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A comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, masked-evaluator, multicenter study
presence of such cellular elements and a statistically less favorable functional outcome after ICG-assisted macular hole surgery. However, we also pointed out that the use of ICG was not necessarily associated with deterioration of visual acuity (VA) in all patients as reported in our article:1 In 9 of 20 patients a postoperative improvement of VA was seen despite ICG application. In contrast, cellular elements on the retinal surface of the ILM were seen in all specimens obtained. Consequently, such morphologic observation cannot be considered the only factor determining an increase or decrease of VA postoperatively; other mechanisms have to be considered. This was also mentioned in our article describing the impact of ICG in macular pucker surgery.3 Third, we suspected an incomplete ILM peeling to be responsible for the failure of our first surgical intervention in the case presented in this brief report. Dr. Meyer and associates refer to an article very recently published by Dr. Sheidow and associates4 and mention that the closure rate was reported to be lower in eyes avoiding ICG, although the functional results did not differ significantly between both groups. Referring to the information provided by Dr. Sheidow and associates, this statement is not correctly cited. Dr. Sheidow and associates compared three groups of patients with surgery for a macular hole: Group 1 without ILM peeling, group 2 with ILM peeling but without ICG staining, and group 3 with ILM peeling and ICG-assistance. Final closure rates were 92.8% in group one, 97.7% in group 2, and 97.1% in group 3. A VA better than 20/50 was observed in 56.7% of patients in group 1, 70.4% in group 2, and only 51.4% in group 3. These data clearly show that closure rates are nearly equal when comparing patients after ILM peeling with and without ICG-assistance. In contrast, VA was significantly lower in patients after ICG staining of the ILM. In conclusion, ILM peeling, in general, had an impact on the closure rate; however, additional ICG application resulted in a significant lower rate of good VA despite successful hole closure. This observation was also discussed by Dr. Sheidow and associates in their article. Whether the strict avoidance of light during ICG application or just the statistical variation lead to a good visual acuity in this singular case of very longstanding macular hole remains under discussion. The purpose of the report was to demonstrate that under certain circumstances even a very long standing macular hole is worth to be operated on. In summary, we still believe that ICG should be used with great care in macular surgery, and general conclusions on the safety of a surgical approach should not be drawn from a single case report. CHRISTOS HARITOGLOU, MD CAROLIN A. GASS, MD ANSELM KAMPIK, MD
Munich, Germany
VOL. 137, NO. 2
REFERENCES
1. Haritoglou C, Gandorfer A, Gass CA, Schaumberger M, Ulbig MW, Kampik A. Indocyanine green-assisted peeling of the internal limiting membrane in macular hole surgery affects visual outcome: A clinicopathologic correlation. Am J Ophthalmol 2002;134:836 –841. 2. Gandorfer A, Haritoglou C, Gandorfer A, Kampik A. Retinal damage from indocyanine green in experimental macular surgery. Invest Ophthalmol Vis Sci 2003;44:316 –323. 3. Haritoglou C, Gandorfer A, Gass CA, Schaumberger M, Ulbig MW, Kampik A. The effect of Indocyanine-green on functional outcome of macular pucker surgery. Am J Ophthalmol 2003;135:328 –337. 4. Sheidow TG, Blinder KJ, Holekamp N, et al. Outcome results in macular hole surgery. An evaluation of internal limiting membrane peeling with and without ICG. Ophthalmology 2003;110:1697–1701.
A Comparison of Latanoprost, Bimatoprost, and Travoprost in Patients With Elevated Intraocular Pressure: A 12-week, Randomized, Masked-evaluator, Multicenter Study EDITOR: PARRISH AND ASSOCIATES (AM J OPHTHALMOL 2003;135:
688 –703) reported a 12-week trial comparing latanoprost, bimatoprost, and travoprost. Unfortunately, the authors concluded that the study drugs were equivalent in intraocular pressure (IOP) lowering. This conclusion is inappropriate and not justified by the data presented. The study was planned to demonstrate treatment superiority. If superiority is not shown, the only valid conclusion is “no statistically significant differences were detected.” Lack of statistical significance is different from equivalence. To support a claim of equivalence, the study must be prospectively designed as an equivalence trial with defined criteria for equivalence. The statistical method required an among-group comparison P value ⱕ0.05 to perform pairwise comparisons. As among-group P values for mean IOP reductions (week 12) in the intent-to-treat (ITT) population ranged from .057 to .128, no between-group comparisons were performed. Appropriate statistical methods are available that would have allowed these comparisons to be made, and they would likely have detected statistically significant differences between groups. Futhermore, at the primary end point, the among-group statistic for the per-protocol patient population was significant, and bimatoprost provided a significantly larger mean IOP reduction than travoprost. Clearly, the authors’ claim of “equivalent ocular hypotensive effects” of the study drugs is unsubstantiated.
CORRESPONDENCE
387
The authors focus on the ITT population, a useful and accepted approach. Parallel analysis of the per-protocol population, which excluded 7% of the ITT population, was reported only for the primary end point (IOP reduction at 8 AM, week 12). Efficacy results for the per-protocol population at other time points should be provided along with a plausible explanation if they differ from those for the ITT population. Efficacy was evaluated by mean IOP reductions from baseline at week 12. Analysis of a single parameter from only one visit is insufficient for evaluating drug efficacy. In their reply, the authors should provide the interim week 6 results. Analyses of other relevant efficacy parameters (percentage of patients responding to treatment or reaching target pressures) would also be useful.1–3 Several aspects of the data presentation require explanation. Tables 3 and 4 of the report summarize ocular adverse events including “ocular hyperemia/red eye.” Information about this adverse event was elicited from patients, which inflates the number of reports. It is inappropriate and misleading to summarize these results along with nonelicited adverse events. Figure 5 of the report presents 8 AM mean IOP levels. At week 2, IOP could be measured at any time of the day. Are all IOP measurements taken at that visit counted as if they were taken at 8 AM? Alternatively, are only those patients with evaluations at 8 AM included in this figure? The whiskers on the IOP box plots “cover approximately 99% of the data range” but do not seem to demarcate either 99% of patients or data. Furthermore, the box plots are inconsistent (Figure 8 of the report shows two latanoprost patients with ⱖ20 mm Hg IOP reductions; Figure 7 of the report shows one). The hypotensive lipids may vary in clinical effectiveness. Careful and complete analysis and presentation of clinical trial data will enhance our understanding of the relative efficacy of these drugs.
AUTHOR REPLY WE ARE PLEASED TO RESPOND TO THE COMMENTS OF MS.
Bernstein, a biostatistician employed by Allergan, Inc., Irvine, California. The writer believes that the validity of our conclusions depends on whether they are based on tests of “statistical significance” or “equivalence”—a distinction reminiscent of the debate about what the meaning of the word “is” is. As explained in detail in the publication,1 our study was designed to determine whether there were significant differences among latanoprost, bimatoprost, or travoprost with regard to effectiveness (intraocular pressure [IOP] reduction) or tolerability (especially hyperemia). The primary endpoint was mean change between baseline and week 12 in IOP measurements obtained at 8:00 AM (time of peak drug effect). Results showed very little difference in mean IOP reductions among treatment groups: latanoprost versus bimatoprost: ⫺0.13 mm Hg (95% confidence interval [CI], ⫺0.84, 0.58); latanoprost versus travoprost: 0.56 mm Hg (95% CI, ⫺0.15, 1.26); and bimatoprost versus travoprost: 0.69 mm Hg (95% CI, ⫺0.02, 1.40). Given the lack of statistical significance, the very small differences in IOP reduction, and the narrow 95% CIs, we concluded that latanoprost, bimatoprost, and travoprost were comparable in their ability to reduce IOP in open-angle glaucoma and ocular hypertension patients. In addition, results of our study1 as well as those by Gandolfi2 and DuBiner,3 both of which were sponsored by Allergan, Inc., suggest that the difference in diurnal IOP reduction between latanoprost and bimatoprost also is modest. Clinical and statistical equivalences have not been reported with regard to tolerability, however. Our study,1 like those by Gandolfi,2 Netland,4 and Noecker,5 clearly shows a two-to-threefold higher rate of hyperemia in patients treated with bimatoprost and a twofold higher rate of the condition in those receiving travoprost compared with latanoprost-treated patients. Moreover, we could not disagree more with Ms. Bernstein’s suggestion that it is inappropriate to elicit information concerning adverse events from patients. Who but patients know how much they suffer from ocular redness and irritation? Although ours was not a phase III trial, it is worth noting that, for labeling purposes, the U.S. Food and Drug Administration considers agents to be equivalent if IOP reductions are less than 1 mm Hg different at the majority of time points and less than 1.5 mm Hg different at all time points. In fact, a post-hoc analysis of our data set demonstrated a power of 0.83 to detect a difference of less than 1 mm Hg between treatment groups. Expert opinion and common sense support our study design. We stand by our conclusions that latanoprost,
PAULA BERNSTEIN, MS
Irvine, California
REFERENCES
1. Cantor LB. Bimatoprost: A member of a new class of agents, the prostamides, for glaucoma management. Expert Opin Investig Drugs 2001;10:721–731. 2. 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. 3. 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.
388
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
FEBRUARY 2004
Munich, Germany
VOL. 137, NO. 2
REFERENCES
1. Haritoglou C, Gandorfer A, Gass CA, Schaumberger M, Ulbig MW, Kampik A. Indocyanine green-assisted peeling of the internal limiting membrane in macular hole surgery affects visual outcome: A clinicopathologic correlation. Am J Ophthalmol 2002;134:836 –841. 2. Gandorfer A, Haritoglou C, Gandorfer A, Kampik A. Retinal damage from indocyanine green in experimental macular surgery. Invest Ophthalmol Vis Sci 2003;44:316 –323. 3. Haritoglou C, Gandorfer A, Gass CA, Schaumberger M, Ulbig MW, Kampik A. The effect of Indocyanine-green on functional outcome of macular pucker surgery. Am J Ophthalmol 2003;135:328 –337. 4. Sheidow TG, Blinder KJ, Holekamp N, et al. Outcome results in macular hole surgery. An evaluation of internal limiting membrane peeling with and without ICG. Ophthalmology 2003;110:1697–1701.
A Comparison of Latanoprost, Bimatoprost, and Travoprost in Patients With Elevated Intraocular Pressure: A 12-week, Randomized, Masked-evaluator, Multicenter Study EDITOR: PARRISH AND ASSOCIATES (AM J OPHTHALMOL 2003;135:
688 –703) reported a 12-week trial comparing latanoprost, bimatoprost, and travoprost. Unfortunately, the authors concluded that the study drugs were equivalent in intraocular pressure (IOP) lowering. This conclusion is inappropriate and not justified by the data presented. The study was planned to demonstrate treatment superiority. If superiority is not shown, the only valid conclusion is “no statistically significant differences were detected.” Lack of statistical significance is different from equivalence. To support a claim of equivalence, the study must be prospectively designed as an equivalence trial with defined criteria for equivalence. The statistical method required an among-group comparison P value ⱕ0.05 to perform pairwise comparisons. As among-group P values for mean IOP reductions (week 12) in the intent-to-treat (ITT) population ranged from .057 to .128, no between-group comparisons were performed. Appropriate statistical methods are available that would have allowed these comparisons to be made, and they would likely have detected statistically significant differences between groups. Futhermore, at the primary end point, the among-group statistic for the per-protocol patient population was significant, and bimatoprost provided a significantly larger mean IOP reduction than travoprost. Clearly, the authors’ claim of “equivalent ocular hypotensive effects” of the study drugs is unsubstantiated.
CORRESPONDENCE
387
The authors focus on the ITT population, a useful and accepted approach. Parallel analysis of the per-protocol population, which excluded 7% of the ITT population, was reported only for the primary end point (IOP reduction at 8 AM, week 12). Efficacy results for the per-protocol population at other time points should be provided along with a plausible explanation if they differ from those for the ITT population. Efficacy was evaluated by mean IOP reductions from baseline at week 12. Analysis of a single parameter from only one visit is insufficient for evaluating drug efficacy. In their reply, the authors should provide the interim week 6 results. Analyses of other relevant efficacy parameters (percentage of patients responding to treatment or reaching target pressures) would also be useful.1–3 Several aspects of the data presentation require explanation. Tables 3 and 4 of the report summarize ocular adverse events including “ocular hyperemia/red eye.” Information about this adverse event was elicited from patients, which inflates the number of reports. It is inappropriate and misleading to summarize these results along with nonelicited adverse events. Figure 5 of the report presents 8 AM mean IOP levels. At week 2, IOP could be measured at any time of the day. Are all IOP measurements taken at that visit counted as if they were taken at 8 AM? Alternatively, are only those patients with evaluations at 8 AM included in this figure? The whiskers on the IOP box plots “cover approximately 99% of the data range” but do not seem to demarcate either 99% of patients or data. Furthermore, the box plots are inconsistent (Figure 8 of the report shows two latanoprost patients with ⱖ20 mm Hg IOP reductions; Figure 7 of the report shows one). The hypotensive lipids may vary in clinical effectiveness. Careful and complete analysis and presentation of clinical trial data will enhance our understanding of the relative efficacy of these drugs.
AUTHOR REPLY WE ARE PLEASED TO RESPOND TO THE COMMENTS OF MS.
Bernstein, a biostatistician employed by Allergan, Inc., Irvine, California. The writer believes that the validity of our conclusions depends on whether they are based on tests of “statistical significance” or “equivalence”—a distinction reminiscent of the debate about what the meaning of the word “is” is. As explained in detail in the publication,1 our study was designed to determine whether there were significant differences among latanoprost, bimatoprost, or travoprost with regard to effectiveness (intraocular pressure [IOP] reduction) or tolerability (especially hyperemia). The primary endpoint was mean change between baseline and week 12 in IOP measurements obtained at 8:00 AM (time of peak drug effect). Results showed very little difference in mean IOP reductions among treatment groups: latanoprost versus bimatoprost: ⫺0.13 mm Hg (95% confidence interval [CI], ⫺0.84, 0.58); latanoprost versus travoprost: 0.56 mm Hg (95% CI, ⫺0.15, 1.26); and bimatoprost versus travoprost: 0.69 mm Hg (95% CI, ⫺0.02, 1.40). Given the lack of statistical significance, the very small differences in IOP reduction, and the narrow 95% CIs, we concluded that latanoprost, bimatoprost, and travoprost were comparable in their ability to reduce IOP in open-angle glaucoma and ocular hypertension patients. In addition, results of our study1 as well as those by Gandolfi2 and DuBiner,3 both of which were sponsored by Allergan, Inc., suggest that the difference in diurnal IOP reduction between latanoprost and bimatoprost also is modest. Clinical and statistical equivalences have not been reported with regard to tolerability, however. Our study,1 like those by Gandolfi,2 Netland,4 and Noecker,5 clearly shows a two-to-threefold higher rate of hyperemia in patients treated with bimatoprost and a twofold higher rate of the condition in those receiving travoprost compared with latanoprost-treated patients. Moreover, we could not disagree more with Ms. Bernstein’s suggestion that it is inappropriate to elicit information concerning adverse events from patients. Who but patients know how much they suffer from ocular redness and irritation? Although ours was not a phase III trial, it is worth noting that, for labeling purposes, the U.S. Food and Drug Administration considers agents to be equivalent if IOP reductions are less than 1 mm Hg different at the majority of time points and less than 1.5 mm Hg different at all time points. In fact, a post-hoc analysis of our data set demonstrated a power of 0.83 to detect a difference of less than 1 mm Hg between treatment groups. Expert opinion and common sense support our study design. We stand by our conclusions that latanoprost,
PAULA BERNSTEIN, MS
Irvine, California
REFERENCES
1. Cantor LB. Bimatoprost: A member of a new class of agents, the prostamides, for glaucoma management. Expert Opin Investig Drugs 2001;10:721–731. 2. 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. 3. 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.
388
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
FEBRUARY 2004