, head) that was in no other way enrollment, and randomization of participants into this RCT, was
involved in the execution of the study. The intervention type was documented in a Consolidated Standards of Reporting Trials
determined by this randomization method. Patients were random- (CONSORT) flow diagram (Fig 1).
ized only after informed consent was obtained and just before the
laser application to reduce the chance of randomized patients not Primary Analysis
participating in the study. Patients were masked to the allocation,
but the physician was not. The primary outcome was analyzed based on the intention-to-treat
principle and was the comparison of IOP change at 12 months
Trial Interventions and Protocol between the 2 groups. The mean difference between the 2 laser
treatments and the 95% CI was derived by an independent-sample t
The intervention was to apply 1 setting of SLT or 1 setting of ALT. test. Before an independent-sample t test was conducted, normality
After instillation of 1% apraclonidine, patients then were treated of the samples of the 2 groups was determined by visualizing the
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Ophthalmology Volume -, Number -, Month 2018
Excluded (n = 27)
♦ Not meeting inclusion criteria (n = 11)
♦ Declined to participate (n = 4)
♦ Unable to travel (n = 1)
♦ Medical disease (n = 1)
♦ Other reasons (n = 10)
Randomized (n = 139)
Allocation
Follow-Up
Analysis
Figure 1. Consolidated Standards of Reporting Trials (CONSORT) diagram showing progress of patients through the study. ALT ¼ argon laser trabe-
culoplasty; SLT ¼ selective laser trabeculoplasty.
distribution histogram. Homogeneity of variance between the 2 postoperative visit; anterior chamber inflammation at every post-
treatment groups was analyzed using the F test. operative visit graded as 0 to 4 based on standard criteria as noted
For the secondary outcomes, an independent-sample t test was above; Snellen visual acuity at every postoperative visit in loga-
used for the continuous outcomes. For the binary outcomes, results rithm of the minimum angle of resolution units; TM pigmentation
were presented as risk difference and relative risk with 95% CI. As recorded as an ordinal variable from 0 to 4þ, where 0 represents no
a secondary analysis, we performed a generalized linear model pigment and 4þ represents dense homogenous pigment; number of
multivariate analysis. However, the results were identical to those glaucoma medications needed per patient in each group; and pro-
of the univariate analysis. Hence, the results shown are from the gression to surgical therapy in each group.
univariate analysis unless otherwise indicated.
Covariates
Time to Failure
Those considered to be confounders or effect modifiers were used
We also performed 3 time-to-failure analyses (KaplaneMeier in the subgroup analysis. These covariates were built into the
curves and Cox proportional hazards testing) with the definitions of exposure-outcome analysis using multivariate generalized linear
failure being (1) IOP reduction by less than 20%, (2) IOP reduction models and included the following: baseline IOP; baseline TM
by 3 mmHg or less, and (3) any medication addition or repeat angle pigmentation; age; gender; glaucoma risk factors by patient history,
laser or interventional surgery needed. Reintervention was per- including hypertension, diabetes, myopia, family history of glau-
formed when the patient’s individual target pressure was no longer coma (a binary variable), and central cornea thickness; and number
met. of glaucoma medications at baseline.
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Hutnik et al
SLT vs. ALT in Patients with Previous SLT
Center PDS 4 3
Western University 16 17 PXF 7 12
University of Toronto 10 11 OHT 6 4
University of Calgary 17 16 PXF and OHT* 1 0
University of Alberta 2 2
Dalhousie University 13 15 ACI ¼ anterior chamber inflammation; ALT ¼ argon laser trabeculoplasty;
McMaster University 5 5 BCVA ¼ best-corrected visual acuity; CCT ¼ central corneal thickness;
McGill University 1 0 IOP ¼ intraocular pressure; logMAR ¼ logarithm of the minimum angle of
Study eye was right eye 28 43 resolution; OHT ¼ ocular hypertension; PAS ¼ peripheral anterior
Male gender 34 40 synechiae; PDS ¼ pigmentary dispersion syndrome; POAG ¼ primary
Age (yrs) open-angle glaucoma; PXF ¼ pseudoexfoliation syndrome; SD ¼ standard
Mean (SD) 64.95 (10.60) 67.07 (9.77) deviation; TMP ¼ trabecular meshwork pigmentation.
Range 35e89 42e89 *Defined as IOP >21 mmHg, open drainage angles observed on gonioscopy
Ethnicity without glaucomatous optic disc damage, detectable nerve fiber layer
White 54 57 defect, or visual field loss.
Black 3 3
Other 7 6
BCVA (logMAR)
Mean (SD) 0.11 (0.12) 0.11 (0.26) medications, had undergone a glaucoma surgery, or had received
Range e0.12 to 0.48 e1 to 1 another glaucoma laser treatment during the 12-month follow-up
IOP (mmHg) were removed from this analysis. A sensitivity test for the pri-
Mean (SD) 21.57 (3.14) 21.52 (3.30)
mary end point also was conducted with extreme case analysis (the
Range 16.5e29.5 15.5e32.5
best and worst case assessment), in which the missing IOP mea-
CCT (mm)
Mean (SD) 552.92 (38.52) 559.74 (38.25)
surements at 12 months were imputed with the minimum IOP of all
Range 452e647 484e682 the participants in the SLT group and the maximum IOP for those
Modified Schaffer (0e4) in the ALT group, and reverse.
2 2 3
3 35 35
4 27 28 Trial Management
TMP (0e4)
0 5 7
A steering committee composed of trial members oversaw the
1 30 31 day-to-day management of the study. The study database creation,
2 23 24 maintenance, and data analysis were performed at the Western
3 5 3 University Clinical Trial Data Center in London, Canada. All data
4 1 1 security standards set out by the Western University Data Safety
PAS (present) 2 1 Monitoring Board were met by the data center. Quality control
Cup-to-disc ratio was undertaken by both the steering committee and the data
Mean (SD) 0.64 (0.20) 0.66 (0.17) management center. An independent 3-member Data Safety
Range 0.2e0.9 0.2e0.9 Monitoring Committee was struck before the start of the study
Risk factors and oversaw the study, performed interim analyses, and audited
Family history of POAG 23 23 all adverse outcomes. The Data Safety Monitoring Committee met
Age (>60 yrs) 47 53 twice yearly.
Myopia 14 19
Elevated IOP (>21 mmHg) 40 42
Ethnic background 10 9
(“yes” if not white) Results
Concomitant medical 22 19
conditions (hypertension, Table 2 provides the baseline characteristics of the patients based
diabetes, hypothyroidism) on demographics, descriptive ocular variables, baseline IOP,
Other 5 0 glaucoma risk factors, and prelaser treatment. Of note, the
No. of glaucoma medication baseline IOP was almost identical in the 2 groups.
used at baseline Table 3 demonstrates the results of the primary outcome,
0 28 35 namely, the IOP change at 1 year compared with baseline for
1 5 3
SLT vs. ALT. This difference was 0.33 mmHg (3.16 mmHg for
2 16 16
SLT and 2.83 mmHg for ALT) and was not statistically
3 13 11
4 2 1
significant (P ¼ 0.71) in the intention-to-treat analysis. Table 4
Diagnosis demonstrates the same analysis as in Table 3 but at all the
POAG 46 47 different follow-up time points. Selective laser trabeculoplasty
had a significantly lower IOP reduction at early time points, 1 week
(Continued) and 1 month, but this effect was lost by 3 months.
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Ophthalmology Volume -, Number -, Month 2018
Difference in the
Selective Laser Argon Laser Intraocular Pressure Change
Trabeculoplasty Trabeculoplasty (95% Confidence Interval) P Value
Complete case analysis 0.33 (e1.40 to 2.05) 0.71
No. 64 66
Mean (SD) 3.16 (4.96) 2.83 (5.06)
Per-protocol analysis 0.56 (e0.91 to 2.03) 0.45
No. 49 41
Mean (SD) 3.37 (3.79) 2.81 (3.12)
SD ¼ standard deviation.
Intraocular pressure measured in millimeters of mercury.
Data were analyzed based on complete cases and are mean (standard deviation) unless otherwise indicated. Intraocular pressure measured in millimeters of
mercury.
*P < 0.05.
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Hutnik et al
SLT vs. ALT in Patients with Previous SLT
Figure 2. KaplaneMeier curve showing survival estimates (success defined Figure 4. KaplaneMeier curve showing survival estimates (success as no
as intraocular pressure [IOP] change of more than 3 mmHg from baseline additional interventions). ALT ¼ argon laser trabeculoplasty; SLT ¼ se-
IOP). ALT ¼ argon laser trabeculoplasty; SLT ¼ selective laser lective laser trabeculoplasty.
trabeculoplasty.
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Ophthalmology Volume -, Number -, Month 2018
Table 5. Intraocular Pressure Change from Baseline to the 12-Month Visit in Subgroups
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Hutnik et al
SLT vs. ALT in Patients with Previous SLT
Table 5. (Continued.)
CAI ¼ carbonic anhydrase inhibitors; CCT ¼ central corneal thickness; IOP ¼ intraocular pressure; PGA ¼ prostaglandin analog; POAG ¼ primary open-
angle glaucoma; SD ¼ standard deviation; SLT ¼ selective laser trabeculoplasty.
Data were analyzed based on complete cases. Intraocular pressure measured in millimeters of mercury.
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Ophthalmology Volume -, Number -, Month 2018
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