- Email: [email protected]
A Comparison of Long-term Intraocular Pressure Fluctuation in Patients Treated With Bimatoprost or Latanoprost
A Comparison of Long-term Intraocular Pressure Fluctuation in Patients Treated With Bimatoprost or Latanoprost STEVEN T. SIMMONS, PAULA BERNSTEIN, AND DAVID A. HOLLANDER ● PURPOSE: To evaluate long-term intraocular pressure (IOP) fluctuation in patients with glaucoma or ocular hypertension treated with bimatoprost or latanoprost. ● DESIGN: Post hoc analysis of prospectively collected data from a previously reported multicenter, investigatormasked, randomized clinical trial of bimatoprost and latanoprost. ● METHODS: Patients were treated bilaterally with bimatoprost (n ⴝ 133) or latanoprost (n ⴝ 136) for six months. IOP measurements were taken at 8 AM, 12 PM, and 4 PM at baseline, week 1, and months 1, 3, and 6. Long-term IOP fluctuation during treatment was determined as the standard deviation (SD) of all 12 follow-up measurements. ● RESULTS: There was no significant between-group difference in short-term daily IOP fluctuation at baseline. Long-term IOP fluctuation over six months of treatment [mean SD (range SD)] was 1.9 (0.5 to 6.3) mm Hg with latanoprost vs 1.7 (0.5 to 3.9) mm Hg with bimatoprost (P ⴝ .050). Latanoprost-treated eyes were more likely than bimatoprost-treated eyes to have long-term IOP fluctuation of >3 mm Hg (7.8% vs 2.5% of eyes; P ⴝ .009). ● CONCLUSIONS: Bimatoprost-treated eyes demonstrated less long-term fluctuation in IOP compared with latanoprost-treated eyes in this six-month study. Additional studies are needed to confirm these findings and to determine their impact on glaucomatous progression. (Am J Ophthalmol 2008;146:473– 477. © 2008 by Elsevier Inc. All rights reserved.)
T
HE INFLUENCE OF LONG-TERM INTRAOCULAR PRES-
sure (IOP) fluctuation on the risk of glaucomatous visual field (VF) progression is currently under debate.1–5 In a multivariate linear regression analysis of data from the Advanced Glaucoma Intervention Study (AGIS), older age at the initial intervention, a larger number of glaucoma interventions, longer follow-up, and greater intervisit IOP fluctuation during follow-up were all associated with a higher probability of VF progression.1 Of
Accepted for publication Apr 18, 2008. From Glaucoma Consultants of the Capital Region (S.T.S.), Slingerlands, New York; and Allergan Inc (P.B., D.A.H.), Irvine, California. Inquiries to Steven T. Simmons, Glaucoma Consultants of the Capital Region, 1240 New Scotland Road, Suite 201, Slingerlands, NY 12159; e-mail: [email protected] 0002-9394/08/$34.00 doi:10.1016/j.ajo.2008.04.030
©
2008 BY
these factors, only intervisit fluctuation in IOP was consistently associated with progression in eyes with and without a history of cataract extraction.1 Each 1 mm Hg increase in IOP fluctuation (defined as the standard deviation [SD] of the IOP measurements taken at all visits after the initial surgery) was associated with a 31% increase in the risk of VF progression.1 Similarly, a strong association between IOP fluctuation and risk of glaucoma progression was found in a cohort study of patients given routine care at glaucoma specialty centers.2 In contrast, IOP fluctuation was not related to glaucomatous progression in a recent analysis of results from the Early Manifest Glaucoma Trial (EMGT) in which only mean follow-up IOP was found to be a significant risk factor.3 Studies in ocular hypertensive patients have also reported no relationship between intervisit IOP fluctuation and the risk of conversion to glaucoma.4,5 The disparate findings regarding the impact of IOP fluctuation on glaucomatous progression may be partially attributed to different patient populations, study designs, and methods for analyzing IOP fluctuation.6 Nevertheless, the importance of IOP fluctuation was underscored in a recent study of glaucoma patients following combined trabeculectomy, cataract extraction, and posterior chamber intraocular lens implantation.7 Although mean IOP was similar and consistently less than 18 mm Hg for patients with either large (SD ⬎ 2) or small (SD ⱕ 2) IOP fluctuation, larger long-term IOP fluctuation was associated with a progressive increase in VF deterioration.7 The authors concluded that reducing long-term IOP fluctuation is critical in minimizing glaucomatous progression.7 Bimatoprost and latanoprost are two commonly used topical medications with first-line indications for reducing IOP in glaucoma and ocular hypertension (OHT).8,9 In large randomized controlled trials, each of these medications has been shown to provide substantial reductions in mean IOP.8,9 However, long-term fluctuation in IOP for individual patients treated with these medications has not been examined. Given the potential importance of IOP fluctuation,1,2,6,7,10 –14 a post hoc analysis was undertaken to examine long-term IOP fluctuation in glaucoma and OHT patients treated with bimatoprost or latanoprost in a previously reported six-month clinical comparison trial.15 This particular trial was chosen for analysis because it had the longest duration and the most time points of all
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TABLE. Intraocular Pressure and Short-term (Daily) Intraocular Pressure Fluctuation at Untreated Baseline for Eyes in the Bimatoprost and Latanoprost Treatment Groups
Baseline IOP
Bimatoprost Treatment Group (n ⫽ 266 eyes)
Latanoprost Treatment Group (n ⫽ 272 eyes)
Mean (SD) IOP, mm Hg 8 AM 12 PM 4 PM Mean (SD) daily IOP fluctuation, mm Hgb [range]
25.0 (2.9) 24.0 (3.2) 22.6 (3.4) 2.0 (1.44) [0.0 to 8.5]
24.9 (2.8) 23.3 (3.2) 22.5 (3.3) 1.9 (1.29) [0.0 to 7.4]
P valuea
.641 .028 .529 .371
IOP ⫽ intraocular pressure; SD ⫽ standard deviation. a From two-way analysis of variance model with treatment and site as fixed effects and patient nested within treatment as a random effect. b Short-term (daily) fluctuation in IOP is the SD of the three diurnal IOP measurements (8 AM, 12 PM, and 4 PM).
head-to-head studies comparing bimatoprost and latanoprost.15–20
follow-up were from an analysis of variance model that included treatment and site as fixed effects. To adjust for use of measurements from two eyes of the same patient that may not be independent, patient nested within treatment was also included in the model as a random effect. The proportion of eyes with long-term IOP fluctuation of ⱖ3 mm Hg (the AGIS criteria)1 was compared between groups using the 2 test.
METHODS THE ANALYSIS WAS PERFORMED ON DATA COLLECTED IN A
previously reported randomized, prospective, multicenter, investigator-masked clinical trial comparing bimatoprost and latanoprost.15 Inclusion criteria for the study were patients with either glaucoma or OHT and baseline IOP (8 AM) following appropriate washout between 22 mm Hg and 34 mm Hg in each eye. There were no significant differences between treatment groups in patient age, gender, race, iris color, diagnosis, or need for washout. Patients were randomized to bilateral treatment with once-daily bimatoprost 0.03% (Lumigan; Allergan Inc, Irvine, California, USA) or latanoprost 0.005% (Xalatan; Pfizer Inc, New York, New York, USA) for six months. IOP was measured at 8 AM, 12 PM, and 4 PM at baseline, week 1, and months 1, 3, and 6. There is currently no clear consensus in the literature regarding what methods of analysis should be used for the purpose of assessing IOP fluctuation. We chose to use the SD of IOP as the measure of IOP fluctuation, as was done in previous studies in the peer-reviewed literature.1–5,7 The current analysis of IOP includes all observed values from both eyes of study patients. All eyes for which complete data were available at all study time points were included. No imputation was performed for missing values. Fluctuation in IOP within each eye was calculated using the SD of IOP measurements. Short-term, daily fluctuation in IOP for an individual eye at baseline was defined as the SD of the baseline 8 AM, 12 PM, and 4 PM measurements. Long-term fluctuation in IOP for an individual eye was defined as the SD of all 12 measurements taken after baseline during the six months of follow-up. The ␣ level for statistical significance was set at 0.05. Comparisons of baseline IOP and long-term IOP fluctuation across 474
AMERICAN JOURNAL
RESULTS ● BASELINE INTRAOCULAR PRESSURE:
Baseline analyses included 266 eyes in the bimatoprost group and 272 eyes in the latanoprost group. The untreated baseline mean IOP at each hour for eyes in the bimatoprost and latanoprost groups is shown in the Table. At 8 AM and 4 PM, the two groups were comparable with respect to mean IOP. At 12 PM, mean IOP was higher in the bimatoprost group compared with the latanoprost group. Short-term daily fluctuation in IOP at untreated baseline was similar between the two groups (Table). ● INTRAOCULAR PRESSURE FLUCTUATION DURING TREATMENT: The number of eyes excluded from analysis
because of missing follow-up data was similar in the two groups (9.8% of bimatoprost-treated eyes and 10.3% of latanoprost-treated eyes). Early discontinuations of patients from the study (nine bimatoprost patients and 11 latanoprost patients) accounted for most of the missing data. The reasons for patient discontinuations were similar between groups and previously reported.13 Long-term IOP fluctuation observed in individual eyes across six months of treatment can be seen in a box-plot of the data (Figure 1). Long-term IOP fluctuation ranged from 0.5 mm Hg to 6.3 mm Hg in latanoprost-treated eyes and 0.5 mm Hg to 3.9 mm Hg in bimatoprost-treated eyes. Mean (SD) long-term fluctuation in IOP across follow-up was smaller for bimatoprost-treated eyes [1.7 (0.56) mm OF
OPHTHALMOLOGY
SEPTEMBER 2008
FIGURE 2. Percentage of bimatoprost- and latanoprost-treated eyes with long-term IOP fluctuation of >3 mm Hg. P ⴝ .009 vs bimatoprost.
low and well-controlled IOP, IOP fluctuation may play a role in leading to progression. Within this context, it may be important to compare topical glaucoma medications for their ability to minimize IOP fluctuation in addition to their IOP-lowering effects.20 –24 The present analysis was undertaken to explore IOP fluctuation in patients treated with bimatoprost or latanoprost. Lower long-term mean IOP fluctuation across all 12 follow-up measurements was observed in the bimatoprosttreated eyes relative to latanoprost-treated eyes. The difference in long-term IOP fluctuation between treatment groups was underscored by the different distributions of IOP fluctuation values observed in the groups, as depicted in the scatter plot in Figure 1. A larger proportion of eyes in the latanoprost group (7.8%) relative to the bimatoprost group (2.5%) exhibited 3 mm Hg or greater long-term fluctuation in IOP. While we acknowledge that any dividing line between high and low IOP fluctuation is somewhat arbitrary, 3 mm Hg was used in this study because this was also the basis for evaluating fluctuation in the AGIS analysis.1 It is possible that the inclusion of data from visits before the study drugs reached full effect could affect the IOP fluctuation observed. Because more than one month of treatment may be needed for the study drugs to reach full effect,9,25 the analysis of long-term IOP fluctuation was repeated including data only from months 3 and 6. Bimatoprost-treated eyes continued to show less IOP fluctuation than latanoprost-treated eyes in this analysis (mean IOP fluctuation of 1.6 mm Hg in bimatoprost-treated eyes vs 1.8 mm Hg in latanoprost-treated eyes; P ⫽ .041). Similar to previous studies,1–5,7 the SD of IOP measurements was used as a measure for IOP fluctuation in this exploratory analysis. The SD may be preferred over range as a measure of IOP fluctuation because it is less influenced by extreme values and takes the number of observations into account.6 The number of outliers in this study with
FIGURE 1. Box-plot of long-term intraocular pressure (IOP) fluctuation across six months in bimatoprost- and latanoprosttreated eyes. Long-term fluctuation in IOP was defined as the standard deviation of all 12 measurements during the six months of follow-up. Boxes show 75th, 50th, and 25th percentiles. (Top whisker) 90th percentile; (Bottom whisker) 10th percentile. Plus signs ⴝ individual data points below the 10th percentile or above the 90th percentile.
Hg] than for latanoprost-treated eyes [1.9 (0.89) mm Hg; P ⫽ .050]. The AGIS criteria of a SD ⱖ 3 mm Hg was applied to the analysis of long-term IOP fluctuation. A lower percentage of eyes in the bimatoprost group (2.5%) than in the latanoprost group (7.8%) had long-term fluctuation in IOP of ⱖ3 mm Hg (P ⫽ .009; Figure 2).
DISCUSSION ELEVATED IOP REMAINS THE PREDOMINANT RISK FACTOR
for glaucoma. While the EMGT analysis revealed only mean IOP as a factor leading to progression, a number of recent studies have suggested that fluctuation in IOP may also serve as an independent risk factor for glaucomatous VF progression.1,2,7,10,11 The recent study by Hong and associates7 demonstrates that in patients with relatively VOL. 146, NO. 3
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unusually large long-term IOP fluctuation can be seen in the box-plot of the data (Figure 1). There are several limitations of the present analysis. The analysis was based on results from a single clinical trial, and based on the original study design, IOP readings were obtained only between 8 AM and 4 PM. IOP measurements taken outside this window may, in fact, contribute to larger IOP fluctuation,26 and a previous study reported a larger range in IOP over 24 hours in latanoprost-treated eyes than in bimatoprost-treated eyes.20 In addition, the trial was only six months in duration, with relatively few IOP readings. Finally, this was a post hoc analysis, and the study was not specifically designed to evaluate IOP fluctuation.
Additional long-term prospective trials may or may not confirm these findings. The AGIS Study was based on a population of patients with uncontrolled IOP necessitating one or more surgical interventions. Nevertheless, the findings of AGIS have emphasized a new method for evaluating IOP control that may be applied to comparisons of IOP-lowering medications. While the results of the present study suggest less long-term IOP fluctuation over six months in bimatoprosttreated eyes relative to latanoprost-treated eyes, additional long-term prospective studies will be necessary to further evaluate IOP fluctuation with both of these medications as well as the impact of IOP fluctuation on disease progression.
THIS STUDY WAS SUPPORTED BY ALLERGAN INC, IRVINE, CALIFORNIA. DR SIMMONS IS A PAID CONSULTANT FOR ALLERGAN and has received reimbursement for research from Allergan and Alcon. Ms Bernstein and Dr Hollander are employees of Allergan Inc. Involved in design of the study (S.T.S.); statistical analysis (P.B.); data interpretation (S.T.S., P.B., D.A.H.); and preparation and approval of the manuscript (S.T.S., P.B., D.A.H.). The clinical trial was carried out in accordance with HIPAA regulations at 18 sites. The study protocol was approved at each site by the University of Alabama at Birmingham Institutional Review Board, the University of Arizona Human Subjects Committee, the New York Eye and Ear Institutional Review Board, or Quorum Review Inc. Allergan Inc provided the study data and provided support for the clinical trial and the statistical analysis of the results.
REFERENCES 10.
1. Nouri-Mahdavi K, Hoffman D, Coleman AL, et al. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology 2004;111:1627–1635. 2. Lee PP, Walt JW, Rosenblatt LC, Siegartel LR, Stern LS, Glaucoma Care Study Group. Association between intraocular pressure variation and glaucoma progression: data from a United States chart review. Am J Ophthalmol 2007;144: 901–907. 3. Bengtsson B, Leske MC, Hyman L, Heijl A, Early Manifest Glaucoma Trial Group. Fluctuation of intraocular pressure and glaucoma progression in the early manifest glaucoma trial. Ophthalmology 2007;114:205–209. 4. Miglior S, Torri V, Zeyen T, Pfeiffer N, Vaz JC, Adamsons I, European Glaucoma Prevention Study (EGPS) Group. Intercurrent factors associated with the development of openangle glaucoma in the European Glaucoma Prevention Study. Am J Ophthalmol 2007;144:266 –275. 5. Medeiros FA, Weinreb RN, Zangwill LM, et al. Long-term intraocular pressure fluctuations and risk of conversion from ocular hypertension to glaucoma. Ophthalmology 2008;115: 934 –940. 6. Caprioli J. Intraocular pressure fluctuation: an independent risk factor for glaucoma? Arch Ophthalmol 2007;125:1124 –1125. 7. Hong S, Seong GJ, Hong YJ. Long-term intraocular pressure fluctuation and progressive visual field deterioration in patients with glaucoma and low intraocular pressures after a triple procedure. Arch Ophthalmol 2007;125:1010 –1013. 8. Hedman K, Alm A. A pooled-data analysis of three randomized, double-masked, six-month clinical studies comparing the intraocular pressure reducing effect of latanoprost and timolol. Eur J Ophthalmol 2000;10:95–104. 9. Higginbotham EJ, Schuman JS, Goldberg I, et al. One-year, randomized study comparing bimatoprost and timolol in
476
AMERICAN JOURNAL
11.
12.
13.
14.
15.
16.
17.
18.
OF
glaucoma and ocular hypertension. Arch Ophthalmol 2002;120:1286 –1293. Nakagami T, Yamazaki Y, Hayamizu F. Prognostic factors for progression of visual field damage in patients with normal-tension glaucoma. Jpn J Ophthalmol 2006;50: 38 – 43. Asrani S, Zeimer R, Wilensky J, Gieser D, Vitale S, Lindenmuth K. Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma 2000;9:134 –142. Gonzalez I, Pablo LE, Pueyo M, et al. Assessment of diurnal tensional curve in early glaucoma damage. Int Ophthalmol 1996;20:113–115. Ishida K, Yamamoto T, Kitazawa Y. Clinical factors associated with progression of normal-tension glaucoma. J Glaucoma 1998;7:372–377. Bergea B, Bodin L, Svedbergh B. Impact of intraocular pressure regulation on visual fields in open-angle glaucoma. Ophthalmology 1999;106:997–1004. Noecker RS, Dirks MS, Choplin NT, et al. A six-month randomized clinical trial comparing the intraocular pressurelowering efficacy of bimatoprost and latanoprost in patients with ocular hypertension or glaucoma. Am J Ophthalmol 2003;135:55– 63. DuBiner H, Cooke D, Dirks M, Stewart WC, VanDenburgh AM, Felix C. Efficacy and safety of bimatoprost in patients with elevated intraocular pressure: a 30-day comparison with latanoprost. Surv Ophthalmol 2001;45: S353–S360. Gandolfi S, Simmons ST, Sturm R, Chen K, VanDenburgh AM, Bimatoprost Study Group 3. Three-month comparison of bimatoprost and latanoprost in patients with glaucoma and ocular hypertension. Adv Ther 2001; 18:110 –121. Parrish R, Palmberg P, Sheu W-P, XLT Study Group. A comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, ran-
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19.
20.
21.
22.
domized, masked-evaluator, multicenter study. Am J Ophthalmol 2003;135:688 –703. Walters TR, DuBiner HB, Carpenter SP, Khan B, VanDenburgh AM, Bimatoprost Circadian Study Group. 24-Hour IOP control with once-daily bimatoprost, timolol gel-forming solution, or latanoprost: a 1-month, randomized, comparative clinical trial. Surv Ophthalmol 2004;49:S26 –S35. Konstas AG, Katsimbris JM, Lallos N, Boukaras GP, Jenkins JN, Stewart WC. Latanoprost 0.005% versus bimatoprost 0.03% in primary open-angle glaucoma patients. Ophthalmology 2005;112:262–266. Konstas AG, Papapanos P, Tersis I, Houliara D, Stewart WC. Twenty-four-hour diurnal curve comparison of commercially available latanoprost 0.005% versus the timolol and dorzolamide fixed combination. Ophthalmology 2003; 110:1357–1360. Konstas AG, Mylopoulos N, Karabatsas CH, et al. Diurnal intraocular pressure reduction with latanoprost 0.005% com-
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23.
24.
25.
26.
IN
pared to timolol maleate 0.5% as monotherapy in subjects with exfoliation glaucoma. Eye 2004;18:893– 899. Konstas AG, Boboridis K, Tzetzi D, Kallinderis K, Jenkins JN, Stewart WC. Twenty-four-hour control with latanoprost-timolol-fixed combination therapy vs latanoprost therapy. Arch Ophthalmol 2005;123:898 –902. Konstas AG, Lake S, Economou AI, Kaltsos K, Jenkins JN, Stewart WC. 24-Hour control with a latanoprost-timolol fixed combination vs timolol alone. Arch Ophthalmol 2006; 124:1553–1557. Camras CB. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six-month masked, multicenter trial in the United States. The United States Latanoprost Study Group. Ophthalmology 1996;103:138 –147. Barkana Y, Anis S, Liebmann J, Tello C, Ritch R. Clinical utility of intraocular pressure monitoring outside of normal office hours in patients with glaucoma. Arch Ophthalmol 2006;124:793–797.
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T
HE INFLUENCE OF LONG-TERM INTRAOCULAR PRES-
sure (IOP) fluctuation on the risk of glaucomatous visual field (VF) progression is currently under debate.1–5 In a multivariate linear regression analysis of data from the Advanced Glaucoma Intervention Study (AGIS), older age at the initial intervention, a larger number of glaucoma interventions, longer follow-up, and greater intervisit IOP fluctuation during follow-up were all associated with a higher probability of VF progression.1 Of
Accepted for publication Apr 18, 2008. From Glaucoma Consultants of the Capital Region (S.T.S.), Slingerlands, New York; and Allergan Inc (P.B., D.A.H.), Irvine, California. Inquiries to Steven T. Simmons, Glaucoma Consultants of the Capital Region, 1240 New Scotland Road, Suite 201, Slingerlands, NY 12159; e-mail: [email protected] 0002-9394/08/$34.00 doi:10.1016/j.ajo.2008.04.030
©
2008 BY
these factors, only intervisit fluctuation in IOP was consistently associated with progression in eyes with and without a history of cataract extraction.1 Each 1 mm Hg increase in IOP fluctuation (defined as the standard deviation [SD] of the IOP measurements taken at all visits after the initial surgery) was associated with a 31% increase in the risk of VF progression.1 Similarly, a strong association between IOP fluctuation and risk of glaucoma progression was found in a cohort study of patients given routine care at glaucoma specialty centers.2 In contrast, IOP fluctuation was not related to glaucomatous progression in a recent analysis of results from the Early Manifest Glaucoma Trial (EMGT) in which only mean follow-up IOP was found to be a significant risk factor.3 Studies in ocular hypertensive patients have also reported no relationship between intervisit IOP fluctuation and the risk of conversion to glaucoma.4,5 The disparate findings regarding the impact of IOP fluctuation on glaucomatous progression may be partially attributed to different patient populations, study designs, and methods for analyzing IOP fluctuation.6 Nevertheless, the importance of IOP fluctuation was underscored in a recent study of glaucoma patients following combined trabeculectomy, cataract extraction, and posterior chamber intraocular lens implantation.7 Although mean IOP was similar and consistently less than 18 mm Hg for patients with either large (SD ⬎ 2) or small (SD ⱕ 2) IOP fluctuation, larger long-term IOP fluctuation was associated with a progressive increase in VF deterioration.7 The authors concluded that reducing long-term IOP fluctuation is critical in minimizing glaucomatous progression.7 Bimatoprost and latanoprost are two commonly used topical medications with first-line indications for reducing IOP in glaucoma and ocular hypertension (OHT).8,9 In large randomized controlled trials, each of these medications has been shown to provide substantial reductions in mean IOP.8,9 However, long-term fluctuation in IOP for individual patients treated with these medications has not been examined. Given the potential importance of IOP fluctuation,1,2,6,7,10 –14 a post hoc analysis was undertaken to examine long-term IOP fluctuation in glaucoma and OHT patients treated with bimatoprost or latanoprost in a previously reported six-month clinical comparison trial.15 This particular trial was chosen for analysis because it had the longest duration and the most time points of all
ELSEVIER INC. ALL
RIGHTS RESERVED.
473
TABLE. Intraocular Pressure and Short-term (Daily) Intraocular Pressure Fluctuation at Untreated Baseline for Eyes in the Bimatoprost and Latanoprost Treatment Groups
Baseline IOP
Bimatoprost Treatment Group (n ⫽ 266 eyes)
Latanoprost Treatment Group (n ⫽ 272 eyes)
Mean (SD) IOP, mm Hg 8 AM 12 PM 4 PM Mean (SD) daily IOP fluctuation, mm Hgb [range]
25.0 (2.9) 24.0 (3.2) 22.6 (3.4) 2.0 (1.44) [0.0 to 8.5]
24.9 (2.8) 23.3 (3.2) 22.5 (3.3) 1.9 (1.29) [0.0 to 7.4]
P valuea
.641 .028 .529 .371
IOP ⫽ intraocular pressure; SD ⫽ standard deviation. a From two-way analysis of variance model with treatment and site as fixed effects and patient nested within treatment as a random effect. b Short-term (daily) fluctuation in IOP is the SD of the three diurnal IOP measurements (8 AM, 12 PM, and 4 PM).
head-to-head studies comparing bimatoprost and latanoprost.15–20
follow-up were from an analysis of variance model that included treatment and site as fixed effects. To adjust for use of measurements from two eyes of the same patient that may not be independent, patient nested within treatment was also included in the model as a random effect. The proportion of eyes with long-term IOP fluctuation of ⱖ3 mm Hg (the AGIS criteria)1 was compared between groups using the 2 test.
METHODS THE ANALYSIS WAS PERFORMED ON DATA COLLECTED IN A
previously reported randomized, prospective, multicenter, investigator-masked clinical trial comparing bimatoprost and latanoprost.15 Inclusion criteria for the study were patients with either glaucoma or OHT and baseline IOP (8 AM) following appropriate washout between 22 mm Hg and 34 mm Hg in each eye. There were no significant differences between treatment groups in patient age, gender, race, iris color, diagnosis, or need for washout. Patients were randomized to bilateral treatment with once-daily bimatoprost 0.03% (Lumigan; Allergan Inc, Irvine, California, USA) or latanoprost 0.005% (Xalatan; Pfizer Inc, New York, New York, USA) for six months. IOP was measured at 8 AM, 12 PM, and 4 PM at baseline, week 1, and months 1, 3, and 6. There is currently no clear consensus in the literature regarding what methods of analysis should be used for the purpose of assessing IOP fluctuation. We chose to use the SD of IOP as the measure of IOP fluctuation, as was done in previous studies in the peer-reviewed literature.1–5,7 The current analysis of IOP includes all observed values from both eyes of study patients. All eyes for which complete data were available at all study time points were included. No imputation was performed for missing values. Fluctuation in IOP within each eye was calculated using the SD of IOP measurements. Short-term, daily fluctuation in IOP for an individual eye at baseline was defined as the SD of the baseline 8 AM, 12 PM, and 4 PM measurements. Long-term fluctuation in IOP for an individual eye was defined as the SD of all 12 measurements taken after baseline during the six months of follow-up. The ␣ level for statistical significance was set at 0.05. Comparisons of baseline IOP and long-term IOP fluctuation across 474
AMERICAN JOURNAL
RESULTS ● BASELINE INTRAOCULAR PRESSURE:
Baseline analyses included 266 eyes in the bimatoprost group and 272 eyes in the latanoprost group. The untreated baseline mean IOP at each hour for eyes in the bimatoprost and latanoprost groups is shown in the Table. At 8 AM and 4 PM, the two groups were comparable with respect to mean IOP. At 12 PM, mean IOP was higher in the bimatoprost group compared with the latanoprost group. Short-term daily fluctuation in IOP at untreated baseline was similar between the two groups (Table). ● INTRAOCULAR PRESSURE FLUCTUATION DURING TREATMENT: The number of eyes excluded from analysis
because of missing follow-up data was similar in the two groups (9.8% of bimatoprost-treated eyes and 10.3% of latanoprost-treated eyes). Early discontinuations of patients from the study (nine bimatoprost patients and 11 latanoprost patients) accounted for most of the missing data. The reasons for patient discontinuations were similar between groups and previously reported.13 Long-term IOP fluctuation observed in individual eyes across six months of treatment can be seen in a box-plot of the data (Figure 1). Long-term IOP fluctuation ranged from 0.5 mm Hg to 6.3 mm Hg in latanoprost-treated eyes and 0.5 mm Hg to 3.9 mm Hg in bimatoprost-treated eyes. Mean (SD) long-term fluctuation in IOP across follow-up was smaller for bimatoprost-treated eyes [1.7 (0.56) mm OF
OPHTHALMOLOGY
SEPTEMBER 2008
FIGURE 2. Percentage of bimatoprost- and latanoprost-treated eyes with long-term IOP fluctuation of >3 mm Hg. P ⴝ .009 vs bimatoprost.
low and well-controlled IOP, IOP fluctuation may play a role in leading to progression. Within this context, it may be important to compare topical glaucoma medications for their ability to minimize IOP fluctuation in addition to their IOP-lowering effects.20 –24 The present analysis was undertaken to explore IOP fluctuation in patients treated with bimatoprost or latanoprost. Lower long-term mean IOP fluctuation across all 12 follow-up measurements was observed in the bimatoprosttreated eyes relative to latanoprost-treated eyes. The difference in long-term IOP fluctuation between treatment groups was underscored by the different distributions of IOP fluctuation values observed in the groups, as depicted in the scatter plot in Figure 1. A larger proportion of eyes in the latanoprost group (7.8%) relative to the bimatoprost group (2.5%) exhibited 3 mm Hg or greater long-term fluctuation in IOP. While we acknowledge that any dividing line between high and low IOP fluctuation is somewhat arbitrary, 3 mm Hg was used in this study because this was also the basis for evaluating fluctuation in the AGIS analysis.1 It is possible that the inclusion of data from visits before the study drugs reached full effect could affect the IOP fluctuation observed. Because more than one month of treatment may be needed for the study drugs to reach full effect,9,25 the analysis of long-term IOP fluctuation was repeated including data only from months 3 and 6. Bimatoprost-treated eyes continued to show less IOP fluctuation than latanoprost-treated eyes in this analysis (mean IOP fluctuation of 1.6 mm Hg in bimatoprost-treated eyes vs 1.8 mm Hg in latanoprost-treated eyes; P ⫽ .041). Similar to previous studies,1–5,7 the SD of IOP measurements was used as a measure for IOP fluctuation in this exploratory analysis. The SD may be preferred over range as a measure of IOP fluctuation because it is less influenced by extreme values and takes the number of observations into account.6 The number of outliers in this study with
FIGURE 1. Box-plot of long-term intraocular pressure (IOP) fluctuation across six months in bimatoprost- and latanoprosttreated eyes. Long-term fluctuation in IOP was defined as the standard deviation of all 12 measurements during the six months of follow-up. Boxes show 75th, 50th, and 25th percentiles. (Top whisker) 90th percentile; (Bottom whisker) 10th percentile. Plus signs ⴝ individual data points below the 10th percentile or above the 90th percentile.
Hg] than for latanoprost-treated eyes [1.9 (0.89) mm Hg; P ⫽ .050]. The AGIS criteria of a SD ⱖ 3 mm Hg was applied to the analysis of long-term IOP fluctuation. A lower percentage of eyes in the bimatoprost group (2.5%) than in the latanoprost group (7.8%) had long-term fluctuation in IOP of ⱖ3 mm Hg (P ⫽ .009; Figure 2).
DISCUSSION ELEVATED IOP REMAINS THE PREDOMINANT RISK FACTOR
for glaucoma. While the EMGT analysis revealed only mean IOP as a factor leading to progression, a number of recent studies have suggested that fluctuation in IOP may also serve as an independent risk factor for glaucomatous VF progression.1,2,7,10,11 The recent study by Hong and associates7 demonstrates that in patients with relatively VOL. 146, NO. 3
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unusually large long-term IOP fluctuation can be seen in the box-plot of the data (Figure 1). There are several limitations of the present analysis. The analysis was based on results from a single clinical trial, and based on the original study design, IOP readings were obtained only between 8 AM and 4 PM. IOP measurements taken outside this window may, in fact, contribute to larger IOP fluctuation,26 and a previous study reported a larger range in IOP over 24 hours in latanoprost-treated eyes than in bimatoprost-treated eyes.20 In addition, the trial was only six months in duration, with relatively few IOP readings. Finally, this was a post hoc analysis, and the study was not specifically designed to evaluate IOP fluctuation.
Additional long-term prospective trials may or may not confirm these findings. The AGIS Study was based on a population of patients with uncontrolled IOP necessitating one or more surgical interventions. Nevertheless, the findings of AGIS have emphasized a new method for evaluating IOP control that may be applied to comparisons of IOP-lowering medications. While the results of the present study suggest less long-term IOP fluctuation over six months in bimatoprosttreated eyes relative to latanoprost-treated eyes, additional long-term prospective studies will be necessary to further evaluate IOP fluctuation with both of these medications as well as the impact of IOP fluctuation on disease progression.
THIS STUDY WAS SUPPORTED BY ALLERGAN INC, IRVINE, CALIFORNIA. DR SIMMONS IS A PAID CONSULTANT FOR ALLERGAN and has received reimbursement for research from Allergan and Alcon. Ms Bernstein and Dr Hollander are employees of Allergan Inc. Involved in design of the study (S.T.S.); statistical analysis (P.B.); data interpretation (S.T.S., P.B., D.A.H.); and preparation and approval of the manuscript (S.T.S., P.B., D.A.H.). The clinical trial was carried out in accordance with HIPAA regulations at 18 sites. The study protocol was approved at each site by the University of Alabama at Birmingham Institutional Review Board, the University of Arizona Human Subjects Committee, the New York Eye and Ear Institutional Review Board, or Quorum Review Inc. Allergan Inc provided the study data and provided support for the clinical trial and the statistical analysis of the results.
REFERENCES 10.
1. Nouri-Mahdavi K, Hoffman D, Coleman AL, et al. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology 2004;111:1627–1635. 2. Lee PP, Walt JW, Rosenblatt LC, Siegartel LR, Stern LS, Glaucoma Care Study Group. Association between intraocular pressure variation and glaucoma progression: data from a United States chart review. Am J Ophthalmol 2007;144: 901–907. 3. Bengtsson B, Leske MC, Hyman L, Heijl A, Early Manifest Glaucoma Trial Group. Fluctuation of intraocular pressure and glaucoma progression in the early manifest glaucoma trial. Ophthalmology 2007;114:205–209. 4. Miglior S, Torri V, Zeyen T, Pfeiffer N, Vaz JC, Adamsons I, European Glaucoma Prevention Study (EGPS) Group. Intercurrent factors associated with the development of openangle glaucoma in the European Glaucoma Prevention Study. Am J Ophthalmol 2007;144:266 –275. 5. Medeiros FA, Weinreb RN, Zangwill LM, et al. Long-term intraocular pressure fluctuations and risk of conversion from ocular hypertension to glaucoma. Ophthalmology 2008;115: 934 –940. 6. Caprioli J. Intraocular pressure fluctuation: an independent risk factor for glaucoma? Arch Ophthalmol 2007;125:1124 –1125. 7. Hong S, Seong GJ, Hong YJ. Long-term intraocular pressure fluctuation and progressive visual field deterioration in patients with glaucoma and low intraocular pressures after a triple procedure. Arch Ophthalmol 2007;125:1010 –1013. 8. Hedman K, Alm A. A pooled-data analysis of three randomized, double-masked, six-month clinical studies comparing the intraocular pressure reducing effect of latanoprost and timolol. Eur J Ophthalmol 2000;10:95–104. 9. Higginbotham EJ, Schuman JS, Goldberg I, et al. One-year, randomized study comparing bimatoprost and timolol in
476
AMERICAN JOURNAL
11.
12.
13.
14.
15.
16.
17.
18.
OF
glaucoma and ocular hypertension. Arch Ophthalmol 2002;120:1286 –1293. Nakagami T, Yamazaki Y, Hayamizu F. Prognostic factors for progression of visual field damage in patients with normal-tension glaucoma. Jpn J Ophthalmol 2006;50: 38 – 43. Asrani S, Zeimer R, Wilensky J, Gieser D, Vitale S, Lindenmuth K. Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma 2000;9:134 –142. Gonzalez I, Pablo LE, Pueyo M, et al. Assessment of diurnal tensional curve in early glaucoma damage. Int Ophthalmol 1996;20:113–115. Ishida K, Yamamoto T, Kitazawa Y. Clinical factors associated with progression of normal-tension glaucoma. J Glaucoma 1998;7:372–377. Bergea B, Bodin L, Svedbergh B. Impact of intraocular pressure regulation on visual fields in open-angle glaucoma. Ophthalmology 1999;106:997–1004. Noecker RS, Dirks MS, Choplin NT, et al. A six-month randomized clinical trial comparing the intraocular pressurelowering efficacy of bimatoprost and latanoprost in patients with ocular hypertension or glaucoma. Am J Ophthalmol 2003;135:55– 63. DuBiner H, Cooke D, Dirks M, Stewart WC, VanDenburgh AM, Felix C. Efficacy and safety of bimatoprost in patients with elevated intraocular pressure: a 30-day comparison with latanoprost. Surv Ophthalmol 2001;45: S353–S360. Gandolfi S, Simmons ST, Sturm R, Chen K, VanDenburgh AM, Bimatoprost Study Group 3. Three-month comparison of bimatoprost and latanoprost in patients with glaucoma and ocular hypertension. Adv Ther 2001; 18:110 –121. Parrish R, Palmberg P, Sheu W-P, XLT Study Group. A comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, ran-
OPHTHALMOLOGY
SEPTEMBER 2008
19.
20.
21.
22.
domized, masked-evaluator, multicenter study. Am J Ophthalmol 2003;135:688 –703. Walters TR, DuBiner HB, Carpenter SP, Khan B, VanDenburgh AM, Bimatoprost Circadian Study Group. 24-Hour IOP control with once-daily bimatoprost, timolol gel-forming solution, or latanoprost: a 1-month, randomized, comparative clinical trial. Surv Ophthalmol 2004;49:S26 –S35. Konstas AG, Katsimbris JM, Lallos N, Boukaras GP, Jenkins JN, Stewart WC. Latanoprost 0.005% versus bimatoprost 0.03% in primary open-angle glaucoma patients. Ophthalmology 2005;112:262–266. Konstas AG, Papapanos P, Tersis I, Houliara D, Stewart WC. Twenty-four-hour diurnal curve comparison of commercially available latanoprost 0.005% versus the timolol and dorzolamide fixed combination. Ophthalmology 2003; 110:1357–1360. Konstas AG, Mylopoulos N, Karabatsas CH, et al. Diurnal intraocular pressure reduction with latanoprost 0.005% com-
VOL. 146, NO. 3
IOP FLUCTUATION
23.
24.
25.
26.
IN
pared to timolol maleate 0.5% as monotherapy in subjects with exfoliation glaucoma. Eye 2004;18:893– 899. Konstas AG, Boboridis K, Tzetzi D, Kallinderis K, Jenkins JN, Stewart WC. Twenty-four-hour control with latanoprost-timolol-fixed combination therapy vs latanoprost therapy. Arch Ophthalmol 2005;123:898 –902. Konstas AG, Lake S, Economou AI, Kaltsos K, Jenkins JN, Stewart WC. 24-Hour control with a latanoprost-timolol fixed combination vs timolol alone. Arch Ophthalmol 2006; 124:1553–1557. Camras CB. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six-month masked, multicenter trial in the United States. The United States Latanoprost Study Group. Ophthalmology 1996;103:138 –147. Barkana Y, Anis S, Liebmann J, Tello C, Ritch R. Clinical utility of intraocular pressure monitoring outside of normal office hours in patients with glaucoma. Arch Ophthalmol 2006;124:793–797.
TREATED PATIENTS
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