ORIGINAL STUDY
`
`Prostaglandin Efficacy and Safety Study Undertaken
`by Race (The PRESSURE Study)
`
`Catherine M. Birt, MA, MD, FRCSC, Yvonne M. Buys, MD, FRCSC,
`Iqbal Ike K. Ahmed, MD, FRCSC, Graham E. Trope, MBBS, PhD, FRCSC,
`and the Toronto Area Glaucoma Society
`
`Purpose: Latanoprost, travoprost, and bimatoprost are prosta-
`glandin or prostamide-type ocular hypotensive medications, all of
`which are effective and safe for lowering intraocular pressure
`(IOP). Most studies with these types of drugs have included
`patients mainly from European or white ethnic backgrounds;
`however, some reports have suggested that there is a difference in
`response between patients of white and African racial heritage. On
`account of the possibility that drugs may act differently in people of
`different ethnic background, we decided to study the effectiveness
`and safety of all 3 drugs in people from various ethnic heritages.
`Our hypothesis was that there might be a possible ethnic-based
`difference in IOP-lowering effectiveness between the 3 medications.
`
`Method: This was a prospective randomized investigator-masked
`multicenter study. Patients newly diagnosed with open-angle
`glaucoma (primary, pseudoexfoliative, or pigmentary), or whose
`pressure became elevated after a washout period, were randomized
`to receive 1 of 3 prostaglandin/prostamide drugs. Assignment
`of drug was balanced by racial group and study site, and the
`investigator was masked to the drug used. The patients were
`requested to self-identify their racial group as White, African,
`East Indian, Asian, or Hispanic; to minimize the possibility of
`heterogeneity, all 4 grandparents had to be known to originate
`from the same group. However, for purposes of analysis, the
`patients were divided into 2 groups—White or Other. Patients
`were followed at 2, 6, 12, and 24 weeks; IOP and local side effects
`were assessed at each visit.
`
`Results: Eighty-three patients were recruited from 9 sites. The mean
`age of the patients was 61.5 ± 10.5 years. There were no differences
`in mean age or the distribution of sex between the patients whether
`examined by the 2 racial groups or the 3 drug groups. There was a
`highly statistically significant decrease in IOP from baseline to 12
`weeks and from baseline to 24 weeks (F = 439.3, P<0.0001;
`F = 305.94, P<0.0001). There were no differences in treatment
`effect between the 3 drugs or between the 2 ethnic groups, (P>0.05
`for all comparisons) and there was no interaction between race and
`drug.
`
`Received for publication December 16, 2008; accepted December 16,
`2008.
`From the Sunnybrook Health Sciences Centre, Toronto, Ontario,
`Canada.
`Supported by a grant from the Glaucoma Research Society of Canada.
`Presented at the European Glaucoma Society meeting in Berlin from
`June 1st to 6th, 2008 and at the Canadian Ophthalmological Society
`meeting in Whistler on June 13th, 2008.
`The Toronto Area Glaucoma Society members who participated in this
`study were: Ike Ahmed, Raj Bindlish, Catherine Birt, Yvonne Buys,
`Dale Gray, Tom Klein, Jeff Martow, Graham Trope, and Elaine
`Woo.
`Reprints: Catherine Birt, MA, MD, FRCSC, Sunnybrook Health
`Sciences Centre, M1 302a, 2075 Bayview Avenue, Toronto, Ontario,
`Canada M4N 3M5 (e-mail: Catherine.birt@sunnybrook.ca).
`Copyright r 2010 by Lippincott Williams & Wilkins
`DOI:10.1097/IJG.0b013e3181c4aeac
`
`460 | www.glaucomajournal.com
`
`Conclusions: All 3 prostaglandin/amide drugs are highly effective at
`lowering IOP. No differences in effect between the drugs or between
`members of different racial groups were detected, although the
`study sample size was too small to be certain to detect differences, if
`they existed.
`
`Key Words: glaucoma, prostaglandin, ethnicity
`
`(J Glaucoma 2010;19:460–467)
`
`The major risk factor for the development of glaucoma-
`
`tous optic neuropathy, a significant cause of irreversible
`blindness in the world,
`is elevated intraocular pressure
`(IOP).1,2 The management of elevated IOP is usually
`initiated with medical therapy. Drugs of several classes
`can be used, including the b-blockers, carbonic anhydrase
`inhibitors, a-agonists, miotics, and prostaglandin analogs.
`Latanoprost (Xalatan, Pfizer Inc), travoprost (Travatan,
`Alcon Laboratories
`Inc), and bimatoprost
`(Lumigan,
`Allergan Inc) are drugs in the prostaglandin class, although
`bimatoprost
`is also referred to as a prostamide. For
`simplicity, this paper will refer to them collectively as
`prostaglandin analogs. These drugs affect a hitherto unused
`mechanism for pressure
`lowering—augmentation of
`uveoscleral outflow3 and all the 3 drugs have been shown
`to be effective and safe for lowering elevated IOP.4–11 The
`first drug in the class was latanoprost, and it was quickly
`evident that the drug had a strong pressure-lowering effect,
`and a good safety profile.12–15 Travoprost was developed
`subsequently,16 and similarly proved to be an effective
`pressure-lowering agent.17–19 The third agent currently
`available in North America is bimatoprost.20
`The reported range of IOP lowering varies between
`drugs and between different published studies. Latanoprost
`has been shown to lower IOP by between 31% and 35%21
`or around 9 mm Hg.5 Netland et al17 and the Travoprost
`Study Group reported a large 12-month prospective study
`that showed mean IOP decreases in the travoprost-treated
`group that ranged from 6.9 to 8.9 mm Hg. The Bimato-
`prost/Latanoprost Study Group reported a 6-month multi-
`center randomized investigator-masked study comparing
`bimatoprost to latanoprost. Their results showed statisti-
`cally more IOP lowering for bimatoprost, with diurnal
`measurements ranging between 16.5 and 17.4 mm Hg for
`bimatoprost and 17.6 to 18.9 mm Hg for latanoprost. There
`was also a higher responder rate for reaching various target
`pressures in the bimatoprost patients. Safety evaluation
`showed no significant differences between the groups other
`than conjunctival hyperemia, which was more evident in the
`bimatoprost-treated patients.22
`A second study that evaluated a smaller number of
`patients but that performed a 24-hour diurnal measurement
`
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`J Glaucoma  Volume 19, Number 7, September 2010
`
`Prostaglandin Efficacy and Safety Study
`
`was reported by Konstas et al.23 This study also showed
`a small advantage for bimatoprost in IOP lowering, with
`a 0.6 mm Hg lower IOP produced by bimatoprost, a
`difference that reached statistical significance. There was
`also a statistically more frequent presence of conjunctival
`hyperemia with bimatoprost (34%) than with latanoprost
`(14%). Cantor et al24 performed a head-to-head compar-
`ison of
`travoprost and bimatoprost and found no
`significant differences between the 2 drugs, although the
`trend was for lower IOP and a larger proportion of
`responders reaching low target pressures with bimatoprost.
`Most studies with these types of drugs have been
`performed with patients mainly from European or white
`ethnic backgrounds. One report, however, suggested that
`there was a difference in response between patients of
`white and African racial heritage. Netland et al17 and the
`Travoprost Study Group had reported that travoprost was
`more effective by 2.4 mm Hg than latanoprost in lowering
`IOP in black patients. Netland et al25 later published a
`reanalysis of 2 studies, pooling the data to examine the
`response to travoprost in black and nonblack patients.
`These data showed that travoprost lowered mean IOP
`further
`in black patients
`than in nonblack patients
`by an average of 8.1 mm Hg compared with 7.0 mm Hg.
`respectively. This conclusion has been challenged, with
`Camras26 suggesting that
`the difference is because of
`differences in baseline IOP. Netland et al27 responded
`that only 1 of 3 baseline measurements was significantly
`different, and that the trend for lower IOP with travoprost
`was present at most time points. They conclude their
`rebuttal by suggesting that a comparative trial of the
`prostaglandins with an analysis of race would be helpful to
`clinicians.
`Although race is not a scientifically well-defined
`concept, it continues to have a role in clinical decision-
`making. On account of the possibility that drugs may act
`differently in people of different ethnic background, we
`decided to compare the effectiveness and safety of all 3
`drugs in individuals from different ethnic heritages. Certain
`side effects have been reported to occur with this class of
`medications, particularly increased conjunctival hyperemia
`and darker iris pigmentation, eyelash growth, periocular
`skin pigmentation, and cystoid macular edema in pseudo-
`phakic patients.28–34 We therefore also attempted to assess
`whether there were any differences in these outcomes
`among patients from different ethnic groups.
`The null hypothesis stated that there is no ethnic-based
`difference in IOP-lowering effectiveness, and/or safety
`profile, between the 3 medications; the alternative hypoth-
`esis was that such a difference existed.
`
`METHODS
`The study design was a prospective randomized
`investigator-masked multicenter
`study and had been
`approved by the Research Ethics Boards of Sunnybrook
`and Women’s College Health Sciences Centre and the
`University Health Network. Patients were eligible if they
`were newly diagnosed with ocular hypertension or open-
`angle glaucoma (primary, pseudoexfoliative, or pigmen-
`tary) or if they were suitable for a washout of an earlier
`prescribed medication and their pressure became elevated
`after a defined period of time. To be eligible, the IOP in at
`least 1 eye had to be greater than 23 mm Hg and less than
`36 mm Hg at 10 AM. Patients were requested to self-identify
`
`their racial group as white, African, South Asian, East Asian,
`or Hispanic; to minimize the possibility of heterogeneity all 4
`grandparents had to be known to originate from the same
`group. Exclusion criteria are listed in Table 1.
`After informed consent was obtained, the participants
`were randomized to receive 1 of the 3 prostaglandin drugs.
`A randomization schedule, balanced for ethnicity and drug
`assignment, was produced for each participating site by
`the biostatistician. The investigator was masked to the
`drug used. Drugs were supplied to the patients, courtesy of
`the manufacturers who provided sufficient samples to the
`participating sites for the duration of the study. The patients
`were instructed to take their dose once daily at 8 PM.
`The patients were followed for a maximum of 24
`weeks. Assessments were performed at baseline, 2, 6, 12,
`and 24 weeks, and were scheduled at 10 AM, with an
`allowable variation of 1 hour on either side and included
`measurement of best-corrected visual acuity, IOP measured
`by Goldmann applanation tonometry using a calibrated
`tonometer, slit-lamp examination at each visit, and fundo-
`scopy on the first and last visits. Corneal thickness was
`recorded at baseline. Baseline demographics were also
`recorded. Local and systemic side effects were specifically
`assessed at each visit. These included hyperemia of the
`conjunctiva and lid margin, rated from 0 to 3 using
`standardized photographs; changes from recorded baseline
`iris color; eyelash growth; periocular skin pigmentation if
`reported by the patient; presence of anterior chamber flare
`and/or cells; and cystoid macular edema in pseudophakic
`patients. Systemic complaints of headache or myalgia were
`also solicited and, if present, recorded.
`The main outcome measure was IOP. A difference of
`1.5 mm Hg for both the drug effect and the race effect was
`selected for the power calculation, approximately at the
`midrange of effects reported earlier. Responses of less than
`3 mm Hg are not usually considered clinically significant, as
`discussed by Netland et al17;
`however, the differences
`between drugs found in that study were approximately
`1.2 mm Hg. The original power calculation had suggested
`
`TABLE 1. Exclusion Criteria
`
`IOP <24 mm Hg in both eyes or >35 mm Hg in 1 eye
`Angle grade <2 (Shaffer classification)
`Abnormalities preventing use of applanation tonometry
`Cup:disc ration greater than 0.80
`Severe central visual field loss (sensitivity <10 dB in at least 2 of
`4 visual field test points closest to point of fixation)
`Pregnant women or those women of child bearing potential not
`using contraception
`Chronic or recutting inflammatory eye disease
`History of ocular trauma or intraocular surgery within 6 mo
`Laser surgery within 3 mo
`History of ocular infection or inflammation within past 3 mo
`History of progressive retinal disease
`Aphakia
`Use of glucocorticoid during eligibility phase or use of topical
`NSAIDs during course of the study
`Use of adjunctive IOP lowering medications in study eye or fellow
`eye during study
`History of severe or serious hypersensitivity to prostaglandins
`Significant hepatic, hematologic, electrolyte, or renal abnormalities
`contraindicating treatment with a prostaglandin
`
`IOP indicates intraocular pressure; NSAIDs, nonsteroidal anti-inflam-
`matory drugs.
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`J Glaucoma  Volume 19, Number 7, September 2010
`
`TABLE 2. Demographic Data by Drug Assignment
`
`Sex, n (%)
`Male
`Female
`Race, n (%)
`White
`Other
`Eye color, n (%)
`Blue
`Brown
`Mixed
`Pachymetry (mm ± SD)
`Age (y ± SD)
`
`Total
`
`Bimatoprost
`
`Travoprost
`
`Latanoprost
`
`45 (54.2)
`38 (45.8)
`
`50 (60.2)
`38 (39.8)
`
`11 (13.3)
`57 (68.6)
`15 (18.1)
`562.0 ± 42.2
`61.7 ± 10.8
`
`16 (59.3)
`11 (40.7)
`
`15 (55.5)
`12 (44.5)
`
`3 (11.1)
`20 (74.1)
`4 (14.8)
`561.2 ± 42.4
`60.6 ± 10.8
`
`13 (50.0)
`13 (50.0)
`
`17 (65.4)
`9 (34.6)
`
`3 (11.5)
`19 (73.1)
`4 (15.4)
`565.1 ± 36.4
`62.2 ± 10.6
`
`16 (53.3)
`14 (46.7)
`
`18 (60.0)
`12 (40.0)
`
`6 (20.0)
`19 (63.3)
`5 (16.7)
`559.5 ± 48.6
`62.3 ± 10.4
`
`(F = 0.94, P = 0.40) or between the 2 ethnic groups,
`(F = 2.20, P = 0.14) and there was also no interaction
`between race and drug (F = 0.47, P = 0.63). Table 4 shows
`the IOP results at baseline, 12, and 24 weeks, subdivided by
`ethnic group and drug type. Figure 1A shows the IOP at all
`the study intervals for the 3 drugs; Figure 1B shows the
`results grouped for the 2 ethnic groups, and Figure 1C
`shows the results at baseline, 12, and 24 weeks for the 3
`drugs and 2 ethnic groups separately.
`Another useful way of examining the relative pressure-
`lowering efficacy of the drugs is to examine the percentage
`of patients who reached a given target pressure, rather than
`examining the mean IOP achieved. As expected, the lower
`the target pressure, the fewer the number of patients who
`achieved it. The targets examined were r21, r18, and
`r14 mm Hg, based on the recommendations of Damji
`et al.35 After 6, 12, or 24 weeks of follow-up, there were no
`significant differences among the 3 drugs, or the 2 ethnic
`groupings, in the distribution of patients who reached each
`of these levels of pressure. The results for the 24 week data
`are shown graphically, by drug class in Figure 2 and by race
`in Figure 3.
`The protocol also included the assessment of various
`possible side effects. At enrollment, eye color was described
`as blue in 11 of the 83 patients (13.3%), brown in 57
`(68.6%), and hazel in 15 (18.1%). At the exit visit, eye color
`was listed in 77 patients, with 11 described as blue (14.3%),
`53 as brown (68.8%), and 13 as hazel (16.9%). Not
`surprisingly, all the blue and hazel irides were found in the
`white population; 100% of the Other group had brown
`irides. The brown and hazel eye colors were evenly
`
`TABLE 3. Demographic Data by Ethnic Group
`
`Total
`
`White
`
`Other
`
`that for a design with 3 drugs and 5 racial groups (15 cells),
`and an expected difference of 1.5 mm Hg between drugs, a
`total of 300 patients would be required to provide 20
`participants per cell. This would have achieved a 41%
`power for finding a drug effect, 46% power for finding a
`racial effect, and 97% for the interaction of drug by race,
`with an analysis of variance used to test at a 5%
`significance level. Unfortunately, our recruitment was
`inadequate to reach the intended sample size of 300 in the
`time available. It had been originally estimated that
`recruitment would take 18 months, with each of the 15
`sites recruiting 20 patients. In the event, only 9 sites
`participated, and after a 1-year extension recruitment was
`closed. We therefore decided to combine the non-white
`subjects into 1 group and test for differences between this
`group and the whites. This resulted in a 3  2 design, with
`approximately 15 patients per cell (range, 9-18). The post
`hoc calculation of the power of this sample was 0.21 for
`the drug effect, 0.31 for the race effect, and 0.12 for the
`interaction, with a set at 0.05. Secondary outcomes were
`local and systemic side effects
`including conjunctival
`hyperemia and lid and lash changes. The main analysis
`was performed on a per protocol basis using the analysis of
`variance, with the Fisher exact test used for categorical
`variables.
`
`RESULTS
`Eighty-three patients were recruited from 9 sites.
`Thirty-eight were female and 45 were male. The mean age
`of the patients was 61.5 ± 10.5 years. There were no
`statistically significant differences in age, sex, eye color, or
`racial group between the 3 drug groups (Table 2) and there
`were no statistically significant differences in demographics
`or drug group among the racial groups (Table 3). The
`majority of the recruited patients were white (50/83, 60.2%)
`with the remaining 33 patients (39.8%) being African (18,
`21.7%), South Asian (7, 8.4%) East Asian (7, 8.4%), and
`Hispanic (1, 1.2%).
`The balancing of recruitment among the 3 drugs
`was successful, with 30 (36.2%) receiving latanoprost, 26
`(31.3%) receiving travoprost, and 27 (32.5%) receiving
`bimatoprost.
`The overall baseline IOP was 27.8 ± 3.4 mm Hg, with
`no statistically significant difference among the 3 groups.
`There was a highly statistically significant decrease in IOP
`from baseline to 12 weeks and from baseline to 24 weeks
`(F = 439.3, P<0.0001; F = 305.94, P<0.0001). There
`were no differences in treatment effect among the 3 drugs
`
`45 (54.2)
`38 (45.8)
`
`27 (32.5)
`26 (31.3)
`30 (36.2)
`
`27 (54.0)
`23 (46.0)
`
`15 (30.0)
`17 (34.0)
`18 (36.0)
`
`Sex, n (%)
`Male
`Female
`Drug, n (%)
`Bimatoprost
`Travoprost
`Latanoprost
`Eye color, n (%)
`11 (22.0)
`11 (13.3)
`Blue
`24 (48.0)
`57 (68.6)
`Brown
`15 (30.0)
`15 (18.1)
`Mixed
`Pachymetry (mm ± SD) 562.0 ± 42.2 573.2 ± 41.9 541.9 ± 35.4
`Age (y ± SD)
`61.7 ± 10.5
`63.2 ± 10.3
`59.6 ± 10.6
`
`18 (54.5)
`15 (45.5)
`
`12 (36.3)
`9 (27.3)
`12 (36.3)
`
`33 (100)
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`J Glaucoma  Volume 19, Number 7, September 2010
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`Prostaglandin Efficacy and Safety Study
`
`TABLE 4. IOP Results by Drug and White Versus Other Ethnic Groups
`
`IOP ± SD (95% Confidence Limits)
`
`Drug
`
`Ethnic Group (n)
`
`Bimatoprost
`
`All (27)
`
`White (15)
`
`Other (12)
`
`Travoprost
`
`All (26)
`
`White (17)
`
`Other (9)
`
`Latanoprost
`
`All (30)
`
`White (18)
`
`Other (12)
`
`Baseline
`
`27.2 ± 2.8
`(26.1-28.3)
`28.3 ± 2.8
`(26.7-29.9)
`259 ± 2.5
`(24.3-27.5)
`28.3 ± 3.3
`(26.1-29.5)
`27.8 ± 3.3
`(26.1-29.5)
`29.2 ± 4.6
`(25.7-32.7)
`28.3 ± 3.6
`(27.0-29.6)
`29.0 ± 3.7
`(27.2-30.8)
`27.2 ± 3.4
`(25.2-29.2)
`
`12 wk
`
`24 wk
`
`17.2 ± 3.7***
`(15.6-18.8)
`17.8 ± 4.2***
`(15.3-20.3)
`16.5 ± 3.2***
`(14.4-18.6)
`18.8 ± 4.1***
`(17.1-20.5)
`19.1 ± 4.7***
`(16.7-21.5)
`18.3 ± 2.7***
`(16.2-20.4)
`17.3 ± 3.2***
`(16.1-18.5)
`17.2 ± 3.4***
`(15.5-18.9)
`17.4 ± 2.9***
`(15.4-19.4)
`
`17.9 ± 5.2***
`(15.5-20.3)
`18.7 ± 1.9***
`(14.9-22.5)
`17.0 ± 4.7***
`(13.4-20.6)
`18.2 ± 3.8***
`(16.5-19.9)
`18.3 ± 4.6***
`(15.7-20.9)
`18.2 ± 1.9***
`(16.6-19.8)
`17.7 ± 3.4***
`(16.3-19.1)
`17.0 ± 3.8***
`(15.0-19.0)
`19.0 ± 2.3***
`(17.1-20.9)
`
`*P<0.05 compared with baseline IOP measurement.
`**P<0.001 compared with baseline IOP measurement.
`***P<0.0001 compared with baseline IOP measurement.
`IOP indicates intraocular pressure.
`
`distributed between the 3 drug groups, however, there were
`more blue eyes (6) in the latanoprost group than in either of
`the other 2 drug groups (3 each) (Table 2). No statistical
`significant difference was found in this distribution of
`the eye colors (P = 0.85). No patient in any group was
`documented as having a significant change in color, for
`example from hazel to brown. Hyperemia was assessed by
`comparison to a photographic comparator with standard-
`ized grading levels of 0, 0.5, 1, 2, 3, and 4. The highest
`rating given during the study was 3, and over half the
`patients in each drug assignment group was graded as
`having zero hyperemia at 6 months. The single patient
`assessed as having grade 3 hyperemia at 2 and 6 weeks was
`an African patient on latanoprost, and by 12 weeks the
`grading for this patient had decreased to 0.5, and to 0 by 24
`weeks. Hyperemia, of any level, was reported in 17 (34%)
`of the white and 14 (42%) of the Other group (P = 0.49).
`Figure 4 shows the distribution of hyperemia scores for the
`3 drugs at 24 weeks. Lash growth and/or periocular skin
`darkening were reported at any point in the study in 20
`bimatoprost patients, 12 travoprost patients, and 10
`latanoprost patients; these data are shown graphically in
`Figure 5. Sixteen (32%) of the white patients had either lash
`or skin changes, or both, as did 12 (36%) of the patients in
`the Other group (P = 0.81). The differences between groups
`in the incidence of either hyperemia, or skin, and lid
`changes were not statistically significant, whether tested by
`racial group or drug assignment. There were no findings of
`any anterior chamber cell or flare reaction, or cystoid
`macular edema, nor did any patient report headache or
`myalgia during the course of the study.
`
`DISCUSSION
`The development of the prostaglandin analogs repre-
`sented a major advance in the medical management of
`glaucoma. Once all 3 medications became part of the
`
`it was logically necessary to
`standard clinical regimen,
`compare their effectiveness to help determine which drug,
`if any, had the advantage either in terms of IOP-lowering
`or side-effect profile. Relatively few studies have directly
`compared all the 3 drugs in this class. The first of these was
`the study by Parrish et al36 and the XLT Study Group that
`enrolled 411 patients and evaluated IOP change at 8 AM
`between baseline and week 12 of follow-up. The study
`results showed comparable IOP-lowering effectiveness for
`all 3 drugs and greater ocular tolerability for latanoprost.
`They also analyzed patients by race, categorized as white,
`Black, and Other, and found no differences in response, but
`their study was not powered to detect subgroup differ-
`ences.36 A smaller study was reported by Orzalesi et al,37
`which also compared the IOP lowering of the 3 drugs in
`44 patients using a cross-over design and a full diurnal
`evaluation of pressure. Although race was not a factor
`in their study, the IOP-lowering outcome showed statisti-
`cally similar effectiveness for all 3 medications. A meta-
`analysis of 27 articles (reporting on 28 clinical trials)
`allowed the results from nearly 7000 patients to be eval-
`uated. The results indicated that all 3 prostaglandin drugs,
`as well as timolol, are the most effective pressure lowering
`agents among the various glaucoma medications currently
`available.38
`Target pressure is a useful concept, recommended
`by the American Academy of Ophthalmology Preferred
`Practice Patterns
`in the management of open-angle
`glaucoma. Once a target pressure has been chosen for a
`given individual,
`it is desirable to attain and maintain
`the pressure with the minimum of medical therapy.39 The
`knowledge, therefore, of the likelihood of a given drug
`reaching the target pressure is clinically important. Unlike
`some earlier studies, we did not find statistically significant
`differences between the 3 drugs, or the 2 ethnic groups.
`As is usual, the lower target pressures were obtained less
`frequently. Noecker et al22 found a statistically significantly
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`Other
`
`Caucasian
`
`< 22
`
`< 19
`Target IOP Level
`
`< 15
`
`p>0.05 for all comparisons
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Number of patients
`
`Latanoprost
`Travoprost
`Bimatoprost
`
`Baseline
`
`Week 2
`
`Week 6
`Time (weeks)
`
`Week 12
`
`Week 24
`
`Other
`Caucasian
`
`FIGURE 3. Percent of all patients reaching target IOP at 24 weeks
`by race. IOP indicates intraocular pressure.
`
`Birt et al
`
`A
`
`30
`
`25
`
`20
`
`15
`
`30
`
`25
`
`20
`
`15
`
`30
`
`25
`
`20
`
`B
`
`C
`
`IOP (mm Hg)
`
`Baseline
`
`2 weeks
`
`6 weeks
`
`12 weeks
`
`24 weeks
`
`Latanoprost - Other
`Latanoprost - Caucasian
`Travoprost - Other
`Travoprost - Caucasian
`Bimatoprost - Other
`Bimatoprost - Caucasian
`
`15
`
`Baseline
`
`12 weeks
`Time (weeks)
`FIGURE 1. A, IOP response by drug class. B, IOP response by
`ethnic group. C, IOP response by drug and ethnic group. IOP
`indicates intraocular pressure.
`
`24 weeks
`
`Latanoprost
`
`Travoprost
`
`Bimatoprost
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`percent
`
`higher responder rate for bimatoprost at all 3 time points
`tested compared with latanoprost, and Cantor et al found a
`nonsignificant superiority of bimatoprost over travoprost in
`reaching target pressures.22,24 Parrish et al did not find
`differences in pressure lowering between the 3 prostaglan-
`din analog drugs, though that report did not include a
`target pressure attainment.36 Our
`specific analysis of
`findings suggest that any therapy in this class is likely to
`be of benefit, with no clear evidence that 1 drug is more
`likely than another to result in a particular level of IOP.
`It is axiomatic that all drugs have side effects. The art
`of therapy is to find the drug that combines maximum effect
`with minimum undesirable consequences. The introduction
`of the prostaglandin agonist drugs was followed shortly
`thereafter by reports of hitherto unknown side effects,
`including iris heterochromia,31 hypertrichiasis,32 and perio-
`cular skin pigmentation.33 Hyperemia of the conjunctiva,28
`and cystoid macular edema34 were also reported, although
`these side effects are not unique to this drug class. Most
`studies report fairly high rates of fairly mild amounts of
`conjunctival hyperemia. Reported rates of hyperemia range
`between 25%24 and 55.4%,17 with latanoprost usually
`
`Latanoprost
`
`Travoprost
`
`Bimatoprost
`
`20
`
`15
`
`10
`
`5
`
`Number of patients
`
`0
`
`0
`
`0.5
`
`2
`
`3
`
`1
`Score
`FIGURE 4. Distribution of hyperemia scores at 24 weeks, by
`drug.
`
`0
`
`< 22
`
`< 15
`
`< 19
`Target IOP Level
`FIGURE 2. Percent of all patients reaching target IOP at 24 weeks
`by drug class. IOP indicates intraocular pressure.
`
`p>0.05 for all comparisons
`
`464 | www.glaucomajournal.com
`
`r 2010 Lippincott Williams & Wilkins
`
`000005
`
`

`

`J Glaucoma  Volume 19, Number 7, September 2010
`
`Prostaglandin Efficacy and Safety Study
`
`hyperemia scores showed a decrease in intensity with longer
`drug exposure.
`Our study was an attempt to provide the analysis
`recommended by Netland et al.27 All of the studied drugs,
`latanoprost,
`travoprost, or bimatoprost, were highly
`effective, both statistically and clinically, in lowering IOP.
`There were no statistically significant differences in effec-
`tiveness between the three. As shown in Table 4, the
`difference from baseline was highly significant for all 3
`medications at both 12 and 24 weeks. There were also some
`trends toward a difference in response between the white
`and the Other groups after 24 weeks of therapy. Using
`bimatoprost, the Whites had a mean IOP of 1.7 mm Hg
`higher than the Other group, whereas for latanoprost, the
`difference was reversed, with the Whites’ mean IOP being
`2.0 mm Hg lower. However, for travoprost the difference
`between the groups was only 0.1 mm Hg. This trend cannot
`be confirmed as statistically significant, but suggests that
`differential responsiveness to drugs may be possible. The
`major weakness in this study relates to sample size. The
`original power calculation estimated that a sample of 300
`patients would be required to detect a 1.5 mm Hg difference
`in lowering the IOP between the interaction of drug
`assignment and ethnic group. We had anticipated adequate
`recruitment in less than 1 year; however, it was slower than
`expected, and after 36 months had passed it was decided to
`close the study and complete the analysis. This resulted in a
`smaller sample size and, thus, a lower power. We had
`adequate power (1.0 with a = 0.05) to find a difference
`between IOP at baseline and study end, but a lower power
`for finding a difference in ethnic group (0.31) or drug
`assignment (0.21). If we had maintained the original 5  3
`design, and given the data produced by our patient sample,
`a post hoc calculation of sample size suggests that 50
`patients per cell, or 750 in total would have been required to
`show statistical significance with a power of 0.8 and an a of
`0.05. Due to losses in degrees of freedom with the smaller
`
`Latanoprost
`
`Travoprost
`
`Bimatoprost
`
`Lash growth
`
`Skin colour
`change
`
`None
`
`p>0.05 for all comparisons
`
`20
`
`15
`
`10
`
`5
`
`0
`
`Number of patients
`
`FIGURE 5. Distribution of reported lash growth and periocular
`skin darkening by drug.
`
`showing lower levels than either of the other 2 drugs.36 Skin
`pigmentation is reported less often, as is iris color change.
`Our study examined the rates of these side effects, as it is
`plausible that there might have been differential responses
`in different ethnic groups. The randomization protocol
`resulted in a higher proportion of patients with blue irides
`in the latanoprost group but the relatively small number of
`blue irides (14% of the total) and the lack of a significant
`difference in this proportion, as assessed by w2 analysis
`means that this is unlikely to have any effect on the final
`data. We did not expect to see iris color change in patients
`whose ethnicity is accompanied by dense dark irides, but
`increased skin pigmentation is more likely in this group
`than in whites who have less melanin in their lids. During
`the 6-month course of this study neither iris color change
`nor increase in skin pigmentation were reported. Our rates
`of hyperemia (34% to 42%) are comparable to those of
`prior publications, and, in keeping with prior reports, the
`
`TABLE 5. IOP Results by Drug and Black Versus Other Ethnic Groups
`
`IOP ± SD (95% Confidence Limits)
`
`Drug
`
`Ethnic Group (n)
`
`Bimatoprost
`
`All (27)
`
`Black (6)
`
`Other (21)
`
`Travoprost
`
`All (26)
`
`Black (4)
`
`Other (22)
`
`Latanoprost
`
`All (30)
`
`Black (8)
`
`Other (22)
`
`Baseline
`
`27.2 ± 2.8
`(26.1-28.3)
`24.8 ± 0.98
`(23.8-24.5)
`27.5 ± 2.9
`(26.2-28.8)
`28.3 ± 3.3
`(26.1-29.8)
`30.5 ± 4.4
`(23.5-37.5)
`27.9 ± 3.6
`(26.3-29.5)
`28.3 ± 3.6
`(27.0-29.6)
`27.5 ± 3.1
`(24.9-30.1)
`28.5 ± 3.8
`(26.8-30.2)
`
`12 wk
`
`17.2 ± 3.7***
`(15.6-18.8)
`16.6 ± 3.7**
`(12.8-20.4)
`17.4 ± 3.8***
`(15.5-19.3)
`18.8 ± 4.1***
`(17.1-20.5)
`18.2 ± 2.6*
`(14.0-22.4)
`19.0 ± 4.4***
`(17.1-20.9)
`17.3 ± 3.2***
`(16.1-18.5)
`17.0 ± 3.4***
`(13.9-20.3)
`17.4 ± 3.2***
`(16.0-18.8)
`
`24 wk
`
`17.9 ± 5.2***
`(15.5-20.3)
`15.0 ± 2.6*
`(11.7-18.3)
`18.9 ± 3.8***
`(16.5-19.9)
`18.2 ± 3.8***
`(16.5-19.9)
`20.0 ± 1.2*
`(17.7-22.3)
`18.0 ± 4.1***
`(16.1-19.9)
`17.7 ± 3.4***
`(16.3-19.1)
`19.5 ± 2.1**
`(16.2-22.8)
`17.3 ± 3.6***
`(15.6-19.0)
`
`*P< 0.05 compared with baseline IOP measurement.
`**P<0.001 compared with baseline IOP measurement.
`***P<0.0001 compared with baseline IOP measurement.
`IOP indicates intraocular pressure.
`
`r 2010 Lippincott Williams & Wilkins
`
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`

`Birt et al
`
`J Glaucoma  Volume 19, Number 7, September 2010
`
`number of cells, the sample size of the final 3  2 design
`would have required an incredible 580 patients per cell, or
`3480 in total to show statistical significance at the same
`power and a levels.
`The differences between the drugs reported in the
`paper by Netland et al ranged from 0.8 to 2.4 in the black
`patients and from 0.1 to 1.5 in the nonblack patients. In our
`sample, the differences between travoprost and latanoprost
`ranged from 1.2 to 1.9 in the White group and from
` 0.8 to 2.0 in the Other group, slightly less than predicted
`based on the findings reported by Netland et al.25 This may
`be due to the true differences in patient population, or
`simply to vagaries in the data. As measurement of IOP is a
`fairly coarse scale, with measurements usually reported
`in whole mm Hg, these small differences are barely larger
`than what measurement precision allows, and may not be
`clinically significant. It is also noteworthy that the paper by
`Netland et al divided participants into 2 groups namely
`black and nonblack, whereas our subjects were divided into
`white and nonwhite. In practice, this means that those who
`are neither black nor white would be included in different
`groups for the 2 studies. If we had used black and nonblack
`as our groups to compare, 4 subjects each would be moved
`from 1 ethnic pool to the other in the bimatoprost and
`latanoprost groups and 5 in the travoprost group. Doing
`this did not have any effect on the statistical outcome of the
`study. Table 5 shows the IOP results when the patients were
`divided into Black and Other groups. Although the sample
`size for the Black group was small, the differences in IOP
`from baseline remained statistically significant. As the
`