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Comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, masked-evaluator multicenter study
tanoprost and bimatoprost (Am J Ophthalmol 2003;124: 55– 63) found significantly greater mean IOP reductions and significantly lower mean IOP with bimatoprost at each follow-up timepoint.1 Three other previous studies also showed a trend for greater IOP lowering with bimatoprost2,3 or travoprost4 compared with latanoprost. In attempting to reconcile their findings with those of previous studies, the authors made several inaccurate and misleading statements. First, the authors claimed that we did not adjust for significant differences in the 12 PM baseline mean IOP when analyzing mean IOP reductions but analysis of covariance (ANCOVA), which took into account baseline IOP, was used for the analyses and showed significant differences between treatment groups at all measurements (P ⱕ .002).1 Although baseline mean IOP at 12 PM was significantly higher in the bimatoprost group (by 0.7 mm Hg), mean IOP at 12 PM, month 6 was significantly lower in the bimatoprost group than in the latanoprost group, further demonstrating that bimatoprost provided better IOP lowering. Second, the authors claimed that our study failed to evaluate the effect of previous prostaglandin treatment, but we reported a subgroup analysis excluding patients previously treated with latanoprost. Efficacy results were similar to those based on all patients.1 Further, we reported that there was no significant interaction between treatment effect and washout medication (latanoprost vs other medications).1 Third, the authors stated that in our study, the mean IOP reductions provided by latanoprost at 8 AM and the percentage of patients responding poorly to latanoprost were inconsistent with literature values. Latanoprost reduced mean IOP by approximately 6.7 and 8.5 mm Hg at month 6 in pivotal trials cited. In another large trial, not cited, latanoprost reduced mean IOP by 6.0 mm Hg at month 6 and by 5.4 mm Hg at month 12.5 The reasons for the inconsistent effectiveness of latanoprost across trials are unexplained. In our trial, latanoprost provided mean IOP reductions of 7.1 mm Hg at month 3 and 6.0 mm Hg at month 6, clearly within the range of IOP reductions reported in previous studies. It is unclear whether the Parrish study included fewer latanoprost nonresponders because the authors did not report these data. Most studies of latanoprost have similarly failed to report response rates, yet studies in addition to ours have suggested that a large number of patients fail to achieve at least 20% IOP lowering on latanoprost monotherapy.6,7 Fourth, the authors stated that analyses showing superiority of travoprost to latanoprost in the study by Netland and colleagues4 and superiority of bimatoprost to latanoprost in the study by Gandolfi and associates3 were performed post hoc, but in fact these analyses were incorporated into the statistical plans of the studies.
sebaceous carcinoma are unilateral, and bilaterality may prompt us to question the diagnosis. Nevertheless, there are well-documented bilateral cases. Second, we agree that congenital disk pigmentation is commonly associated with other disk anomalies, as shown in Dr. Brodsky’s publications. However, it is possible that such pigmentation could be identical histopathologically to melanocytoma. Third, we agree that melanocytoma is generally diagnosed in older individuals, raising a question as to whether it is congenital. We believe that melanocytoma and other uveal nevi represent congenital rests of amelanotic melanocytes that are not evident at birth, but acquire pigmentation at puberty or later in life. Finally, we agree that histopathological confirmation is lacking. However, the same is true for most cases of pigmentation in optic disk hypoplasia. Because that pigmented tissue must represent either uveal melanocytes or pigment epithelial cells, it is likely that the pigmentation seen in Dr. Brodsky’s cases could be abnormal uveal melanocytes on the disk and, therefore, definable as melanocytoma. We are currently reviewing our experience with 115 patients with disk melanocytoma. We plan to keep this case in the series but, in view of Dr. Brodsky’s legitimate concerns, we will mention that the bilaterality and early onset could raise questions about the diagnosis. JERRY A. SHIELDS, MD HAKAN DEMIRCI, MD CAROL L. SHIELDS, MD
Philadelphia, Pennsylvania
Comparison of Latanoprost, Bimatoprost, and Travoprost in Patients With Elevated Intraocular Pressure: A 12-Week, Randomized, Masked-Evaluator Multicenter Study EDITOR: PARRISH AND ASSOCIATES HAVE REPORTED A 3-MONTH
clinical trial evaluating latanoprost, bimatoprost, and travoprost (Am J Ophthalmol 2003;135:688 –703). The authors asserted that the study drugs had “equivalent ocular hypotensive effects,” based solely on a lack of statistically significant among-group differences at month 3 in the intent-to-treat patient population. Analysis of the perprotocol patient population, however, showed significantly greater intraocular pressure (IOP) lowering with bimatoprost compared with travoprost at the primary end point (8 AM, week 12). Neither the findings of this study nor those of previous studies support a claim of drug equivalency. Our previously reported 6-month study comparing la210
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
JANUARY 2004
Differences in results between studies might be explained, in part, by patient selection. Latanoprost is more effective in reducing IOP in glaucoma than in ocular hypertension and tends to reduce IOP more in African American than in Caucasian patients. Approximately 75% of the patients in the Parrish study were diagnosed with primary open-angle glaucoma and 30% were African American, so latanoprost would be expected to reduce IOP very effectively. Importantly, newly diagnosed, previously untreated patients were excluded (for unstated reasons) from the study, introducing a potential bias. Approximately half of the patients had been previously treated with a prostaglandin analog (latanoprost). The authors concluded that their study “did not include an unrepresentative sample of super-responders to latanoprost,” but box plots of IOP reductions at the primary end point showed three outliers with outstanding responses, all previously treated with a prostaglandin analog, in the latanoprost group. In contrast to the bimatoprost and travoprost groups, the latanoprost group had no outliers with a substandard IOP reduction. That suggests that the study may indeed have been biased to select patients responsive to latanoprost. Analyses of responder rates and the achievement of target pressures could be helpful in determining whether this was the case. Previous studies comparing bimatoprost with latanoprost have sometimes, but not always, shown statistically significant differences in efficacy between the two drugs. Of the 30 reported measurements comparing these drugs (all measurements in the DuBiner,2 Gandolfi,3 and Noecker1 studies, and the 6 reported measurements in the Parrish study), bimatoprost provided numerically greater mean IOP reductions than latanoprost at 29 measurements and numerically lower mean IOP at 28 measurements. A lower mean IOP was never found with latanoprost treatment, although that would be expected at approximately 50% of the measurements if the drugs were truly equivalent in efficacy. Future additional long-term studies comparing the hypotensive lipids and increased clinical experience with these drugs should allow us to better evaluate their relative efficacy, and safety and tolerability. At the current time, however, the preponderance of evidence indicates that bimatoprost provides greater IOP lowering than latanoprost. ROBERT S. NOECKER, MD MONTE S. DIRKS, MD NEIL CHOPLIN, MD
Tucson, Arizona ACKNOWLEDGMENTS
The study by Noecker, Dirks, Choplin, et al, for the Bimatoprost/Latanoprost Study Group, “A six-month randomized clinical trial comparing the intraocular pressurelowering efficacy of bimatoprost with latanoprost in VOL. 137, NO. 1
patients with ocular hypertension or glaucoma,” was supported by a grant from Allergan. Members of the Bimatoprost/Latanoprost Study Group are Richard S. Bennion, MD; Leonard Cacioppo, MD; Neil Choplin, MD; Andrew Dannemann, MD; Monte S. Dirks, MD; Harvey B. DuBiner, MD; Christopher Girkin, MD; David Godfrey, MD; Donald L. Kellum, MD; Dennis Kilpatrick, MD; Richard Lewis, MD; Charles McMahon, MD; Robert J. Noecker, MD; Stacey Pittman, MPM; Mark S. Rubin, MD; Lisa P. Simpson, BS; Lloyd E. Suter, MD; Celso Tello, MD; Michael Tepedino, MD; Amanda M. VanDenburgh, PhD; and Jeffrey Whitsett, MD
REFERENCES
1. 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. 2. DuBiner H, Cooke D, Dirks M, et al. Efficacy and safety of bimatoprost in patients with elevated intraocular pressure: a 30-day comparison with latanoprost. Surv Ophthalmol 2001; 45:S353–360. 3. Gandolfi S, Simmons ST, Sturm R, et al. Three-month comparison of bimatoprost and latanoprost in patients with glaucoma and ocular hypertension. Adv Ther 2001;18:110 – 121. 4. Netland PA, Landry T, Sullivan EK, et al. Travoprost compared with latanoprost and timolol in patients with openangle glaucoma or ocular hypertension. Am J Ophthalmol 2001;132:472–484. 5. Suzuki M, Mishima HK, Masuda K, et al. Efficacy and safety of latanoprost eye drops for glaucoma treatment: a 1-year study in Japan. Jpn J Ophthalmol 2000;44:33–38. 6. Scherer WJ. A retrospective review of non-responders to latanoprost. J Ocul Pharmacol Ther 2002;18:287–291. 7. Aung T, Chew PT, Yip CC, et al. A randomized doublemasked crossover study comparing latanoprost 0.005% with unoprostone 0.12% in patients with primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol 2001;131: 636 –642.
AUTHOR REPLY DOCTOR NOECKER AND COWORKERS’ LETTER SUGGESTS
that our study1 might have included an unrepresentative sample of super-responders to latanoprost. They believe that an “analysis of responder rates and [of] the achievement of target pressures could be helpful in determining whether this was the case.” We provide below the requested information in the identical format with the same definitions used in their paper.2 The responder rates at 8:00 AM in our study were: 15% or greater response
20% or greater response
latanoprost bimatoprost travoprost latanoprost bimatoprost travoprost 91.9% 91.9% 91.3% 86.8% 87.5% 84.8%
CORRESPONDENCE
211
sebaceous carcinoma are unilateral, and bilaterality may prompt us to question the diagnosis. Nevertheless, there are well-documented bilateral cases. Second, we agree that congenital disk pigmentation is commonly associated with other disk anomalies, as shown in Dr. Brodsky’s publications. However, it is possible that such pigmentation could be identical histopathologically to melanocytoma. Third, we agree that melanocytoma is generally diagnosed in older individuals, raising a question as to whether it is congenital. We believe that melanocytoma and other uveal nevi represent congenital rests of amelanotic melanocytes that are not evident at birth, but acquire pigmentation at puberty or later in life. Finally, we agree that histopathological confirmation is lacking. However, the same is true for most cases of pigmentation in optic disk hypoplasia. Because that pigmented tissue must represent either uveal melanocytes or pigment epithelial cells, it is likely that the pigmentation seen in Dr. Brodsky’s cases could be abnormal uveal melanocytes on the disk and, therefore, definable as melanocytoma. We are currently reviewing our experience with 115 patients with disk melanocytoma. We plan to keep this case in the series but, in view of Dr. Brodsky’s legitimate concerns, we will mention that the bilaterality and early onset could raise questions about the diagnosis. JERRY A. SHIELDS, MD HAKAN DEMIRCI, MD CAROL L. SHIELDS, MD
Philadelphia, Pennsylvania
Comparison of Latanoprost, Bimatoprost, and Travoprost in Patients With Elevated Intraocular Pressure: A 12-Week, Randomized, Masked-Evaluator Multicenter Study EDITOR: PARRISH AND ASSOCIATES HAVE REPORTED A 3-MONTH
clinical trial evaluating latanoprost, bimatoprost, and travoprost (Am J Ophthalmol 2003;135:688 –703). The authors asserted that the study drugs had “equivalent ocular hypotensive effects,” based solely on a lack of statistically significant among-group differences at month 3 in the intent-to-treat patient population. Analysis of the perprotocol patient population, however, showed significantly greater intraocular pressure (IOP) lowering with bimatoprost compared with travoprost at the primary end point (8 AM, week 12). Neither the findings of this study nor those of previous studies support a claim of drug equivalency. Our previously reported 6-month study comparing la210
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
JANUARY 2004
Differences in results between studies might be explained, in part, by patient selection. Latanoprost is more effective in reducing IOP in glaucoma than in ocular hypertension and tends to reduce IOP more in African American than in Caucasian patients. Approximately 75% of the patients in the Parrish study were diagnosed with primary open-angle glaucoma and 30% were African American, so latanoprost would be expected to reduce IOP very effectively. Importantly, newly diagnosed, previously untreated patients were excluded (for unstated reasons) from the study, introducing a potential bias. Approximately half of the patients had been previously treated with a prostaglandin analog (latanoprost). The authors concluded that their study “did not include an unrepresentative sample of super-responders to latanoprost,” but box plots of IOP reductions at the primary end point showed three outliers with outstanding responses, all previously treated with a prostaglandin analog, in the latanoprost group. In contrast to the bimatoprost and travoprost groups, the latanoprost group had no outliers with a substandard IOP reduction. That suggests that the study may indeed have been biased to select patients responsive to latanoprost. Analyses of responder rates and the achievement of target pressures could be helpful in determining whether this was the case. Previous studies comparing bimatoprost with latanoprost have sometimes, but not always, shown statistically significant differences in efficacy between the two drugs. Of the 30 reported measurements comparing these drugs (all measurements in the DuBiner,2 Gandolfi,3 and Noecker1 studies, and the 6 reported measurements in the Parrish study), bimatoprost provided numerically greater mean IOP reductions than latanoprost at 29 measurements and numerically lower mean IOP at 28 measurements. A lower mean IOP was never found with latanoprost treatment, although that would be expected at approximately 50% of the measurements if the drugs were truly equivalent in efficacy. Future additional long-term studies comparing the hypotensive lipids and increased clinical experience with these drugs should allow us to better evaluate their relative efficacy, and safety and tolerability. At the current time, however, the preponderance of evidence indicates that bimatoprost provides greater IOP lowering than latanoprost. ROBERT S. NOECKER, MD MONTE S. DIRKS, MD NEIL CHOPLIN, MD
Tucson, Arizona ACKNOWLEDGMENTS
The study by Noecker, Dirks, Choplin, et al, for the Bimatoprost/Latanoprost Study Group, “A six-month randomized clinical trial comparing the intraocular pressurelowering efficacy of bimatoprost with latanoprost in VOL. 137, NO. 1
patients with ocular hypertension or glaucoma,” was supported by a grant from Allergan. Members of the Bimatoprost/Latanoprost Study Group are Richard S. Bennion, MD; Leonard Cacioppo, MD; Neil Choplin, MD; Andrew Dannemann, MD; Monte S. Dirks, MD; Harvey B. DuBiner, MD; Christopher Girkin, MD; David Godfrey, MD; Donald L. Kellum, MD; Dennis Kilpatrick, MD; Richard Lewis, MD; Charles McMahon, MD; Robert J. Noecker, MD; Stacey Pittman, MPM; Mark S. Rubin, MD; Lisa P. Simpson, BS; Lloyd E. Suter, MD; Celso Tello, MD; Michael Tepedino, MD; Amanda M. VanDenburgh, PhD; and Jeffrey Whitsett, MD
REFERENCES
1. 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. 2. DuBiner H, Cooke D, Dirks M, et al. Efficacy and safety of bimatoprost in patients with elevated intraocular pressure: a 30-day comparison with latanoprost. Surv Ophthalmol 2001; 45:S353–360. 3. Gandolfi S, Simmons ST, Sturm R, et al. Three-month comparison of bimatoprost and latanoprost in patients with glaucoma and ocular hypertension. Adv Ther 2001;18:110 – 121. 4. Netland PA, Landry T, Sullivan EK, et al. Travoprost compared with latanoprost and timolol in patients with openangle glaucoma or ocular hypertension. Am J Ophthalmol 2001;132:472–484. 5. Suzuki M, Mishima HK, Masuda K, et al. Efficacy and safety of latanoprost eye drops for glaucoma treatment: a 1-year study in Japan. Jpn J Ophthalmol 2000;44:33–38. 6. Scherer WJ. A retrospective review of non-responders to latanoprost. J Ocul Pharmacol Ther 2002;18:287–291. 7. Aung T, Chew PT, Yip CC, et al. A randomized doublemasked crossover study comparing latanoprost 0.005% with unoprostone 0.12% in patients with primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol 2001;131: 636 –642.
AUTHOR REPLY DOCTOR NOECKER AND COWORKERS’ LETTER SUGGESTS
that our study1 might have included an unrepresentative sample of super-responders to latanoprost. They believe that an “analysis of responder rates and [of] the achievement of target pressures could be helpful in determining whether this was the case.” We provide below the requested information in the identical format with the same definitions used in their paper.2 The responder rates at 8:00 AM in our study were: 15% or greater response
20% or greater response
latanoprost bimatoprost travoprost latanoprost bimatoprost travoprost 91.9% 91.9% 91.3% 86.8% 87.5% 84.8%
CORRESPONDENCE
211