Selective Laser Trabeculoplasty Versus Brimonidine Tartrate 0.2%/Timolol Maleate 0.5% As Adjunct Therapy in Primary Open Angle Glaucoma: A Randomized Prospective Trial CURRENT STATUS:

Purpose: To compare the intraocular pressure lowering efficacy of selective laser trabeculoplasty to brimonidine tartrate 0.2%/timolol maleate 0.5% in patients with uncontrolled primary open-angle glaucoma on a prostaglandin analog alone. A secondary outcome was to evaluate the complication rates of selective laser trabeculoplasty. Patients and Methods: Twenty-three patients were randomized to two treatment groups within this prospective, observer-masked single site, all optometrist, pilot study. Group 1 (N=12) received 360 degrees of selective laser trabeculoplasty as additional treatment while Group 2 (N=11) was started on FCBT. Outcomes of both groups were measured at eight weeks. Results: Both treatment regimens were found to be statistically significant in lowering IOP when used as adjunct therapy. The average IOP reduction for Group 1 and Group 2 was 28.4% (SD = .17) and 28.2% (SD = .12) respectively. The incidence of an intraocular pressure spike following SLT in this patient population was found to be 8.3%. No major complications were observed in this study. Conclusion: Selective laser trabeculoplasty and brimonidine tartrate 0.2%/timolol maleate 0.5% were shown to be equivalent in lowering intraocular pressure in uncontrolled primary open angle glaucoma patients when used as adjunct therapy for patients on a prostaglandin analog. Additionally, this is the first prospective study of optometrists performing selective laser trabeculoplasty. Although this study had a small sample size, the results appeared to show that efficacy and complication rates were comparable to previously published data; however, these results need to be confirmed with a larger multi-centered trial.


1.
The ability to recruit patients was one of the main issues with the studies feasibility.
To fully power the study, we knew we needed a large n so that is why we choose to do a pilot study first to see if a larger study would be indicated. We knew both treatments were effective individually but wanted to compare them to see if one was superior to the other in a head to head study.

2.
A larger study can be completed at a relatively low cost and a larger n is needed to provide a stronger powered study which could help clinicians choose the most appropriate second line therapy for their glaucoma patients.

3.
The main study needs to be a larger multicentered trial with a much higher sample size and longer follow up period. Ideally at least 1 year of data should be collected to ensure the effect of SLT or drops don't wear off quickly as glaucoma is a chronic disease. Additionally, stratified randomization needs to be utilized to ensure both treatment groups have similar demographics. Using simple randomization was a weakness of the pilot study. uveoscleral outflow. 2 Once-daily dosing has minimized the treatment burden on patients, and declining costs as well as generic options have increased adherence making PGAs ideal for monotherapy. 3,4 It is not uncommon for a PGA alone to insufficiently reach an IOP target. If IOP fails to drop adequately or progression is confirmed, or suspected, additional treatment should be considered. Commonly, second-line medical therapy includes a topical fixed-dose combination agent due to its efficacy and expectation that it will provide the best chance of adherence. 5 Other nonpharmacological therapies, such as selective laser trabeculoplasty (SLT), a frequency-doubled Qswitched Neodymium-doped Yttrium Aluminum Garnet 532 nm green laser that was first introduced by Latina and Park in 1995, may provide some advantages in certain patients and perhaps deserves equal consideration. 6,7 Treatment decisions should be individualized, and the best results are most likely achieved when multiple treatment modalities are considered. Mead et al. suggests "an encounter that is patientcentered and focuses on collaborative goal setting is one in which the provider is (a) receptive to the patient's opinions and expectations and (b) involves the patient in decision-making about treatment." 8 Inaccessibility of non-pharmacologic treatments have historically and continue to limit some patients to only medical therapy when other treatments may be better suited for their care.
However, legislation in several states has modernized patient access to laser glaucoma treatments.
A potential shift in paradigm thinking between medical and laser therapy is evolving and will shape future choices for adjunct treatment in patients who fail prostaglandin analog monotherapy. Several studies have previously looked at using SLT as initial therapy. 6,[9][10][11][12][13][14]  were pregnant or who intended to become pregnant during the study (as verbally asked during the medical history and consenting process, no formal pregnancy test was administered for this study), or patients with significant dementia who were not able to fully comprehend the informed consent.
Subjects enrolled in the study were randomized with simple randomization, using concealed envelopes, to either receive 360 degrees of SLT treatment or use brimonidine tartrate 0.2%/timolol maleate 0.5% twice a day (q12h). If the patient needed additional treatment in both eyes, then the second eye received the same treatment as the first; however, only one eye was eligible to participate in the study. The eye with the higher baseline intraocular pressure was chosen to be the study eye. If the baseline intraocular pressure was equal in both eyes, then the right eye was chosen as the study eye. All participants continued to use their PGA once a day at nighttime during the study.
Compliance in each group was monitored using a daily drop log.
A baseline exam was performed and included a detailed ocular, family, social, and medical history.
Additionally, blood pressure, pulse, pupils, extraocular muscles, visual acuity, Goldmann applanation tonometry, gonioscopy, pachymetry, and a slit lamp exam were conducted. Participants randomized to the SLT treatment arm had a one-hour IOP check to monitor for IOP spikes. Any rise in IOP above 10 mm Hg from baseline at the one-hour follow-up was treated with brimonidine tartrate 0.2%. If this did not control IOP spike, then treatment to control the IOP was at the doctor's discretion. All SLT patients also received Prednisolone acetate 1% four times a day for four days, to help improve patient comfort following the procedure.
The eight-week follow-up exam for both groups was performed by a different investigator than the enrolling doctor to ensure masking, thereby minimizing bias, and was done within two hours of the initial baseline exam to control for potential diurnal IOP fluctuations. The follow-up exam included visual acuity, Goldmann applanation tonometry, blood pressure, pulse, pupils, extraocular muscles, and a slit lamp exam.
Baseline IOP was calculated by averaging two IOP measurements taken 30 minutes apart during the baseline exam. If these IOP measurements were greater than +/-2 mm Hg, then a third IOP measurement was taken 30 minutes later. At each IOP measurement, two readings were taken and averaged together.
SLT was performed using a standard protocol and followed specific study guidelines. 10 A Lumenis Selecta II (Lumenis Ltd., Yokneum, Israel) was used to treat 360 degrees of the angle with 100 (+/-10) evenly spaced spots. The pigment in the angle was graded, using the Scheie scale, and the initial power setting for patients with Grade I or II pigment was set at 1.0 mj. 15 The power was then titrated in 0.1 mj steps until there was a visible response of cavitation bubbles or pigment blanching. For patients with Grade III or IV angle pigment the initial power was set at 0.8 mj.
The target sample size for this pilot study was 30 patients. Twenty-six patients met enrollment criteria for the study. Three patients were excluded from the data analysis due to noncompliance, scheduling issues, and observer unmasking. Therefore, data from 23 patients was analyzed for this study. No subjects were lost to follow up. Given the effect sizes seen in the results of changes in IOP levels for each group from baseline to 8-weeks, statistical power of this sample size is 0.75. To fully power this study to p=0.05, a sample size of 42 patient would have been needed.
All collected data was analyzed by computing a combination of descriptive statistics and inferential statistics (specifically frequency distributions, correlation coefficients, independent t-test, dependent t-test, two-factor analysis of variance, and Chi-square) using SPSS v. 24.

Results
Patients were evenly distributed between the two study groups; the demographics of each group can be found in Table 1. The first group (n=12) received 360 degrees of SLT in one eye and the second group (n=11) received brimonidine tartrate 0.2%/timolol maleate 0.5% bid in one eye. The gender distribution was also similar between both groups, approximately 55 percent male and 45 percent female. However, the racial distribution of the two groups was not similar. While the first group was half Caucasian and half African-American, the second group was overwhelmingly Caucasian (82%).
In addition, there were differences between the two groups in the brand of PGA eye drops used by the patients, with Group 1 being relatively equally distributed between the three brands while almost three-fourths of the patients in Group 2 used Lumigan 0.01% (Allergan, Inc. Irvine, CA/USA) eye drops.
The patients were also dissimilar in the amount of pigmentation in the posterior trabecular meshwork with two-thirds of the patients in Group 1 being at Grade II while patients in Group 2 ranged from Grade 0 to Grade III.  the 15% reduction or the 20% reduction difference was statistically or clinically significant.
Additional differences were found when analyzing the percent change in IOP by the gonioscopy pigment grades for each group, F(1, 6) = 1.103, p = .405 (Table 3). For patients receiving 360 degrees of SLT in one eye (Group 1), the average percent reduction was greater at Grade II, while for patients receiving brimonidine tartrate 0.2%/timolol maleate 0.5% bid in one eye (Group 2), the average percent reduction was greater at grade 1.  (Table 4). However, at the 15 percent or higher IOP reduction level, there was a statistical difference between both the gonioscopy pigment grades, F(3) = 5.454, p = .010; and between SLT and drops, F(1) = 6.885, p = .019. Since these results follow what is seen in Table 3, it should not be surprising that the same conclusion can be made about angle pigment and treatment. The incidence of an IOP spike following SLT in this patient population was found to be 8.3%. No major complications or adverse events associated with SLT such as iritis, hyphema, macular edema, or corneal edema were observed in the study. Additionally, no patients reported any adverse events or allergies in the brimonidine tartrate 0.2%/timolol maleate 0.5% group.

Discussion
Standard initial therapy for POAG patients is often a PGA. 12 However, when PGA therapy does not achieve adequate IOP control, there is no consensus for second-line therapy. Typically, second-line treatment includes additional topical therapy (whether it be a single agent or combination drop) or a laser treatment. 16 Previous studies have compared laser treatments to single agent drops. 6,[9][10][11][12][13][14] To the authors' knowledge, there has not been a study comparing laser procedures to combination medications as adjunct therapy in a head-to-head trial. 6,[9][10][11][12][13][14] The main finding from this single site, prospective, randomized, masked study, that compared SLT and brimonidine tartrate 0.2%/timolol maleate 0.5% as adjunct therapy in patients with uncontrolled POAG, was that both treatment groups demonstrated a statistically equivalent reduction in IOP. SLT Though the results were statistically equivalent, there were several differences between the two treatments. Brimonidine tartrate 0.2%/timolol maleate 0.5% achieved a 20% or greater pressure reduction in 81.8% of patients compared to 58.3% with SLT. However, the 20% IOP reduction was not statistically or clinically significant.
In a prospective randomized trial by Katz  The efficacy of the current SLT study was also consistent with other previously reported data.
McIlraith et al. compared a 180 degrees SLT treatment to Latanoprost .005% as initial therapy in patients diagnosed with POAG or ocular hypertension. Their SLT group achieved an IOP reduction of 8.3 mm Hg (31%). 6 Their study also reported that the SLT group achieved a greater than 20% reduction in 83% of patients. 6 19 There was no statistically significant difference in IOP reduction between either group when SLT was added to patients using a PGA or non-prostaglandin agent. The current study showed a similar IOP percentage reduction to Ayala and Chen, despite difference in treatment protocol. Also, their cohort included a large percentage of patients with pseudoexfoliation (53.75%) while those patients were excluded in the current study. Since the early days of SLT, techniques have continued to be refined, and with the proper titration of laser energy, the safety profile of 360-degree SLT treatment is excellent as shown in the current study. 12,13 In keeping with the methodology of Katz et al., patients, not eyes, were randomized to receive either SLT or drops. This eliminated the possible concern of a crossover effect with topical medications, which was a criticism of the Glaucoma Laser Trial. 24,25 In the current study, patients that were treated with SLT were prescribed a topical anti-inflammatory drop following the procedure, which was intended to help improve patient comfort during the postoperative period. Prednisolone acetate 1% four times a day for four days was selected based on a study performed by Relani et al., which showed no negative effect on IOP reduction at three months with this postoperative anti-inflammatory medicine. 26 A subgroup analysis of efficacy in the SLT arm showed a difference with respect to the amount of pigment in the trabecular meshwork. Pigment dependency could help explain the variation in pressure reduction with SLT. In the current study, SLT therapy was found to be less effective in patients when the angle pigment was graded I or less. Pigment cells in the trabecular meshwork exhibit a greater optical absorbance of applied laser energy than non-pigmented surrounding cells. 21 It has been shown that since SLT only targets cells that contain melanin, adjacent or non-pigmented structures are not affected. 21  are consistent with the current study and both suggest that less pigmented angles do not benefit as much from SLT as compared to more heavily pigmented angles. Therefore, it may be reasonable to consider brimonidine tartrate 0.2%/timolol maleate 0.5%, which showed no obvious difference between angle pigmentation subgroups, before SLT as adjunct therapy for patients who have minimal to no angle pigment. Other factors such as the patient's preference, IOP reduction need, compliance, and cost considerations will ultimately influence the final decision.
SLT has proven to be a safe treatment for glaucoma. 6,[9][10][11][12][29][30][31] Major complications are rare and usually do not require any further surgical intervention. 6,9,10,12,[29][30][31]  This study demonstrated that the efficacy and complication rates of SLT when performed by optometrists at this single site are comparable to the rates previously published in the literature.
Additionally, the current and previous studies have shown that SLT is a viable option for both initial and adjunct therapy for the treatment of POAG. 6,[11][12][13] Not only does SLT lower IOP, but also it provides better patient compliance and adherence and may be more cost effective than topical drops. 3,34 SLT has been shown to reduce the nocturnal mean IOP and may blunt the nocturnal peak IOP. 35,36 Possible limitations of the current study include its' small sample size, single study site, and short follow-up period. Although the follow up for the current study is short, a previous study showed that intraocular pressure remains stable at six months; therefore, one month values may be predictive of future intraocular pressure control. 11,19,21 The authors suggest that the results of the current study be confirmed with a larger multicenter randomized prospective trial that includes different glaucoma subtypes, a longer follow up period, and a more diverse patient population.

Conclusion
In conclusion, SLT and brimonidine tartrate 0.2%/timolol maleate 0.5% have been shown to be equivalent in lowering intraocular pressure in uncontrolled POAG patients when used as adjunct therapy for patients already taking a PGA Additionally, this is the first prospective study of optometrists performing SLT. Although this study had a small sample size, the results appeared to show that efficacy and complication rates were comparable to previously published data; however, these results need to be confirmed with a larger multi-centered trial.