A 1-Year Study of Brimonidine Twice Daily
`in Glaucoma and Ocular Hypertension
`A Controlled, Randomized, Multicenter Clinical Trial
`Joel S. Schuman, MD; Barry Horwitz, MD; Neil T. Choplin, MD; Robert David, MD; Diane Albracht, MD;
`Kuankuan Chen, MS; and the Chronic Brimonidine Study Group
`
`Objective: Brimonidine tartrate is a highly selective \g=a\2\x=req-\
`agonist. This study investigates the safety and efficacy of
`0.2% brimonidine administered twice daily for 1 year in
`patients with glaucoma or ocular hypertension.
`Methods: The study design was a multicenter, double\x=req-\
`masked, randomized, parallel-group, active-controlled com-
`parison clinical trial. Subjects instilled 0.2% brimonidine
`or 0.5% timolol maleate twice daily for 12 months. Subjects
`were examined at baseline, week 1, and months 1, 2,3,6,
`9, and 12. A subset of subjects was examined at week 2.
`Results: Of 443 subjects enrolled in this study, 374 met
`the entry criteria; 186 received brimonidine and 188 re-
`ceived timolol. Brimonidine-treated subjects showed an
`overall mean peak reduction in intraocular pressure (IOP)
`of 6.5 mm Hg; timolol-treated subjects had a mean peak
`reduction in IOP of 6.1 mm Hg. Brimonidine lowered
`mean peak IOP significantly more than timolol at week
`
`2 and month 3 (P<.03); no significant difference was ob-
`served between the groups for this variable at other vis-
`its throughout the 1-year course of the study. No evi-
`dence of tachyphylaxis was seen in either group. Allergy
`was seen in 9% of subjects treated with brimonidine. Dry
`mouth was more common in the brimonidine-treated
`group than in the timolol-treated group (33.0% vs 19.4%),
`but complaints of burning and stinging were more com-
`mon in the timolol-treated group (41.9%) than in the bri-
`monidine-treated patients (28.1%). Headache, fatigue, and
`drowsiness were similar in the 2 groups. In general, the
`tolerance to medication was acceptable.
`Conclusions: Brimonidine is safe and effective in low-
`ering IOP in glaucomatous eyes. Brimonidine provides
`a sustained long-term ocular hypotensive effect, is well
`tolerated, and has a low rate of allergic response.
`Arch Ophthalmol. 1997;115:847-852
`
`BRIMONtDINE TARTRATE is a po¬
`
`tent a-adrenoceptor agonist
`with highselectivity for the a2
`receptor. It has notably higher
`affinity for the ot2 receptor than
`does clonidine hydrochloride or apracloni-
`dinehydrochloride.1 This selectivity and the
`chemical structure of the drug may provide
`an advantage for brimonidine over apracloni-
`dine. Apraclonidine has been reported to be
`effective in lowering intraocular pressure
`(IOP) in patients with glaucoma and ocu¬
`lar hypertension,23 but its long-term use is
`limited by allergy and tachyphylaxis.6"10
`Brimonidine effectively lowers IOP in
`animal models" and in normotensive,12
`glaucomatous, and ocular hypertensive
`eyes.13 The 0.5% concentration has been
`shown to reduce the incidence of IOP
`spikes after laser trabeculoplasty.14"'6 Bri¬
`monidine seems to reduce IOP by a dual
`mechanism of decreasing inflow and in¬
`creasing uveoscleral outflow.17 This study
`was designed to evaluate the 1-year effi¬
`cacy and safety of 0.2% brimonidine used
`twice daily in patients with glaucoma or
`ocular hypertension.
`
`RESULTS
`
`DEMOGRAPHICS
`A total of443 subjects received study medi¬
`cation, with 221 in the brimonidine group
`and 222 in the timolol group. Ofthese, 15%
`ofsubjects (35/221 for brimonidine; 34/222
`for timolol) did not meet entry criteria (rea¬
`sons included IOP outside of entry range,
`IOP asymmetry between eyes, inadequate
`washout period, patient receiving medica¬
`tion that could affect IOP, or patient aller¬
`gic to timolol), and were not included in
`the primary efficacy analysis. The remain¬
`ing 374 subjects met the protocol entry cri¬
`teria ( 186 in the brimonidine group and 188
`in the timolol group) and were included in
`the efficacy evaluation. All 443 subjects were
`included in the analysis of safety.
`Sixty-two percent of all subjects in
`each group had open-angle glaucoma, 36%
`had ocular hypertension, and 2% had a vi¬
`sual field defect in 1 eye and no field de¬
`fect in the other. The mean (±SD) age
`overall was 63±11 years, and the male-
`female ratio was 50:50. Most subjects were
`
`From the New England Eye
`Center, Tufts University School
`of Medicine, Boston, Mass
`(Dr Schuman); the Naval
`Medical Center, San Diego,
`Calif (Dr Choplin); Allergan
`Inc, Irvine, Calif (Dr David and
`Ms Chen); Dr Horwitz is in
`private practice in Houston,
`Tex, and Dr Albracht is in
`private parctice in Castro
`Valley, Calif. Drs Schuman,
`Horwitz, Choplin, and Albracht
`have no proprietary interest in
`Allergan Inc or brimonidine.
`Dr David and Ms Chen are
`employees ofAllergan Inc.
`Participants in the Chronic
`Brimonidine Study Group are
`listed in the acknowledgments
`at the end of the article.
`
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`SUBJECTS AND METHODS
`
`STUDY DESIGN
`
`The study design was a multicenter, double-masked, ran¬
`domized, parallel-group, active-controlled comparison clini¬
`cal trial. The clinical protocol received institutional re¬
`view board approval at each participating site. Subjects
`instilled 0.2% brimonidine tartrate or 0.5% timolol male-
`ate twice daily for 12 months. Examinations were per¬
`formed at baseline, week 1, and month 1, 2, 3, 6, 9, and
`12. A subset of subjects (40% of all subjects) was evalu¬
`ated at week 2.
`The 0.2% concentration of brimonidine was selected
`for long-term evaluation after a l'-month dose-response study
`that showed similar efficacy to the 0.5% concentration.13
`A twice-daily regimen of brimonidine was chosen because
`this frequency was shown to be as effective as a 3-times daily
`regimen.18
`PATIENT SELECTION
`
`Adults with primary open-angle glaucoma or ocular
`hypertension who gave written informed consent to par¬
`ticipate and were receiving no more than 2 ocular hypo-
`tensive agents were recruited for this study. After appro¬
`priate washout of prestudy ocular hypotensive
`medications (including a 4-week washout of ß-blockers),
`subjects were required to have untreated IOP of 23
`mm Hg or more and less than 35 mm Hg in each eye, and
`best-corrected visual acuity of 20/100 or better in each
`eye. Patients were evenly randomized in a masked fashion
`to the 2 treatment groups.
`The systemic exclusion criteria included uncon¬
`trolled systemic disease, pregnancy or childbearing poten¬
`tial, contraindications to a-adrenoceptor agonist or ß-
`adrenoceptor antagonist therapy, abnormally low heart rate
`
`or blood pressure for age, and known hypersensitivity to
`any ingredients in the study medication. Other exclusion
`criteria included long-term treatment with any other topi¬
`cal or systemic ot-adrenoceptor agonist or antagonist, al¬
`teration during the study of existing long-term therapy that
`could have a substantial effect on IOP or ocular activity of
`the study drugs, treatment with adrenergic-augmenting psy-
`chotropic drugs, and participation in a current or recent
`(past 30 days) research study.
`Ophthalmic exclusion criteria were corneal abnor¬
`malities that would interfere with tonometry, wearing of
`contact lenses, active ocular disease, dry eye, Sjögren syn¬
`drome, keratitis sicca, required use of other ocular medi¬
`cations, asymmetry of IOP between eyes of more than 5
`mm Hg, extensive visual field loss, laser treatment or ocu¬
`lar surgery within the past 6 months, and optic nerve-
`head cup.disc ratio of 0.8 or more in either eye. Subjects
`who met these entry criteria were included in the primary
`(per-protocol) efficacy analysis. All subjects who received
`study medication were evaluated in the safety analysis.
`
`EFFICACY AND SAFETY VARIABLES
`
`The primary efficacy variable was IOP. Intraocular pres¬
`sure was measured in millimeters of mercury using appla-
`nation tonometry affixed to a slit-lamp. Cup:disc ratios (re¬
`corded as 0.0-0.9) and visual fields (using Humphrey
`program 30-2 or Octopus program 32) were secondary ef¬
`ficacy variables.
`Patients were monitored for signs and symptoms of
`adverse events, ocular and general discomfort, and other
`ocular and systemic safety factors. At each visit, patients
`were asked specifically about any discomfort, whether ocu¬
`lar (burning or stinging, blurring, foreign body sensation,
`or photophobia) or general (headache, dry mouth, or fa¬
`tigue or drowsiness). Adverse events were graded for se¬
`verity (trace, mild, moderate, or severe) and assessed for
`relation to the study treatment. Symptoms of ocular dis-
`
`white (79%), with blue, green, or hazel iris color (51%).
`No significant between-group differences were seen in
`age, race, sex, iris color, diagnosis, prestudy history, or
`baseline values for any variable.
`
`INTRAOCULAR PRESSURE
`
`The mean peak IOP change from baseline was mea¬
`sured 2 hours after dosing in both groups. Intraocular
`pressures were similar between treatment groups at base¬
`line (brimonidine, 24.8 mm Hg; timolol, 24.6 mm Hg)
`(P=.70). Mean peak IOP decreases from baseline were
`statistically significant in both treatment groups at all
`follow-up visits (P<.001) and ranged from 5.9 to 7.0
`mm Hg for brimonidine subjects and 5.2 to 6.3 mm Hg
`for timolol subjects (Figure I). Overall, brimonidine
`subjects showed a mean 6.5 mm Hg IOP reduction at peak,
`and timolol subjects had a mean 6.1 mm Hg IOP de¬
`crease with no significant difference between the 2 groups.
`There was no evidence of tachyphylaxis and no signifi¬
`cant correlation between iris color and IOP lowering ef¬
`fect in either group.
`
`Intraocular pressure at hour 0 (morning trough, 12
`hours after the evening drug instillation) showed mean de¬
`creases from similar baseline values (26 mm Hg) ranging
`from 3.7 to 5.3 mm Hg in the brimonidine group, and from
`5.8 to 6.8 mm Hg in the timolol group. Mean decreases
`from baseline values were statistically significant in both
`treatment groups at all follow-up visits (P<.001). Both bri¬
`monidine and timolol subjects showed a sustained thera¬
`peutic effect during the 12-month period. Trough IOP re¬
`ductions were significantly greater for timolol subjects than
`brimonidine subjects during the study (P<.03). Overall
`mean decreases from baseline at trough were 4.3 mm Hg
`in the brimonidine group and 6.3 mm Hg in the timolol
`group. As with the peak effect, no IOP drift was seen in
`the timolol- orbrimonidine-treated subjects at trough. Both
`drugs showed a sustained therapeutic effect at peak and
`trough during the 1-year follow-up.
`An additional efficacy analysis was performed in
`which all subjects who received medication were in¬
`cluded (including the 15% ofsubjects who did not meet
`the entry criteria). This analysis showed similar find¬
`ings with the primary analysis.
`
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`comfort were evaluated on a 0- to 3-point scale (0=none,
`l=mild, 2=moderate, and 3=severe) at all visits.
`Biomicroscopic evaluation was performed at each visit
`without pupillary dilation, using the same 0- to 3-point scale.
`Direct and indirect ophthalmoscopy was used to evaluate
`the fundus and optic nerve head. The Schirmer tear test
`was performed at baseline and at months 6 and 12 using
`standard Schirmer strips. The strips were inserted into the
`conjunctlval sac near the inner angle for 5 minutes, fol¬
`lowing the administration of 1 drop (about 20 pL) of topi¬
`cal anesthetic. Visual acuity was measured with a Snellen
`chart and pupil size with a pupillometer or millimeter ruler.
`Heart rate and blood pressure were measured at each
`visit with patients in a resting position. Blood samples were
`obtained at baseline and at months 6 and 12 for assess¬
`ment of hématologie and blood chemistry values.
`
`STATISTICAL ANALYSIS
`
`Intraocular pressure was the key efficacy variable. Be¬
`cause subjects were treated bilaterally, average values from
`both eyes were used in the analysis. Data were analyzed us¬
`ing the 2-way analysis of variance (ANOVA) with fixed ef¬
`fects for treatment, investigator, and treatment-by-
`investigator interaction.19 Within each treatment group,
`mean changes from baseline at each follow-up visit were
`analyzed using a paired Student t test.20 Overall mean
`changes from baseline were analyzed using the ANOVA for
`repeated measures.19
`The study was designed as an active-control equiva¬
`lence trial. Thus, in addition to test for superiority, test for
`equivalence in efficacy was applied. The two 1-sided hypoth¬
`eses for equivalence were tested by constructing a 95% con¬
`fidence interval for the between-group difference in mean IOP
`changes from baseline. Other than IOP, the continuous vari¬
`ables were analyzed using 2-way ANOVA. The ordinal cat¬
`egorical variables were analyzed using Cochran-Mantel-
`Haenszel methods with modified ridit scores.21 Nominal
`
`variables were analyzed using the Fisher exact test, the Pear¬
`son 2 test, or Cochran-Mantel-Haenszel methods with table
`scores. All hypothesis tests were 2-sided. A value of .05 or
`less was considered significant for main effects and .10 for the
`treatment-by-investigator interaction effects.
`For visual fields, mean defect values were analyzed
`based on the eye with the worse changes from baseline com¬
`pared with its fellow eye. Investigators were asked to as¬
`sess whether visual fields had changed from baseline. Base¬
`line values and mean changes from baseline were
`summarized with descriptive statistics and compared be¬
`tween the 2 treatment groups using the ANOVA. The
`changes from baseline in mean defect values were also tabu¬
`lated in 3 categories: -5 decibels (dB) or less, -5 or more
`to 5 dB or more, and more than 5 dB. The distributions were
`analyzed using the Cochran-Mantel-Haenszel method with
`modified ridit scores.
`In addition, a secondary visual field analysis was con¬
`ducted on a subset of patients in whom visual fields were
`performed using the full threshold strategy of Program 30-2
`of the Humphrey Field Analyzer (Humphrey Instru¬
`ments, San Leandro, Calif) at baseline, 6 months, and 12
`months. Data collected included mean deviation, short-
`term fluctuation, corrected-pattern SD, and reliability in¬
`dexes.22 Data were averaged for the 2 eyes. Changes over
`time were assessed using the glaucoma change probability
`plot of STATAC II (Humphrey Instruments). This soft¬
`ware identifies points in the most recent field that show
`improvement or worsening compared with the first 2 ex¬
`aminations taken together as baseline, and calculates the
`change in mean deviation from baseline to the most re¬
`cent field. The number of points that showed worsening
`or improvement in a manner expected in less than 5% of a
`stable glaucoma population were counted from the print¬
`out. Finally, the series of visual fields was objectively ex¬
`amined by 1 of us (N.T.C.), looking for the development
`of a new scotomata or for deepening or broadening of sco-
`tomata present on the initial examination.
`
`SECONDARY EFFICACY VARIABLES
`
`No significant within-group or between-group change was
`seen in cup:disc ratio or visual fields during the study.
`As evaluated by the clinical investigators, visual fields
`were completely unchanged, or within 5 dB of baseline
`values in 95% of patients in each treatment group, 4%
`improved and 1% worsened. An additional visual field
`analysis was performed on a subset of patients in
`whom complete Humphrey 30-2 visual field data were
`collected (total, 188 subjects; 77 receiving bri¬
`monidine and 111 receiving timolol).22 In this sub-
`analysis, the mean deviation, short-term fluctuation,
`and corrected pattern SD did not differ between the 2
`groups in any variable at any examination. Similarly,
`the difference in the change in each index from base¬
`line to the third examination was not statistically dif¬
`ferent between the groups. There was no statistically
`significant difference in the net change in points wors¬
`ening or improving from baseline to final examination
`between the 2 groups and no statistically significant
`difference in mean deviation change. Finally, 23
`
`(20.7%) of 111 subjects treated with timolol were
`judged to have subjectively worsened in the 1-year
`period. Seventeen (22%) of the 77 subjects in the bri¬
`monidine group were similarly judged to have wors¬
`ened. The difference was not statistically significant
`(c2=0.0; P=.97).
`
`OCULAR SAFETY
`
`Schirmer Tear Test
`
`Of patients randomized to the brimonidine and timolol
`groups, 17.6% (38/216) and 21.5% (46/214), respec¬
`tively, experienced a clinically significant decrease from
`baseline defined as (1) baseline less than 10 mm and
`follow-up below 5 mm, or (2) baseline 10 mm or more
`and follow-up below 10 mm and a decrease from base¬
`line of more than 5 mm in Schirmer tear test results.
`The between-group difference was not significant.
`Overall, the mean changes from baseline were negli¬
`gible in both treatment groups during the 12-month
`study period.
`
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`0.2% Brimonidine Tartrate
`0.5% Timolol Maleale
`
`28
`27
`26
`25
`24
`23
`22
`21
`20
`19
`18
`17-
`16-
`15-
`1
`
`Time, mo
`
`Time, mo
`
`Figure 1. The peak mean change in intraocular pressure from baseline
`occurs at hour 2 after dosing in the brimonidine- and timolol-treated groups.
`Vertical bars represent 1 SE. Overall, at peak, no significant difference in
`IOP-lowering efficacy was seen between brimonidine and timolol. There was
`no evidence of tachyphylaxis throughout the 1-year course of the study.
`
`Visual Acuity
`Comparing final-visit visual acuity with baseline, no
`change in visual acuity occurred in 94.1% (208/221) of
`subjects in the brimonidine group and 90.5% (201/222)
`of those in the timolol group. Worsening of visual acu¬
`ity of 2 lines or more occurred in 5.9% (13/221) of the
`patients in the brimonidine group and 9.5% (21/222) of
`those in the timolol group. The between-group differ¬
`ence was not significant. These findings were assumed
`not to be drug-related and may have been associated
`with the progression of cataracts, which can be
`expected considering the demographic profile of this
`patient population.
`
`Pupil Size
`Mean changes in pupil size ranged from -0.13 to -0.22
`mm with brimonidine and from 0.07 to -0.17 mm with
`timolol in this study. No clinically significant differ¬
`ences were observed between the treatment groups
`throughout the follow-up.
`SYSTEMIC SAFETY
`
`Heart Rate
`
`No significant change in heart rate was seen with bri¬
`monidine, but a statistically significant mean reduction
`in heart rate was seen in the timolol group, ranging from
`1.7 to 3.0 beats per minute compared with baseline
`(Figure 3É). This decrease with timolol was statistically
`significantly higher than the mean changes seen in the
`brimonidine group at most of the follow-up visits.
`
`Blood Pressure
`
`Some mean changes in systolic and diastolic blood pres¬
`sure were seen in both treatment groups. These changes
`were statistically but not clinically significant. No clini¬
`cally significant differences were observed between the
`treatment groups.
`
`Figure 2. A statistically significant mean reduction in heart rate is seen in the
`timolol-treated group, ranging from 1.7 to 3.0 beats per minute compared
`with baseline. No significant change in heart rate is seen with brimonidine.
`Vertical bars represent 1 SE.
`
`Laboratory Analysis
`Although there were several statistically significant changes
`from baseline in hématologie and blood chemistry vari¬
`ables in both groups, these changes were not clinically sig¬
`nificant or associated with adverse events. Several shifts
`were observed in blood lipid values for both treatments,
`but these shifts were in both directions and were not re¬
`flected in the mean laboratory values. A statistically sig¬
`nificant mean increase from baseline in serum glucose lev¬
`els of approximately 10% occurred in the brimonidine
`group at 12 months. This change is not considered to be
`clinically significant because the samples were from non-
`fasting subjects, and because the change did not differ sta¬
`tistically from that occurring with timolol.
`Adverse Events
`
`The Table gives the adverse events seen for the timolol and
`brimonidine groups, with their incidence and the percent¬
`age ofsubjects terminated from the study due to an adverse
`event. Information about occurrence and severity ofadverse
`events was actively elicited from the patients at each visit.
`Overall, the number of patients with adverse events
`was similar between the 2 treatment groups (191of221
`subjects for brimonidine and 181 of 222 subjects for timo¬
`lol). The most commonly reported adverse events in both
`groups were burning and stinging, dry mouth, blurring,
`fatigue and drowsiness, headache, foreign body sensa¬
`tion, ocular pruritus, and photophobia. Dry mouth and
`allergic reaction were reported significantly more often
`in patients receiving brimonidine (P<.001); burning and
`stinging was reported significantly more often in pa¬
`tients receiving timolol (P=.002).
`Allergy (allergic conjunctivitis, allergic blepharo-
`conjunctivitis, and follicular conjunctivitis) was seen in
`9% of subjects treated with brimonidine and caused dis¬
`continuation of the drug in 7.2%. No timolol-treated sub¬
`jects experienced allergy, and few were terminated from
`the study for any reason; this may be because most sub¬
`jects in each treatment group were treated with a topical
`ß-blocker just before washout for this study, and a se-
`
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`

`Adverse Events for Timolol and Brimonidine Treatment Groups*
`
`Adverse Events!
`Ocular
`Allergyt-
`Blurring
`Burning/stinging
`Conjunctlval follicles
`Foreign body sensation
`Hyperemia
`Lid erythema
`Ocular pruritus
`Photophobia
`Systemic
`Dry mouth
`Fatigue/drowsiness
`Headache
`
`0.2% Brimonidine Tartrate
`(n=221)
`
`I
`
`Overall %
`
`Exited Study %
`
`9.0
`22.2
`28.1
`8.1
`15.4
`30.3
`10.4
`12.2
`11.3
`
`33.0
`19.9
`19.0
`
`7.2
`1.8
`<1.0
`0.0
`<1.0
`2.3
`0.0
`0.0
`0.0
`
`1.4
`2.7
`<1.0
`
`0.0
`22.5
`41.9
`2.3
`16.2
`23.4
`7.2
`9.5
`11.3
`
`19.4
`17.1
`19.8
`
`0.5% Timolol Maléate
`(n=222)
`
` -
`Overall %
`
`Exited Study %
`
`0.0
`<1.0
`<1.0
`0.0
`0.0
`0.0
`0.0
`0.0
`0.0
`
`<1.0
`0.0
`<1.0
`
`<.001
`.93
`.002
`.005
`.81
`.10
`.24
`.35
`.99
`
`.001
`.45
`.83
`
`*ln both groups, more than 50% had been treated before study with a topical ß -blocker.
`\Data reflect events with an incidence of 10% and greater or those with a significant between-group difference. Lens and fundus abnormalities, which occurred
`in greater than 10% of patients, were excluded as the incidence was similar in both groups and assumed not to be drug related.
`XAIIerglc conjunctivitis, allergic blepharoconjunctivitis, follicular conjunctivitis.
`
`lection bias may exist for these subjects that would ac¬
`count for the low numbers of subjects in the timolol group
`who left the study early because of side effects.
`
`COMMENT
`This multicenter, double-masked, randomized, parallel-
`group, active-controlled comparison clinical trial shows the
`safety and efficacy of brimonidine in the management of
`subjects with elevated IOP and glaucoma. Peak IOP re¬
`duction was similar for brimonidine and timolol. In the
`timolol group, the mean change from baseline in trough
`IOP was similar to that seen at peak measurements. The
`trough decrease in the brimonidine group was somewhat
`less than its peak effect. A sustained reduction in peak and
`trough IOP for the 1-year duration of the study was seen
`for brimonidine and timolol. Overall, in this study, 95%
`of visual fields were judged by the clinical investigators to
`be unchanged from baseline, with a similar distribution be¬
`tween the treatment groups. The subanalysis on visual fields
`showed no statistically significant difference between the
`treatment groups. In subjects in whom visual fields were
`judged to have subjectively worsened, there is insufficient
`information to differentiate among the multiple factors that
`may influence the apparent worsening of the visual field.
`Longer periods of observation will be necessary to deter¬
`mine whether any visual field changes will occur in the long-
`term treatment of glaucoma with brimonidine that are
`irrespective of IOP control.
`As in previous studies,20 brimonidine did not re¬
`duce heart rate, which is a common effect associated with
`topical ß-blocker use and has been confirmed in this study.
`In addition, the effect brimonidine had on blood pres¬
`sure was of no clinical significance.
`We found a low incidence of adverse events over¬
`all, even though subjects were explicitly questioned about
`the potential side effects. There was more burning and
`stinging in the timolol group than in the brimonidine
`
`group, but allergy and dry mouth were more frequent
`among brimonidine subjects than timolol subjects. Al¬
`though fatigue and drowsiness and headache have been
`observed with other -agonists, the incidence of these
`complaints in this study was similar in the brimonidine
`and timolol groups. The first report of allergy in the bri¬
`monidine group in this study did not occur until day 44.
`It is important to discriminate between mild side ef¬
`fects and those that require that the subject be termi¬
`nated from the study. In this context, this study was bi¬
`ased in favor of timolol, in that most of the subjects in each
`treatment group had been tolerating a ß-blocker just be¬
`fore enrollment. This preselected population may ex¬
`plain why adverse events typically associated with ß-blocker
`therapy were less prominent in the timolol-treated group.
`Several advantages of brimonidine over other topi¬
`cal -agonists may be inferred from this study. The al¬
`lergy rate seen in this 1-year study for brimonidine (9%)
`was much lower than that reported in the literature for
`apraclonidine (ranging from 20%-48% with 1% apracloni¬
`dine810 and 14%-36% with the 0.5% concentration).7·8·23·24
`No tachyphylaxis was seen with brimonidine during the
`1-year follow-up of this investigation; apraclonidine has
`been reported to lose potency over time.210 Brimonidine,
`in this study, was effective as a twice-daily drug, and my-
`driasis and eyelid retraction, commonly seen with apra¬
`clonidine,3 were not seen in this study.
`Brimonidine seems to offer several advantages over
`existing glaucoma medications and may be appropriate for
`first-line therapy in many patients. Nordlund et al25 have
`shown a safety profile superior to timolol, with no effect
`ofbrimonidine on exercise-induced tachycardia. In the pres¬
`ent study, unlike timolol, brimonidine had no effect on
`heart rate, and the effect on systemic blood pressure was
`not clinically significant. Moreover, reduction in IOP was
`similar to timolol. Based on this profile, there may be sub¬
`groups of patients, especially those receiving a systemic
`ß-blocker, who may not respond well to a topical ß-blocker;
`
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`or persons with cardiopulmonary disease, for whom bri¬
`monidine would be an obvious drug of first choice.
`Acceptedfor publication January 31, 1997.
`Supported in part by a grantfrom Allergan Ine, Irvine,
`Calif.
`The views contained herein are those of the authors and
`do not reflect the official policy or position of the Department
`of the Navy, Department ofDefense, or the US government.
`Presented in part at the Annual Meeting of the Asso¬
`ciationfor Research in Vision and Ophthalmology, Fort Lau-
`derdale, Fla, April 21-26, 1996.
`Participants in the Brimonidine Study Group are
`Diane Albracht, MD, Castro Valley, Calif; Neil T. Choplin,
`MD, Naval Medical Center, San Diego, Calif; Ronald
`Gross, MD, Baylor College of Medicine, Houston, Tex;
`Barry Horwitz, MD, Houston; Frank Sloan, MD, Myrtle
`Beach, SC; Jacob Wilensky, MD, University of Illinois,
`Chicago; L. Jay Katz, MD, Wills Eye Hospital, Philadel¬
`phia, Pa; Howard Barnebey, MD, Seattle, Wash; Robert
`Jones, MD, Newport Beach, Calif; Walter Atlas, MD,
`Charlotte, NC; Larry Labarta, MD, Miami Beach, Fla;
`David Silverstone, MD, New Haven, Conn; Thorn
`Zimmerman, MD, University of Louisville, Louisville, Ky;
`Itamar Klemperer, MD, Ben-Gurion University of the
`Negev, Beer-Sheva, Israel; E. Randy Craven, MD, Denver,
`Colo; Kathleen Lamping, MD, Gates Mills, Ohio; Howard
`F. Perell, MD, Baltimore, Md; Joel S. Schuman, MD, New
`England Eye Center, Boston, Mass; Richard Sturm, MD,
`Lynbrook, NY; Christopher M. Tortora, MD, Wahiawa,
`Hawaii; Stanley Hersh, MD, Waterbury, Conn; Norman S.
`Levy, MD, Gainesville, Fla; Michael H. Rotberg, MD,
`Charlotte; Les Siegel, MD, Southfield, Mich; Stuart Terry,
`MD, San Antonio, Tex; and Amy L. Batoosingh, Carol
`Drain, Elaine Kelley, and John G. Walt, Allergan Inc.
`Reprints:Joel S. Schuman, MD, New England Eye Cen¬
`ter, New England Medical Center Hospitals, Tufts Univer¬
`sity School ofMedicine, 750 Washington St, Box 450, Bos¬
`ton, MA 02111 (e-mail: jss@mediaone.net).
`
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