To compare the alpha2-adrenergic agonist brimonidine tartrate 0.2% to the beta-adrenergic antagonist timolol maleate 0.5% in preserving visual function in low-pressure glaucoma.
Randomized, double-masked, multicenter clinical trial.
Exclusion criteria included untreated intraocular pressure (IOP) >21 mm Hg, visual field mean deviation worse than −16 decibels, or contraindications to study medications. Both eyes received twice-daily monotherapy randomized in blocks of 7 (4 brimonidine to 3 timolol). Standard automated perimetry and tonometry were performed at 4-month intervals. Main outcome measure was field progression in either eye, defined as the same 3 or more points with a negative slope ≥−1 dB/year at P < 5%, on 3 consecutive tests, assessed by pointwise linear regression. Secondary outcome measures were progression based on glaucoma change probability maps (GCPM) of pattern deviation and the 3-omitting method for pointwise linear regression.
Ninety-nine patients were randomized to brimonidine and 79 to timolol. Mean (± SE) months of follow-up for all patients was 30.0 ± 2. Statistically fewer brimonidine-treated patients (9, 9.1%) had visual field progression by pointwise linear regression than timolol-treated patients (31, 39.2%, log-rank 12.4, P = .001). Mean treated IOP was similar for brimonidine- and timolol-treated patients at all time points. More brimonidine-treated (28, 28.3%) than timolol-treated (9, 11.4%) patients discontinued study participation because of drug-related adverse events ( P = .008). Similar differences in progression were observed when analyzed by GCPM and the 3-omitting method.
Low-pressure glaucoma patients treated with brimonidine 0.2% who do not develop ocular allergy are less likely to have field progression than patients treated with timolol 0.5%.
Open-angle glaucoma is a slowly progressive neurodegeneration of retinal ganglion cells (RGCs) and their axons characterized by a specific pattern of optic nerve head and visual field damage. Low-pressure (normal-tension) glaucoma is a clinical term often used to describe patients with open-angle glaucoma in whom the measured untreated intraocular pressure (IOP) is always within a statistically normal range. While any separation between normal and abnormally elevated IOP is intrinsically arbitrary, population-based studies demonstrate that low-pressure glaucoma represents 20% to 39% of patients with open-angle glaucoma in the United States and Europe.
The pathophysiologic mechanisms of glaucomatous neurodegeneration are incompletely understood. Elevated IOP is the most important known risk factor for disease onset and progression that is amenable to modification. Multicenter clinical trials confirm the value of reducing IOP in patients with ocular hypertension, open-angle glaucoma with elevated IOP, and low-pressure glaucoma. However, many patients continue to experience disease progression despite IOP reduction.
Laboratory studies have demonstrated that alpha2-adrenergic agonists are neuroprotective in experimental optic nerve injury, models of glaucoma, ischemia-induced injury, and photoreceptor degeneration. Yet clinical trials in nonglaucomatous diseases such as nonarteritic anterior ischemic optic neuropathy, Leber hereditary optic neuropathy, and retinal dystrophies have failed to show treatment benefit with alpha2-adrenergic agonist use. We performed a 4-year double-masked, randomized, multicenter clinical trial of the efficacy of monotherapy with brimonidine tartrate 0.2% vs timolol maleate 0.5% eye drops, medications with equal IOP-lowering efficacy, in preventing or delaying visual field progression in patients with low-pressure glaucoma.
Methods are fully described elsewhere.
Inclusion and Exclusion Criteria
Study patients had previously diagnosed low-pressure glaucoma that fulfilled the following eligibility criteria: all known untreated IOP ≤21 mm Hg, open iridocorneal angles by gonioscopy, at least 2 reproducible visual fields with glaucomatous defects in 1 or both eyes on automated perimetry (Humphrey Field Analyzer; Carl Zeiss Meditec, Inc, Dublin, California, USA) with the location of the field defect consistent with the photographic appearance of the optic nerve head, and age ≥30 years. To determine eligibility based on IOP, all patients receiving IOP-lowering treatment underwent a 4-week washout without therapy. Baseline IOP (measured with a calibrated Goldmann applanation tonometer) had to be ≤21 mm Hg in both eyes with <5 mm Hg difference between the eyes on a diurnal curve (8:00 AM, 10:00 AM, noon, 4:00 PM) assessed prior to randomization.
Ocular exclusion criteria included the following: a history of IOP >21 mm Hg in the patient record, best-corrected visual acuity worse than 20/40 in either eye, a history of angle closure or an occludable angle by gonioscopy, prior glaucoma incisional surgery, inflammatory eye disease, prior ocular trauma, diabetic retinopathy or other diseases capable of causing visual field loss or optic nerve deterioration, extensive glaucomatous visual field damage with a mean deviation worse than −16 decibels (dB), or a clinically determined threat to central fixation in either eye. Systemic exclusion criteria included a resting pulse <50 beats/minute; severe or uncontrolled cardiovascular, renal, or pulmonary disease that would preclude safe administration of a topical beta-adrenergic antagonist; and a prior myocardial infarction or stroke. Continuation of systemic medications that could affect IOP was allowed as long as the doses remained constant throughout the trial.
Randomization, Treatment, and Masking
Patients were randomly assigned to receive monotherapy with either brimonidine tartrate 0.2% containing 0.005% (50 ppm) benzalkonium chloride (Alphagan; Allergan, Inc, Irvine, California, USA) or timolol maleate 0.5% containing 0.01% (100 ppm) benzalkonium chloride (Timoptic; Merck & Co, West Point, Pennsylvania, USA) twice daily in both eyes, including the morning before each visit. To allow for higher patient attrition in the brimonidine group attributable to an expected rate of adverse events of approximately 20%, randomization and delivery of medications (provided by Allergan, Inc) to the sites were stratified in blocks of 7 (4 brimonidine to 3 timolol). The randomization list was maintained and masked study medications were provided in new 10-mL white bottles labeled with the assigned randomization number directly to the clinical centers by an independent pharmacy (Fountain Valley Cancer Center Pharmacy, Fountain Valley, California, USA). Ocular treatment other than the study medication was not permitted. Investigators, patients, and the visual field reading and coordinating centers were all masked to patient assignment.
Endpoints requiring discontinuation from the study included: treated IOP >21 mm Hg that was repeated within 1 month, safety concern as judged by the treating physician, symptomatic ocular allergic adverse events (hyperemia, pruritus, stinging, and/or conjunctival folliculosis) requiring medication cessation, retinal events that could alter visual acuity or visual field (eg, age-related macular degeneration), the occurrence of systemic (eg, respiratory or cardiovascular) adverse events that prevented the administration of topical timolol, nonocular intolerable events associated with topical brimonidine (eg, xerostomia, fatigue, drowsiness), or if the patient moved or declined continued participation. Collection of data from discontinued patients ceased at their final study visit. Data up to this point were included in the analysis, but discontinued patients were no longer followed as part of the study.
Patients were examined at 1 and 4 months after initiation of treatment. Subsequent visits were at 4-month (± 2 weeks) intervals. Pre- and post-randomization morning visits recorded the following: ocular and systemic history, blood pressure, pulse, corrected visual acuity, IOP, slit-lamp examination, and optic disc evaluation for cup-to-disc ratio and the presence or absence of disc hemorrhage. Gonioscopy and stereoscopic optic disc photographs were performed annually. Full-threshold standard achromatic perimetry (Humphrey 24-2) visual field was performed at 4-month intervals throughout the study according to protocol guidelines.
The primary outcome measure was visual field progression in either eye as determined by pointwise linear regression analysis of all study visual fields with Progressor software (Medisoft Inc., Leeds, UK). Visual field analysis was performed by an independent reading center (Devers Eye Institute, Legacy Health System, Portland, Oregon, USA) masked to the treatment assignment. Linear regression of the sensitivity (in dB) was performed at each test location to obtain the rate of change at that location, based on all fields up to and including the current examination. Default Progressor criteria were used to define a significant negative slope (worse than −1 dB/year for inner points and −2 dB/year for edge points) at the P < 5% level. Edge points for the Humphrey 24-2 field included the 2 outer nasal locations, 1 above and 1 below the horizontal. Criteria for visual field progression required confirmation at the next 2 examinations (ie, 4 and 8 months later) of a significant negative slope at the same 3 or more test locations. Therefore, the earliest that field progression could be detected was the month-16 examination (8 months to calculate the pointwise linear regression for the negative slopes and months 12 and 16 for confirmation). Progression criteria did not require the progressing locations to be contiguous.
A secondary outcome was visual field progression in either eye evaluated by Humphrey glaucoma change probability maps (GCPM). The GCPM was based on pattern deviation maps rather than the total deviation plot used in the glaucoma change probability software to eliminate change caused by generalized depression of the visual field (eg, cataract). Progression by GCPM was defined as a significant worsening at P < 5% for the same 3 or more test locations that were confirmed at the next 2 examinations. Progressing locations did not have to be contiguous.
To verify the results of the primary Progressor outcome measure, a post hoc analysis was performed using a 3-omitting method for pointwise linear regression that used the default Progressor software criteria. This method was reported during the study and increases specificity by requiring that progression must be confirmed at 2 further visits when omitting from the series the visual field that caused progression to be suspected.
Pre-study sample size calculations indicated that 64 subjects would be required in each treatment arm to have an 80% power to detect a difference in visual field progression (at α = .05 by 2-tailed test) based on the following assumptions: 1) a 4-year progression rate of 30% in the brimonidine group and 55% in the timolol group ; 2) an attrition rate of 25%; and 3) 20% of subjects having only 1 eye eligible. Patients were analyzed in the group to which they were randomized. Analysis was patient-based and the event time to field progression was defined based on progression in either eye. The log-rank test was used to compare the time to field progression between treatment groups. Point estimates of proportion of subjects progressing were derived from Kaplan-Meier analysis, with standard errors from Greenwood’s formula. Univariate comparisons between treatment groups were nonparametric (Mann-Whitney U test, Wilcoxon signed rank test) and the Fisher exact test for categorical variables. Reported values are mean ± SD and P values separately in the 2 arms are 2-sided. Statistical significance was defined as P < .05.
Recruitment was between April 28, 1998 and June 19, 2000, with 193 individuals assessed for enrollment ( Figure 1 ). A total of 178 randomized participants were followed: 99 (55.6%) were allocated to brimonidine and 79 (44.4%) to timolol. There were no significant differences at baseline in demographics, ocular parameters, or systemic factors between the 2 treatment groups ( Table 1 ).
|Brimonidine (n = 99)||Timolol (n = 79)||P Value a|
|Age, mean (SD) years||64.3 (10.9)||65.7 (10.4)||.28|
|Diurnal IOP, mean (SD) mm Hg||15.8 (2.1)||15.2 (2.4)||.13|
|Visual field, mean (SD) dB|
|Mean deviation||−5.3 (3.5)||−4.8 (3.0)||.32|
|Pattern standard deviation||5.9 (3.0)||5.8 (2.4)||.86|
|Unilateral field loss, patients (%)||27 (27.3)||21 (26.6)||>.99|
|Visual acuity (Snellen decimal fraction)||0.89 (0.2)||0.90 (0.2)||.74|
|Refraction spherical equivalent||−0.70 (2.2)||−0.54 (2.5)||.61|
|Corneal thickness, mean (SD) μm||540 (30)||547 (36)||.18|
|New glaucoma diagnosis, patients (%)||24 (24.2)||20 (25.3)||1.00|
|Blood pressure, mean (SD) mm Hg|
|Systolic||130 (17)||123 (17)||.41|
|Diastolic||76 (10)||76 (10)||.81|
|Diastolic ≤60 mm Hg, number (%)||8 (8.1)||6 (7.6)||1.00|
|First-degree history glaucoma (%)||30 (30.3)||28 (35.4)||.52|
|Ocular hypotensive therapy, patients (%)|
|None||41 (41.4)||27 (34.2)||.35|
|Timolol||45 (45.5)||38 (48.1)||.76|
|Brimonidine||10 (10.1)||13 (16.4)||.26|
|Systemic disorders, patients (%)|
|Migraine||6 (6.1)||3 (3.8)||.73|
|Diabetes mellitus||10 (10.1)||5 (6.3)||.43|
|Hypertension||41 (41.4)||36 (45.6)||.65|
|Systemic medications, patients (%)|
|Beta-adrenergic antagonist||15 (15.2)||10 (12.6)||.67|
|Calcium channel blocker||14 (14.1)||16 (20.2)||.32|
|Alpha-adrenergic agonist||2 (2.0)||3 (3.8)||.66|
|Angiotensin converting enzyme inhibitor||23 (23.2)||16 (20.2)||.72|
|Statins||15 (15.2)||14 (17.7)||.69|
a P values for comparison of baseline parameters for the brimonidine and the timolol groups: Mann-Whitney U test and Fisher exact test for categorical variables. Ocular measurements based on the mean of patient eyes.
Statistically more subjects assigned to brimonidine (36/99, 36.4%) dropped out prior to the year-1 examination than assigned to timolol (8/79, 10.1%) ( P = .001, see Figure 1 ). The most common reason for discontinuation before the year-1 examination was localized ocular allergy that necessitated discontinuing the study medication in 20 of the 99 (20.2%) brimonidine and 3 of the 79 (3.8%) timolol subjects ( P = .001). There were no statistically significant baseline differences between patients discontinued prior to the year-1 and patients completing the year-1 and later study visits within either treatment randomization group. Eleven brimonidine patients (11.1%) and 1 timolol patient (1.3%) dropped out prior to the first treatment visual field at month 4 ( P = .013).
Mean (± SE) months of follow-up for all patients was 30.0 ± 1.2 (range, 3.2–50.2; 95% confidence interval [CI], 27.5–32.4) and in patients completing the year-1 study visit (n = 134) was 35.6 ± 1.0 (range, 11.5–50.2; 95% CI, 33.5–37.7). Baseline characteristics for the 63 of 99 (63.6%) brimonidine and the 71 of 79 (89.9%) timolol patients completing the year-1 visit were not significantly different between the 2 groups except for IOP, which was statistically higher ( P = .031) in the brimonidine (16.2 ± 1.9) compared to the timolol patients (15.3 ± 2.4). An additional 18 brimonidine (8 of 99 with ocular allergy, 8.1%) and 15 timolol (6 of 79 with ocular allergy, 7.6%) patients were discontinued at or after the year-1 study visit (see Figure 1 ). For active patients, there were no missed visits (ie, visual field examinations) with subsequent 4-month follow-up examinations.
Six patients died during the study, 5 (5.0%) assigned to brimonidine and 1 (1.3%) to timolol, from causes unrelated to the study medications (see Figure 1 ). Causes for the 5 brimonidine patients were trauma, myocardial infarction (n = 2), pulmonary embolism, and complications following bowel surgery. The cause of death in the timolol patient was complications following bowel surgery.
A visual field endpoint for the pointwise linear regression primary outcome measure ( Figure 2 ) was reached in significantly (log-rank 12.4, P = .001) fewer patients assigned to brimonidine (n = 9, estimate ± standard error = 10 ± 4%) than to timolol (n = 31, 33 ± 6%) ( Table 2 ). Positive slopes (sensitivity increasing >1 dB/yr) on the same 3 or more test locations, not necessarily contiguous, on 3 consecutive fields were used to calculate the false-positive rate. There was no statistical difference in the frequency of significantly positive slopes in the 2 treatment groups: 9 patients assigned to brimonidine (8 reaching study end and 1 discontinued after year 1) and 8 patients to timolol (7 reaching study end and 1 discontinued after year 1). Two patients assigned to brimonidine and 1 to timolol who had field progression (significant negative slopes) also had significant positive slopes at other field locations.
|Brimonidine No. (%)||Timolol No. (%)||P|
|Randomized||99 (100)||79 (100)|
|Discontinued prior to year 1||36 (36.4)||8 (10.1)||<.001 d|
|Discontinued ≥year 1||18 (18.2)||15 (19.0)|
|Progressor analysis a||Log-rank e|
|Visual field progression||9 (9.1)||31 (39.2)||12.4, <.001|
|Trial end without progression||36 (36.4)||25 (31.6)|
|Glaucoma change probability maps b||22.0, <.001|
|Visual field progression||8 (8.1)||35 (44.3)|
|Trial end without progression||37 (37.4)||24 (30.4)|
|3-omitting method c||9.5, <.002|
|Visual field progression||5 (5.0)||21 (26.6)|
|Trial end without progression||40 (40.4)||36 (45.6)|
Baseline characteristics of the 9 brimonidine and the 31 timolol patients manifesting visual field progression by pointwise linear regression were not significantly different with respect to age (66.0 ± 9.1 vs 65.7 ± 10.1 years), visual field mean deviation (−5.19 ± 3.90 vs −4.69 ± 5.02 dB), visual field pattern standard deviation (5.33 ± 2.23 vs 6.05 ± 2.52 dB), and diurnal IOP mean (16.9 ± 2.4 vs 15.4 ± 2.5) and standard deviation (1.5 ± 0.6 vs 1.5 ± 0.6). Baseline Snellen decimal fraction acuity in the 9 brimonidine progressing patients (0.92 ± 0.21) was statistically unchanged at the time of progression (0.89 ± 0.21), while the 31 timolol progressing patients had decreased Snellen decimal acuity (baseline 0.92 ± 0.21 vs 0.82 ± 0.19, P = .008) and decreased heart rate (baseline 70.1 ± 10.0 vs 66.0 ± 11.1, P = .016). Baseline refraction spherical equivalent was not significantly changed at the time of progression in either treatment group. Comparison of the linear regression slopes of the Snellen decimal fraction over time between brimonidine and timolol groups did not show a statistical difference for progressing patients (−0.001 ± 0.004 vs −0.002 ± 0.005), patients reaching study end (−0.001 ± 0.003 vs −0.002 ± 0.003), and patients not reaching the year-1 visit (0.009 ± 0.021 vs 0.018 ± 0.026). The linear regression slope for the brimonidine discontinued patients (−0.001 ± 0.004) was statistically negative ( P = .051) compared to the timolol discontinued patients (0.003 ± 0.005).
The decrease in IOP was not significantly different in patients assigned to brimonidine or timolol ( Figure 3 ). The distribution of IOP between the 2 groups during the study was similar at all time points for the total groups, discontinued patients, patients reaching study end without visual field progression, and the eyes manifesting visual field progression. The percent reduction of IOP and the number of patients with ≥20% IOP reduction during the study was not significantly different in the 2 treatment groups. IOP reduction ≥20% at the time of visual field progression by Progressor analysis was not significantly different ( P = 1.000, Fisher 2-tailed test) between the timolol-treated (12/31, 39%) and the brimonidine-treated patients (4/9, 44%). Patients reaching study end without visual field progression (months 36–48) were also not significantly different ( P = .403) regarding IOP reductions ≥20% (timolol 9/23, 39% and brimonidine 10/36, 28%).
Analyses were performed to determine whether there was a differential IOP between or within study groups ( Table 3 ). There were no statistically significant differences in IOP between the treatment groups for subjects dropping out before month 16. Within treatment groups, there were no statistically significant IOP differences for subjects dropping out before month 16 compared to subjects in the study after month 16 or to subjects reaching study end (month 36 or after) without visual field progression.
|Num||Mean (SD)||95% CI||P a||Num||Mean (SD)||95% CI||P a||P b|
|Dropout mo 16 c||46||13.6 (2.6)||12.9–14.3||14||13.6 (2.2)||12.2–15.1||.86|
|vs >mo 16 d||53||14.4 (1.9)||13.6–14.7||.23||65||14.2 (2.5)||13.6–14.9||.17|
|vs study end e||43||14.2 (1.9)||13.6–14.8||.22||48||14.0 (2.6)||13.2–14.7||.21|