- Email: [email protected]
Anti-inflammatory Therapy after Selective Laser Trabeculoplasty
Anti-inflammatory Therapy after Selective Laser Trabeculoplasty A Randomized, Double-Masked, Placebo-Controlled Clinical Trial Delan Jinapriya, MD,1 Mark D’Souza, 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-inflammatory 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 (artificial 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 significantly different among groups (P ¼ 0.99). Likewise, a repeated-measures, mixed-effects model did not find significant differences in IOP outcome at the 1-month time point (P ¼ 0.95). The IOP was reduced in all groups at the 1-month post-SLT time point and all other time points, and no significant 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 ¼ 0.75), and at 1 year after SLT, the percentage of patients maintaining a 20% IOP reduction ranged from 18% to 22% in the 3 study groups. Conclusions: Anti-inflammatory therapy after SLT does not seem to substantially influence the IOP-lowering effect of SLT. In this study of patients with low baseline IOP, SLT showed limited efficacy in achieving a sustained reduction in IOP. Ophthalmology 2014;121:2356-2361 ª 2014 by the American Academy of Ophthalmology.
Selective laser trabeculoplasty (SLT) effectively lowers intraocular pressure (IOP) with minimal risk of complications 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 outflow.9 In particular, SLT induces the release of chemotactic and vasoactive agents, including the inflammatory mediators interleukin-1a, interleukin-1b, and tumor necrosis factor-a.1 These mediators have numerous effects, including macrophage recruitment, matrix metalloproteinaseeinduced extracellular matrix remodeling, and improved permeability of Schlemm’s canal endothelial cells.1,8,10 Many studies of SLT have described the routine use of antiinflammatory 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 inflammation over extended periods of time can cause
2356
2014 by the American Academy of Ophthalmology Published by Elsevier Inc.
complications, the degree of inflammation seen after SLT is minimal. In light of the likelihood that inflammatory mediators are important in the positive clinical effect of SLT, high-level evidence is needed to inform the use of anti-inflammatory 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 Technology Assessment identified the need for research into pharmacologic methods that could enhance the response to trabeculoplasty.13 Thus, we conducted a randomized, doublemasked, placebo-controlled trial to determine whether postlaser anti-inflammatory therapy modifies 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. http://dx.doi.org/10.1016/j.ophtha.2014.07.017 ISSN 0161-6420/14
Jinapriya et al
Anti-inflammatory Therapy after SLT
Enrollment
Randomized (n = 125)
Tears (placebo) ♦ Received allocated intervention (n = 38)
Allocation
Follow-Up at 1 Month
Analysis
♦
Not available for 1 month follow-up (n = 1)
♦
Total included in primary outcome end point (n = 37)
Prednisolone acetate (steroid) ♦ Received allocated intervention (n = 46)
♦
Not available for 1 month follow-up (n = 3)
♦
Total included in primary outcome end point (n = 43)
Ketorolac tromethamine (NSAID) ♦ Received allocated intervention (n = 41)
♦
Not available for 1 month follow-up (n = 4)
♦
Total included in primary outcome end point (n = 37)
Figure 1. Consolidated Standards of Reporting Trials diagram. NSAID ¼ nonsteroidal anti-inflammatory drug.
All patients provided written, informed consent before any studyrelated procedures. The Queen’s University and Affiliated Teaching Hospitals Health Sciences Research Ethics Board approved the study before enrolling study participants. The study is listed on ClinicalTrials.gov, under the identifier NCT00485108.
Study Population and Inclusion/Exclusion Criteria Patients were recruited from study ophthalmologists’ practices within the Department of Ophthalmology at Queen’s 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 trabeculoplasty. 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.
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 Random Treatment Assignment Patients undergoing SLT were assigned to 1 of 3 post-laser treatment arms in blocks of 6 to maintain balanced groups: (1) carboxymethyl cellulose sodium 1.5% artificial 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-inflammatory drug [NSAID] group) 1 drop 4 times daily for 5 days after SLT (Fig 1). Randomization was stratified 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
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 defined as the average of the 4 measurements taken on 2 separate days before laser treatment. Anterior chamber inflammation 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 Artificial Tears (Placebo) n [ 38
Prednisolone Acetate (Steroid) n [ 46
Ketorolac Tromethamine (NSAID) n [ 41
71.911.5 50 19.14.6
69.310.1 50 19.64.6
70.611.6 63 18.53.5
87 13 1.41.4
70 30 1.51.3
83 17 1.61.3
34 66
43 57
26 73
Age (yrs) Female sex (%) Baseline IOP (mmHg) Study eye diagnosis (%) POAG PEXG No. of medications at baseline Timing of SLT (%) Initial therapy Adjunctive therapy
IOP ¼ intraocular pressure; NSAID ¼ nonsteroidal anti-inflammatory drug; PEXG ¼ pseudoexfoliation glaucoma; POAG ¼ primary open-angle glaucoma; SLT ¼ selective laser trabeculoplasty. Data are reported as mean standard deviation unless otherwise specified.
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, defined as not maintaining a 20% IOP reduction from baseline or requiring additional glaucoma therapy (at the treating ophthalmologist’s discretion), was assessed as a secondary outcome. Finally, anterior chamber inflammation 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 withingroup standard deviation of 4 mmHg, using the F-test from analysis of variance (ANOVA), 40 patients per arm provide at least 85% power at alpha ¼ 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 trial’s 3 stratification factors (physician, diagnosis, and initial vs. adjunctive treatment) as fixed covariates. The estimated adjusted between-group differences were then plotted with 95% confidence 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 correlation between the 5 post-baseline assessments.17 The conclusions were confirmed by a simple unadjusted cross-sectional analysis comparing the mean and variance between arms separately at each time by a 1-way ANOVA with Levene’s test for homogeneity variance. The ManteleHaenszel mean test score was used to compare our secondary outcome, anterior chamber inflammation, between arms at 1 hour, 2 days, and 1 month after SLT. In the secondary analysis examining time to treatment failure, failure was defined a priori as (1) an IOP at month 1, 3, 6, or 12 that
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was not at least 20% below baseline or (2) requiring additional IOP-lowering therapy. Cause-specific 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 analyses were carried out using SAS version 9.2 (SAS Inc., Cary, NC).
Results In total, 125 patients were randomized to placebo (n ¼ 38), steroid (n ¼ 46), or NSAID (n ¼ 41). The Consolidated Standards of Reporting Trials flow 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 significantly different among groups (P ¼ 0.99). At all other time points, mean change in IOP was not significantly 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 stratification factors (physician, diagnosis, and SLT as initial vs. adjunctive treatment), the repeated measures mixed-effects model did not show any significant 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 significant 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 significantly different between treatment arms (P ¼ 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-inflammatory 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% confidence 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 ¼ day 2 after selective laser trabeculoplasty (SLT); H1 ¼ hour 1 after SLT; M1 ¼ month 1 after SLT; M3 ¼ month 3 after SLT; M6 ¼ month 6 after SLT; NSAID ¼ nonsteroidal antiinflammatory drug; Y1 ¼ year 1 after SLT.
Anterior Chamber Inflammation Mean anterior chamber inflammation scores at 1 hour, 2 days, and 1 month after SLT treatment were not significantly different between any of the treatment arms (P > 0.2 for all comparisons). By 1 month after SLT, anterior chamber inflammation was observed in only 1 patient.
Discussion Despite the widespread use of anti-inflammatory medication after SLT, high-level data supporting this practice have been lacking. In this randomized clinical trial, we found that the use of anti-inflammatory therapy after SLT did not influence the IOP-lowering effect of SLT when compared with placebo. This finding 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-inflammatory therapy were not designed to address the question of efficacy, 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. Consequently, 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 influences SLT success.4,12 Indeed, the efficacy 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 influence our comparisons between 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. Stratified 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 findings 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
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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 ¼ baseline 1; B2 ¼ baseline 2; D2 ¼ day 2 after selective laser trabeculoplasty (SLT); H1 ¼ hour 1 after SLT; M1 ¼ month 1 after SLT; M3 ¼ month 3 after SLT; M6 ¼ month 6 after SLT; NSAID ¼ nonsteroidal anti-inflammatory drug; Y1 ¼ 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 expected to be aware of the specific 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
Proportion Surviving
0.8
0.6 Placebo Steroid 0.4
NSAID
0.2
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 generalizability to 360 treatments is not known. In conclusion, our findings suggest that the therapeutic mechanism of SLT may be less dependent on inflammatory mediators than some studies have postulated.1,8 However, although we studied commonly used doses of widely used anti-inflammatory 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-inflammatory treatment on SLT responses in subtypes of glaucoma other than POAG and PEXG, such as pigment dispersion glaucoma. The results of this randomized, double-masked, placebocontrolled study suggest that the IOP-lowering effect of SLT is not substantially influenced by the use of post-laser antiinflammatory medications.
References 0
0
3
6 Time (months)
9
12
Figure 4. The selective laser trabeculoplasty (SLT) success survival curves. P ¼ 0.75 by log-rank test comparing time to treatment failure between groups. NSAID ¼ nonsteroidal anti-inflammatory drug.
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1. Latina MA, de Leon JM. Selective laser trabeculoplasty. Ophthalmol Clin North Am 2005;18:409–19. vi. 2. Campbell RJ, Bell CM, Gill SS, et al. Subspecialization in glaucoma surgery. Ophthalmology 2012;119:2270–3.
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Anti-inflammatory Therapy after SLT
3. Nagar M, Ogunyomade A, O’Brart DP, et al. A randomised, prospective study comparing selective laser trabeculoplasty with latanoprost for the control of intraocular pressure in ocular hypertension and open angle glaucoma. Br J Ophthalmol 2005;89:1413–7. 4. Hodge WG, Damji KF, Rock W, et al. Baseline IOP predicts selective laser trabeculoplasty success at 1 year post-treatment: results from a randomised clinical trial. Br J Ophthalmol 2005;89:1157–60. 5. Melamed S, Ben Simon GJ, Levkovitch-Verbin H. Selective laser trabeculoplasty as primary treatment for open-angle glaucoma: a prospective, nonrandomized pilot study. Arch Ophthalmol 2003;121:957–60. 6. McIlraith I, Strasfeld M, Colev G, Hutnik CM. Selective laser trabeculoplasty as initial and adjunctive treatment for openangle glaucoma. J Glaucoma 2006;15:124–30. 7. Latina MA, Sibayan SA, Shin DH, et al. Q-switched 532-nm Nd:YAG laser trabeculoplasty (selective laser trabeculoplasty): a multicenter, pilot, clinical study. Ophthalmology 1998;105:2082–90. 8. Alvarado JA, Alvarado RG, Yeh RF, et al. A new insight into the cellular regulation of aqueous outflow: how trabecular meshwork endothelial cells drive a mechanism that regulates the permeability of Schlemm’s canal endothelial cells. Br J Ophthalmol 2005;89:1500–5. 9. Ayala M, Chen E. The influence of topical prostaglandin analogues in inflammation after selective laser trabeculoplasty treatment. J Ocul Pharmacol Ther 2012;28:118–22. 10. Stein JD, Challa P. Mechanisms of action and efficacy of argon laser trabeculoplasty and selective laser trabeculoplasty. Curr Opin Ophthalmol 2007;18:140–5. 11. Realini T, Charlton J, Hettlinger M. The impact of anti-inflammatory therapy on intraocular pressure reduction following selective laser trabeculoplasty. Ophthalmic Surg Lasers Imaging 2010;41:100–3.
12. Mao AJ, Pan XJ, McIlraith I, et al. Development of a prediction rule to estimate the probability of acceptable intraocular pressure reduction after selective laser trabeculoplasty in open-angle glaucoma and ocular hypertension. J Glaucoma 2008;17:449–54. 13. Samples JR, Singh K, Lin SC, et al. Laser trabeculoplasty for open-angle glaucoma: a report by the American Academy of Ophthalmology. Ophthalmology 2011;118: 2296–302. 14. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. results of the First International Workshop. Am J Ophthalmol 2005;140:509–16. 15. Verbeke G, Molenberghs G. A Model for Longitudinal Data. In: Linear Mixed Models for Longitudinal Data. New York: Springer-Verlag; 2000:23–9. 16. Kramer CY. Extension of multiple range tests to group means with unequal numbers of replications. Biometrics 1956;12: 309–10. 17. Littell RC, Pendergast J, Natarajan R. Modelling covariance structure in the analysis of repeated measures data. Stat Med 2000;19:1793–819. 18. Lanzetta P, Menchini U, Virgili G. Immediate intraocular pressure response to selective laser trabeculoplasty. Br J Ophthalmol 1999;83:29–32. 19. Gracner T. Intraocular pressure response to selective laser trabeculoplasty in the treatment of primary open-angle glaucoma. Ophthalmologica 2001;215:267–70. 20. Damji KF, Bovell AM, Hodge WG, et al. Selective laser trabeculoplasty versus argon laser trabeculoplasty: results from a 1-year randomised clinical trial. Br J Ophthalmol 2006;90: 1490–4. 21. Song J, Lee PP, Epstein DL, et al. High failure rate associated with 180 degrees selective laser trabeculoplasty. J Glaucoma 2005;14:400–8.
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, Queen’s University and Hotel Dieu Hospital, Kingston, Ontario, Canada. 2
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 Pfizer. H.H.: received payment for the development of educational presentations from Novartis. D.S.: consultant to Tear Science.
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; preparation, 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. Abbreviations and Acronyms: ANOVA ¼ analysis of variance; CI ¼ confidence interval; IOP ¼ intraocular pressure; NSAID ¼ nonsteroidal anti-inflammatory drug; PEXG ¼ pseudo-exfoliation glaucoma; POAG ¼ primary openangle glaucoma; SLT ¼ 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: [email protected].
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Selective laser trabeculoplasty (SLT) effectively lowers intraocular pressure (IOP) with minimal risk of complications 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 outflow.9 In particular, SLT induces the release of chemotactic and vasoactive agents, including the inflammatory mediators interleukin-1a, interleukin-1b, and tumor necrosis factor-a.1 These mediators have numerous effects, including macrophage recruitment, matrix metalloproteinaseeinduced extracellular matrix remodeling, and improved permeability of Schlemm’s canal endothelial cells.1,8,10 Many studies of SLT have described the routine use of antiinflammatory 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 inflammation over extended periods of time can cause
2356
2014 by the American Academy of Ophthalmology Published by Elsevier Inc.
complications, the degree of inflammation seen after SLT is minimal. In light of the likelihood that inflammatory mediators are important in the positive clinical effect of SLT, high-level evidence is needed to inform the use of anti-inflammatory 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 Technology Assessment identified the need for research into pharmacologic methods that could enhance the response to trabeculoplasty.13 Thus, we conducted a randomized, doublemasked, placebo-controlled trial to determine whether postlaser anti-inflammatory therapy modifies 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. http://dx.doi.org/10.1016/j.ophtha.2014.07.017 ISSN 0161-6420/14
Jinapriya et al
Anti-inflammatory Therapy after SLT
Enrollment
Randomized (n = 125)
Tears (placebo) ♦ Received allocated intervention (n = 38)
Allocation
Follow-Up at 1 Month
Analysis
♦
Not available for 1 month follow-up (n = 1)
♦
Total included in primary outcome end point (n = 37)
Prednisolone acetate (steroid) ♦ Received allocated intervention (n = 46)
♦
Not available for 1 month follow-up (n = 3)
♦
Total included in primary outcome end point (n = 43)
Ketorolac tromethamine (NSAID) ♦ Received allocated intervention (n = 41)
♦
Not available for 1 month follow-up (n = 4)
♦
Total included in primary outcome end point (n = 37)
Figure 1. Consolidated Standards of Reporting Trials diagram. NSAID ¼ nonsteroidal anti-inflammatory drug.
All patients provided written, informed consent before any studyrelated procedures. The Queen’s University and Affiliated Teaching Hospitals Health Sciences Research Ethics Board approved the study before enrolling study participants. The study is listed on ClinicalTrials.gov, under the identifier NCT00485108.
Study Population and Inclusion/Exclusion Criteria Patients were recruited from study ophthalmologists’ practices within the Department of Ophthalmology at Queen’s 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 trabeculoplasty. 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.
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 Random Treatment Assignment Patients undergoing SLT were assigned to 1 of 3 post-laser treatment arms in blocks of 6 to maintain balanced groups: (1) carboxymethyl cellulose sodium 1.5% artificial 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-inflammatory drug [NSAID] group) 1 drop 4 times daily for 5 days after SLT (Fig 1). Randomization was stratified 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
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 defined as the average of the 4 measurements taken on 2 separate days before laser treatment. Anterior chamber inflammation 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 Artificial Tears (Placebo) n [ 38
Prednisolone Acetate (Steroid) n [ 46
Ketorolac Tromethamine (NSAID) n [ 41
71.911.5 50 19.14.6
69.310.1 50 19.64.6
70.611.6 63 18.53.5
87 13 1.41.4
70 30 1.51.3
83 17 1.61.3
34 66
43 57
26 73
Age (yrs) Female sex (%) Baseline IOP (mmHg) Study eye diagnosis (%) POAG PEXG No. of medications at baseline Timing of SLT (%) Initial therapy Adjunctive therapy
IOP ¼ intraocular pressure; NSAID ¼ nonsteroidal anti-inflammatory drug; PEXG ¼ pseudoexfoliation glaucoma; POAG ¼ primary open-angle glaucoma; SLT ¼ selective laser trabeculoplasty. Data are reported as mean standard deviation unless otherwise specified.
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, defined as not maintaining a 20% IOP reduction from baseline or requiring additional glaucoma therapy (at the treating ophthalmologist’s discretion), was assessed as a secondary outcome. Finally, anterior chamber inflammation 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 withingroup standard deviation of 4 mmHg, using the F-test from analysis of variance (ANOVA), 40 patients per arm provide at least 85% power at alpha ¼ 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 trial’s 3 stratification factors (physician, diagnosis, and initial vs. adjunctive treatment) as fixed covariates. The estimated adjusted between-group differences were then plotted with 95% confidence 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 correlation between the 5 post-baseline assessments.17 The conclusions were confirmed by a simple unadjusted cross-sectional analysis comparing the mean and variance between arms separately at each time by a 1-way ANOVA with Levene’s test for homogeneity variance. The ManteleHaenszel mean test score was used to compare our secondary outcome, anterior chamber inflammation, between arms at 1 hour, 2 days, and 1 month after SLT. In the secondary analysis examining time to treatment failure, failure was defined a priori as (1) an IOP at month 1, 3, 6, or 12 that
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was not at least 20% below baseline or (2) requiring additional IOP-lowering therapy. Cause-specific 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 analyses were carried out using SAS version 9.2 (SAS Inc., Cary, NC).
Results In total, 125 patients were randomized to placebo (n ¼ 38), steroid (n ¼ 46), or NSAID (n ¼ 41). The Consolidated Standards of Reporting Trials flow 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 significantly different among groups (P ¼ 0.99). At all other time points, mean change in IOP was not significantly 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 stratification factors (physician, diagnosis, and SLT as initial vs. adjunctive treatment), the repeated measures mixed-effects model did not show any significant 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 significant 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 significantly different between treatment arms (P ¼ 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).
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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% confidence 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 ¼ day 2 after selective laser trabeculoplasty (SLT); H1 ¼ hour 1 after SLT; M1 ¼ month 1 after SLT; M3 ¼ month 3 after SLT; M6 ¼ month 6 after SLT; NSAID ¼ nonsteroidal antiinflammatory drug; Y1 ¼ year 1 after SLT.
Anterior Chamber Inflammation Mean anterior chamber inflammation scores at 1 hour, 2 days, and 1 month after SLT treatment were not significantly different between any of the treatment arms (P > 0.2 for all comparisons). By 1 month after SLT, anterior chamber inflammation was observed in only 1 patient.
Discussion Despite the widespread use of anti-inflammatory medication after SLT, high-level data supporting this practice have been lacking. In this randomized clinical trial, we found that the use of anti-inflammatory therapy after SLT did not influence the IOP-lowering effect of SLT when compared with placebo. This finding 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-inflammatory therapy were not designed to address the question of efficacy, 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. Consequently, 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 influences SLT success.4,12 Indeed, the efficacy 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 influence our comparisons between 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. Stratified 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 findings 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
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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 ¼ baseline 1; B2 ¼ baseline 2; D2 ¼ day 2 after selective laser trabeculoplasty (SLT); H1 ¼ hour 1 after SLT; M1 ¼ month 1 after SLT; M3 ¼ month 3 after SLT; M6 ¼ month 6 after SLT; NSAID ¼ nonsteroidal anti-inflammatory drug; Y1 ¼ 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 expected to be aware of the specific 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
Proportion Surviving
0.8
0.6 Placebo Steroid 0.4
NSAID
0.2
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 generalizability to 360 treatments is not known. In conclusion, our findings suggest that the therapeutic mechanism of SLT may be less dependent on inflammatory mediators than some studies have postulated.1,8 However, although we studied commonly used doses of widely used anti-inflammatory 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-inflammatory treatment on SLT responses in subtypes of glaucoma other than POAG and PEXG, such as pigment dispersion glaucoma. The results of this randomized, double-masked, placebocontrolled study suggest that the IOP-lowering effect of SLT is not substantially influenced by the use of post-laser antiinflammatory medications.
References 0
0
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6 Time (months)
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Figure 4. The selective laser trabeculoplasty (SLT) success survival curves. P ¼ 0.75 by log-rank test comparing time to treatment failure between groups. NSAID ¼ nonsteroidal anti-inflammatory drug.
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1. Latina MA, de Leon JM. Selective laser trabeculoplasty. Ophthalmol Clin North Am 2005;18:409–19. vi. 2. Campbell RJ, Bell CM, Gill SS, et al. Subspecialization in glaucoma surgery. Ophthalmology 2012;119:2270–3.
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3. Nagar M, Ogunyomade A, O’Brart DP, et al. A randomised, prospective study comparing selective laser trabeculoplasty with latanoprost for the control of intraocular pressure in ocular hypertension and open angle glaucoma. Br J Ophthalmol 2005;89:1413–7. 4. Hodge WG, Damji KF, Rock W, et al. Baseline IOP predicts selective laser trabeculoplasty success at 1 year post-treatment: results from a randomised clinical trial. Br J Ophthalmol 2005;89:1157–60. 5. Melamed S, Ben Simon GJ, Levkovitch-Verbin H. Selective laser trabeculoplasty as primary treatment for open-angle glaucoma: a prospective, nonrandomized pilot study. Arch Ophthalmol 2003;121:957–60. 6. McIlraith I, Strasfeld M, Colev G, Hutnik CM. Selective laser trabeculoplasty as initial and adjunctive treatment for openangle glaucoma. J Glaucoma 2006;15:124–30. 7. Latina MA, Sibayan SA, Shin DH, et al. Q-switched 532-nm Nd:YAG laser trabeculoplasty (selective laser trabeculoplasty): a multicenter, pilot, clinical study. Ophthalmology 1998;105:2082–90. 8. Alvarado JA, Alvarado RG, Yeh RF, et al. A new insight into the cellular regulation of aqueous outflow: how trabecular meshwork endothelial cells drive a mechanism that regulates the permeability of Schlemm’s canal endothelial cells. Br J Ophthalmol 2005;89:1500–5. 9. Ayala M, Chen E. The influence of topical prostaglandin analogues in inflammation after selective laser trabeculoplasty treatment. J Ocul Pharmacol Ther 2012;28:118–22. 10. Stein JD, Challa P. Mechanisms of action and efficacy of argon laser trabeculoplasty and selective laser trabeculoplasty. Curr Opin Ophthalmol 2007;18:140–5. 11. Realini T, Charlton J, Hettlinger M. The impact of anti-inflammatory therapy on intraocular pressure reduction following selective laser trabeculoplasty. Ophthalmic Surg Lasers Imaging 2010;41:100–3.
12. Mao AJ, Pan XJ, McIlraith I, et al. Development of a prediction rule to estimate the probability of acceptable intraocular pressure reduction after selective laser trabeculoplasty in open-angle glaucoma and ocular hypertension. J Glaucoma 2008;17:449–54. 13. Samples JR, Singh K, Lin SC, et al. Laser trabeculoplasty for open-angle glaucoma: a report by the American Academy of Ophthalmology. Ophthalmology 2011;118: 2296–302. 14. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. results of the First International Workshop. Am J Ophthalmol 2005;140:509–16. 15. Verbeke G, Molenberghs G. A Model for Longitudinal Data. In: Linear Mixed Models for Longitudinal Data. New York: Springer-Verlag; 2000:23–9. 16. Kramer CY. Extension of multiple range tests to group means with unequal numbers of replications. Biometrics 1956;12: 309–10. 17. Littell RC, Pendergast J, Natarajan R. Modelling covariance structure in the analysis of repeated measures data. Stat Med 2000;19:1793–819. 18. Lanzetta P, Menchini U, Virgili G. Immediate intraocular pressure response to selective laser trabeculoplasty. Br J Ophthalmol 1999;83:29–32. 19. Gracner T. Intraocular pressure response to selective laser trabeculoplasty in the treatment of primary open-angle glaucoma. Ophthalmologica 2001;215:267–70. 20. Damji KF, Bovell AM, Hodge WG, et al. Selective laser trabeculoplasty versus argon laser trabeculoplasty: results from a 1-year randomised clinical trial. Br J Ophthalmol 2006;90: 1490–4. 21. Song J, Lee PP, Epstein DL, et al. High failure rate associated with 180 degrees selective laser trabeculoplasty. J Glaucoma 2005;14:400–8.
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, Queen’s University and Hotel Dieu Hospital, Kingston, Ontario, Canada. 2
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 Pfizer. H.H.: received payment for the development of educational presentations from Novartis. D.S.: consultant to Tear Science.
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; preparation, 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. Abbreviations and Acronyms: ANOVA ¼ analysis of variance; CI ¼ confidence interval; IOP ¼ intraocular pressure; NSAID ¼ nonsteroidal anti-inflammatory drug; PEXG ¼ pseudo-exfoliation glaucoma; POAG ¼ primary openangle glaucoma; SLT ¼ 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: [email protected].
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