Risk Factors for Visual Field Progression in the
Low-pressure Glaucoma Treatment Study
CARLOS GUSTAVO DE MORAES, JEFFREY M. LIEBMANN, DAVID S. GREENFIELD, STUART K. GARDINER,
ROBERT RITCH, AND THEODORE KRUPIN, ON BEHALF OF THE LOW-PRESSURE GLAUCOMA TREATMENT
STUDY GROUP
● PURPOSE: To investigate risk factors associated with
visual field progression in the Low-pressure Glaucoma
Treatment Study, a prospective trial designed to compare
the effects of the alpha2-adrenergic agonist brimonidine
tartrate 0.2% to the beta-adrenergic antagonist timolol
maleate 0.5% on visual function in low-pressure glau-
coma.
● DESIGN: Prospective cohort study.
● METHODS: Low-pressure Glaucoma Treatment Study
patients with >5 visual field tests during follow-up were
included. Progression was determined using pointwise
linear regression analysis, defined as the same 3 or more
visual field locations with a slope more negative than
ⴚ1.0 dB/year at P < 5%, on 3 consecutive tests. Ocular
and systemic risk factors were analyzed using Cox pro-
portional hazards model and further tested for indepen-
dence in a multivariate model.
● RESULTS: A total of 253 eyes of 127 subjects (mean
age, 64.7 ⴞ 10.9 years; mean follow-up, 40.6 ⴞ 12
months) were analyzed. Eyes randomized to timolol
progressed faster than those randomized to brimonidine
(mean rates of progression, ⴚ0.38 ⴞ 0.9 vs 0.02 ⴞ 0.7
dB/y, P < .01). In the final multivariate model adjusting
for all tested covariates, older age (hazard ratio [HR] ⴝ
1.41/decade older, 95% confidence interval [CI] ⴝ 1.05
to 1.90, P ⴝ .022), use of systemic antihypertensives
(HR ⴝ 2.53, 95% CI ⴝ 1.32 to 4.87, P ⴝ .005), and
mean ocular perfusion pressure (HR ⴝ 1.21/mm Hg
lower, 95% CI ⴝ 1.12 to 1.31, P < .001) were
associated with progression whereas randomization to
brimonidine revealed a protective effect (HR ⴝ 0.26,
95% CI ⴝ 0.12 to 0.55, P < .001).
● CONCLUSIONS: While randomization to brimonidine
0.2% was protective compared to timolol 0.5%, lower
Accepted for publication April 24, 2012.
From the Einhorn Clinical Research Center, New York Eye and Ear
Infirmary, New York, New York (C.G.D.M., J.M.L., R.R.); Department of
Ophthalmology, New York University School of Medicine, New York,
New York (C.G.D.M., J.M.L.); Bascom Palmer Eye Institute, University
of Miami Miller School of Medicine, Palm Beach Gardens, Florida
(D.S.G.); Devers Eye Institute, Legacy Health, Portland, Oregon
(S.K.G.); Department of Ophthalmology, New York Medical College,
Valhalla, New York (R.R.); Department of Ophthalmology, Feinberg
School of Medicine, Northwestern University, Chicago, Illinois (T.K.);
and The Chicago Center for Vision Research, Chicago, Illinois (T.K.).
Inquiries to Carlos Gustavo De Moraes, 310 East 14th St, New York,
NY 10003; e-mail: demoraesmd@gmail.com
702 © 2012 BY ELSEVIER INC. ALL
mean ocular perfusion pressure increased the risk for
reaching a progression outcome in the Low-pressure
Glaucoma Treatment Study. This suggests that the ben-
eficial effect of randomization to the brimonidine arm was
independent of possible differences in ocular perfusion
pressures between the 2 treatment arms. The current
results and large number of drop-outs in the brimonidine
0.2% arm suggest that more research is necessary before
altering clinical practice paradigms. (Am J Ophthalmol
2012;154:702–711. © 2012 by Elsevier Inc. All rights
reserved.)
G
LAUCOMA IS A PROGRESSIVE DISORDER CHARAC-
terized by structural and functional abnormalities
of the optic nerve.1–3 Even though intraocular
pressure (IOP) is the most important modifiable risk factor
for disease onset and progression,4 – 8 glaucoma can exist
even among individuals for whom IOP measurements are
within the statistically defined “normal range.”9 –12 Al-
though an artificial construct, low-pressure (normal-ten-
sion, normal-pressure, or low-tension) glaucoma is a widely
used term to classify the disease in patients with glauco-
matous optic neuropathy with or without visual field loss
whose pressures are within the 95th percentile of the
normal distribution of IOP measurements in the healthy
population (IOP ⬍22 mm Hg using Goldmann applana-
tion tonometry).9
The Low-pressure Glaucoma Treatment Study13–15 is
a multicenter, double-masked, prospective, randomized
clinical trial that aimed to investigate visual field
outcomes in low-pressure glaucoma patients treated
with either a topical beta-adrenergic antagonist (timolol
maleate 0.5%) or alpha2-adrenergic agonist (brimoni-
dine tartrate 0.2%). The results of this trial revealed
that subjects randomized to topical brimonidine 0.2%
had better preservation of visual function than those
receiving timolol 0.5% despite similar IOP levels.15 It is
unclear, however, whether this outcome was attribut-
able to different mechanisms of drug action or whether
other risk factors, including IOP, also played a signifi-
cant role. In the present study, we investigated baseline
and intercurrent risk factors for visual field progression
among participants enrolled in the Low-pressure Glau-
coma Treatment Study.
RIGHTS RESERVED. 0002-9394/$36.00
http://dx.doi.org/10.1016/j.ajo.2012.04.015
 PATIENTS AND METHODS
THE METHODOLOGY OF THE LOW-PRESSURE GLAUCOMA
Treatment Study, including baseline characteristics and
study design, has been described in detail elsewhere.13–15
In brief, the Low-pressure Glaucoma Treatment Study
Group was a multicenter, prospective clinical trial in
which patients were randomized to treatment with topical
brimonidine tartrate 0.2% vs timolol maleate 0.5%. The
institutional review boards at all 13 participating centers
approved the study protocol and informed consent was
obtained.
● INCLUSION AND EXCLUSION CRITERIA: Study pa-
tients had previously diagnosed low-pressure glaucoma that
fulfilled the following eligibility criteria: all known un-
treated IOP ⱕ21 mm Hg; open iridocorneal angles; 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 being consis-
tent with the photographic appearance of the optic nerve
head; and age ⱖ30 years. To determine eligibility based on
IOP, all patients receiving IOP-lowering treatment under-
went a 4-week washout without therapy. Baseline IOP
(measured with a calibrated Goldmann applanation
tonometer) had to be ⱕ21 mm Hg in both eyes with ⬍5
mm Hg difference between the eyes on an office diurnal
curve (8:00 AM, 10:00 AM, 12:00 PM, 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 gonios-
copy, 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: Pa-
tients were randomly assigned to receive monotherapy
with either brimonidine tartrate 0.2% containing ben-
zalkonium chloride (Alphagan; Allergan, Inc, Irvine, Cal-
ifornia, USA) or timolol maleate 0.5% containing
benzalkonium chloride (Timoptic; Merck & Co Inc, West
Point, Pennsylvania, USA) twice daily in both eyes,
including the morning before each visit. To allow for
VOL. 154, NO. 4 RISK FACTORS IN
higher patient attrition in the brimonidine group attribut-
able to an expected rate of adverse events of approximately
20%, randomization and delivery of medications (provided
by Allergan, Inc, Irvine, California, USA) to the sites were
stratified in blocks of 7 (4 to brimonidine and 3 to
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. Inves-
tigators, patients, and the visual field reading and coordi-
nating 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 (hy-
peremia, pruritus, stinging, and/or conjunctival folliculo-
sis) 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 pre-
vented 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 discon-
tinued patients were no longer followed as part of the
study.
● STUDY VISITS: 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: oc-
ular 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 ab-
sence 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
according to protocol guidelines.
● OUTCOME MEASURES: The main outcome measure was
visual field progression in 1 eye as determined by pointwise
linear regression.15 Visual field progression analysis was
performed using Progressor software (Medisoft, Inc, Leeds,
UK).16 Visual field analyses were performed by an inde-
pendent 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 last examination. Default Progressor criteria
LOW-PRESSURE GLAUCOMA 703
 TABLE 1. Low-pressure Glaucoma Treatment Study: Comparison of Clinical Characteristics Between Patients Randomized to
Timolol Maleate 0.5% and Brimonidine Tatrate 0.2%a

Timolol Brimonidine
Parameter (n ⫽ 69) (n ⫽ 58) P Value

Age (years) 65.2 ⫾ 10.8 63.3 ⫾ 11.1 .18b

Sex (male/female) 26/43 27/31 .36c
Follow-up time (months) 41.1 ⫾ 11.6 40.4 ⫾ 12.4 .68b
Positive family history for glaucoma (%) 25 (36) 17 (29) .45c
Use of systemic antihyptertensives (%) 32 (46) 24 (41) .59c
Use of systemic beta-blockers (%) 11 (16) 6 (10) .43c
Treatment for diabetes mellitus (%) 6 (8) 11 (18) .11c
Positive history of migraine (%) 3 (4) 6 (10) .29c
Positive history of Raynaud phenomenon (%) 10 (14) 5 (8) .41c
Spherical equivalent (diopters) ⫺0.64 ⫾ 2.6 ⫺0.55 ⫾ 2.2 .78b
Lens status (per eye) (pseudophakic eyes, %) 10 (7) 16 (13) .08c
At least 1 disc hemorrhage detected (%) 12 (8) 6 (5) .33c
Number of eyes with recurrent disc hemorrhages 10 (7) 3 (2) .15c
Cup-to-disc ratio 0.72 ⫾ 0.1 0.67 ⫾ 0.1 .03b
Central corneal thickness (␮m) 547.8 ⫾ 38.6 540.6 ⫾ 29.0 .10b
Untreated diurnal curve IOP (mm Hg)
Mean 15.2 ⫾ 2.5 16.2 ⫾ 1.9 ⬍.01b
Peak 16.7 ⫾ 2.7 17.7 ⫾ 2.0 .04b
Fluctuation 1.28 ⫾ 0.7 1.37 ⫾ 0.6 .30b
Treated follow-up IOP (mm Hg)
Mean 13.9 ⫾ 2.3 14.1 ⫾ 1.9 .38b
Peak 16.4 ⫾ 2.6 17.0 ⫾ 2.3 .03b
Fluctuation 1.59 ⫾ 0.5 1.86 ⫾ 0.6 ⬍.01b
Mean % IOP reduction from baseline (%) 8 ⫾ 10 12 ⫾ 10 ⬍.01b
Baseline blood pressure (mm Hg)
Systolic 132.3 ⫾ 17.0 128.9 ⫾ 18.2 .13b
Diastolic 76.9 ⫾ 9.2 74.7 ⫾ 10.7 .08b
Follow-up blood pressure (mm Hg)
Mean systolic 128.7 ⫾ 13.1 129.4 ⫾ 14.0 .68b
Mean diastolic 75.8 ⫾ 6.9 74.5 ⫾ 7.9 .14b
Fluctuation systolic 10.9 ⫾ 6.1 10.9 ⫾ 5.6 .95b
Fluctuation diastolic 6.4 ⫾ 3.8 6.2 ⫾ 3.3 .55b
Mean ocular perfusion pressure (mm Hg)
Average follow-up 48.4 ⫾ 5.5 47.7 ⫾ 5.8 .32b
Fluctuation follow-up 3.7 ⫾ 2.7 3.2 ⫾ 2.4 .19b
Heart rate (beats/min)
Follow-up mean 66.0 ⫾ 6.7 70.9 ⫾ 10.1 ⬍.01b
Follow-up fluctuation 5.68 ⫾ 3.3 6.26 ⫾ 3.5 .18b

IOP ⫽ intraocular pressure.

a
All data are presented as mean ⫾ standard deviation unless otherwise specified.
b
Independent samples t test.
c
Fisher exact test.

were used to define a significant negative slope (at least
⫺1.0 dB/year for inner points and ⫺2.0 dB/year for edge
points) at the P ⬍ 5% level.15–17 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 examina-
tions of a significant negative slope at the same 3 or more
test locations. For eyes not reaching a progression end-
point, we used the time to last follow-up visit (either the
final scheduled visit or the censored one). Progressing
visual field locations were not required to be contiguous.
Because of these criteria, progression could not be deter-
mined until 5 visual field tests had been collected (the
16-month visit). Consequently, for the purposes of this
manuscript, only those eyes with enough visual field tests
to determine a progression outcome (yes/no) were included
in the analysis (1 at baseline plus 4 tests following
randomization).

704 AMERICAN JOURNAL OF OPHTHALMOLOGY OCTOBER 2012

 We examined clinical characteristics that predicted the
development of visual field progression. The following
demographic and ocular parameters were investigated: age
at baseline, sex, family history of glaucoma, central corneal
thickness (CCT), cup-to-disc ratio (estimated during slit-
lamp examination), refractive error spherical equivalent
(SE), and lens status. Pre-randomization data collected and
investigated for risk assessment were: IOP mean, peak, and
fluctuation during the diurnal curve; baseline pulse; sys-
tolic (SBP) and diastolic blood pressure (DBP); presence of
systemic comorbidities (migraine, Raynaud phenomenon,
systemic hypertension, and diabetes mellitus); and use
of systemic medications (categorized as systemic antihyper-
tensives, systemic beta-blockers, and antidiabetic agents).
Post-randomization variables consisted of series length
(ie, follow-up time), detection of at least 1 optic disc
FIGURE 1. Low-pressure Glaucoma Treatment Study: Com-
hemorrhage on stereophotographs any time during fol-
parison of mean deviation (MD) rates of change (dB/y) between
low-up, and mean, peak, and fluctuation of IOP and progressing (light gray) and nonprogressing eyes (dark gray)
blood pressure during follow-up. For numerical vari- based on the pointwise linear regression criteria. The black
ables, the mean was calculated by averaging all values curve corresponds to Gaussian curves based on the estimates
recorded during the follow-up period. Fluctuation was from study patients.
defined as the standard deviation (SD) of all measure-
ments in the same interval. Mean ocular perfusion
pressure (MOPP) was estimated by the equation MOPP ⫽
2/3 ⫻ [DBP ⫹ 1/3 ⫻ (SBP – DBP)] – IOP.18 Data on
systemic comorbidities and medications were obtained
from participants’ self-reports.

● STATISTICAL ANALYSIS: Descriptive statistics are pre-

sented with frequency tables and graphs, whereas estimates
of center and dispersion are described as mean and SD,
respectively. Cox proportional hazards model was used to
investigate the risk of progression (progression: yes or no,
based on the progression criteria described above) based on
follow-up time (progression endpoint or data censoring for
progressing and nonprogressing eyes, respectively). Vari-
ables with P ⬍ .10 in the univariate model were entered in
a multivariate model. Generalized estimating equations
were used to control for inter-eye relationships.19 Since FIGURE 2. Low-pressure Glaucoma Treatment Study: Com-
one of the assumptions of regression analyses is that the parison of mean deviation (MD) rates of change (dB/y) between
predictors should not be strongly and significantly corre- eyes on timolol 0.5% (dark gray) and brimonidine 0.2% (light
lated with one another (ie, no colinearity),20 if pairs of gray). The black curve corresponds to Gaussian curves based
predictor variables had moderate to strong significant on the estimates from study patients.
correlation, the variable with the most significant P
value in the univariate analysis was entered in the
multivariate model. Cox proportional hazards multivar-
iate model was performed using a backward elimination RESULTS
approach based on likelihood ratios. Variables in the
saturated multivariate model with P ⬎ .10 were subse- ONE HUNDRED NINETY-THREE PATIENTS WERE ASSESSED
quently removed and variables were entered in the for eligibility in the Low-pressure Glaucoma Treatment
model if P ⬍ .05. Alpha level was set at 5% (2-sided) Study, of which 178 were randomized to treatment with
and computerized statistical analyses were performed either timolol or brimonidine. The characteristics of these
using SPSS for Windows (version 16.1; IBM SPSS patients are described in detail elsewhere.13–15 Of those,
Statistics Inc, Armonk, New York, USA). 253 eyes of 127 subjects (mean age, 64.7 ⫾ 10.9 years;

VOL. 154, NO. 4 RISK FACTORS IN LOW-PRESSURE GLAUCOMA 705

 TABLE 2. Low-pressure Glaucoma Treatment Study: Cox Proportional Hazards Univariate
Analysis Testing the Association Between Each Variable and the Hazards of Visual Field
Progression Based on Pointwise Linear Regression Criteria

Parameter HR 95% Confidence Interval P Value

Randomization (brimonidine) 0.29 0.14 to 0.58 .001

Age (per decade older) 1.21 0.90 to 1.62 .078
Sex (female) 1.48 0.82 to 2.69 .192
Positive family history for glaucoma 1.04 0.57 to 1.90 .882
Use of systemic antihypertensives 1.65 0.63 to 2.91 .082
Use of systemic beta-blockers 1.71 0.85 to 3.43 .131
Treatment for diabetes mellitus 0.79 0.31 to 2.02 .629
Positive history of migraine 0.33 0.04 to 2.46 .284
Positive history of Raynaud phenomenon 0.83 0.30 to 2.32 .732
Spherical equivalent (per diopter more positive) 1.00 0.89 to 1.11 .964
Lens status (pseudophakic) 0.41 0.10 to 1.70 .222
Disc hemorrhage detection 2.14 0.90 to 5.08 .082
Cup-to-disc ratio (per 0.1-unit increase) 1.16 0.95 to 1.41 .127
Central corneal thickness (per ␮m thicker) 1.00 0.99 to 1.01 .212
Heart rate (beats/min, per unit higher)
Follow-up mean 0.98 0.95 to 1.02 .552
Follow-up fluctuation 0.95 0.86 to 1.04 .333

HR ⫽ hazard ratio.

TABLE 3. Low-pressure Glaucoma Treatment Study: Cox Proportional Hazards Univariate Analysis Testing the Association
Between Intraocular Pressure and Blood Pressure Parameters and the Hazards of Visual Field Progression Based on Pointwise
Linear Regression Criteria

Parameter Progression Stable HR 95% Confidence Interval P Value

Untreated baseline diurnal IOP (per mm Hg higher)

Mean 15.8 ⫾ 2.6 15.6 ⫾ 2.2 1.05 0.92 to 1.19 .437
Peak 17.4 ⫾ 2.3 17.7 ⫾ 2.8 1.00 0.96 to 1.04 .903
Fluctuation 1.38 ⫾ 0.8 1.31 ⫾ 0.6 1.15 0.79 to 1.67 .462
Treated follow-up IOP (per mm Hg higher)
Mean 13.9 ⫾ 2.0 14.0 ⫾ 2.2 1.00 0.88 to 1.13 .926
Peak 16.6 ⫾ 2.2 16.7 ⫾ 2.6 1.00 0.90 to 1.11 .991
Fluctuation 1.38 ⫾ 0.8 1.31 ⫾ 0.6 1.06 0.67 to 1.70 .780
Mean % IOP reduction from baseline (per 0.1% greater) 11 ⫾ 10 9 ⫾ 10 1.08 0.91 to 1.29 .343
Baseline blood pressure (per mm Hg lower)
Systolic 130.9 ⫾ 18.3 130.7 ⫾ 17.5 0.99 0.98 to 1.01 .740
Diastolic 75.9 ⫾ 9.3 76.0 ⫾ 10.1 0.99 0.96 to 1.02 .508
Follow-up blood pressure
Mean systolic (per mm Hg lower) 125.5 ⫾ 11.8 129.8 ⫾ 13.8 1.02 1.01 to 1.05 .016
Mean diastolic (per mm Hg lower) 73.1 ⫾ 5.3 75.7 ⫾ 7.7 1.08 1.03 to 1.13 ⬍.001
Fluctuation systolic (per mm Hg higher) 11.7 ⫾ 6.2 10.7 ⫾ 5.8 1.03 0.98 to 1.08 .228
Fluctuation diastolic (per mm Hg higher) 6.9 ⫾ 3.5 6.2 ⫾ 3.6 1.04 0.96 to 1.13 .286
Mean ocular perfusion pressure
Baseline (per mm Hg higher) 47.1 ⫾ 7.1 47.4 ⫾ 8.0 0.98 0.94 to 1.01 .31
Average follow-up (per mm Hg lower) 46.4 ⫾ 4.6 48.4 ⫾ 5.8 1.10 1.04 to 1.17 .001
Fluctuation follow-up (per mm Hg higher) 4.0 ⫾ 2.5 3.4 ⫾ 2.6 1.08 0.96 to 1.22 .196

HR ⫽ hazard ratio; IOP ⫽ intraocular pressure.

women, 58%; European ancestry, 71%) had at least 5 required for PLR trend analysis.21 Table 1 shows the
visual field tests and met the inclusion and exclusion clinical characteristics of this population.
criteria for this study. The following results, therefore, refer Of the 127 participants, 69 (54%) were randomized to
to this subset of eyes with the minimum number of fields timolol and 58 (46%) to brimonidine (P ⫽ .20). Forty-

706 AMERICAN JOURNAL OF OPHTHALMOLOGY OCTOBER 2012

 TABLE 4. Low-pressure Glaucoma Treatment Study: Cox Proportional Hazards Multivariate
Model Using a Backward Elimination Approach Based on Likelihood Ratiosa
Parameter
Randomization (brimonidine)
Age (per decade older)
Use of systemic antihypertensives
Mean ocular perfusion pressure during
follow-up (per mm Hg lower)
HR ⫽ hazard ratio.
Variables were entered in the model if P ⬍ .05 and removed if P ⬎ .10 in the saturated multivariate
a
model.
eight eyes (48/253; 19%) of 40 patients (40/127; 31%) met
the predefined PLR progression criteria (31 patients ran-
domized to timolol; 9 patients randomized to brimonidine,
P ⬍ .01, Fisher exact test). Patients were followed for a
mean of 40.6 ⫾ 12 months. As expected, the rate of mean
deviation (MD) change (dB/y) was significantly faster in
eyes that met our progression criteria than in those that did
not (⫺0.87 ⫾ 0.7 vs ⫺0.04 ⫾ 0.8 dB/y, P ⬍ .01). Figures
1 and 2 show the distribution of MD rates of change
between progressing and nonprogressing eyes, as well as
between the timolol (⫺0.38 ⫾ 0.9 dB/y) and brimonidine
(0.02 ⫾ 0.7 dB/y) groups, respectively (P ⬍ .01).
In this subset of participants with at least 5 visual field
tests, eyes on brimonidine had significantly higher diurnal
mean and peak IOP measurements prior to treatment
randomization (respectively, 16.2 ⫾ 1.9 vs 15.2 ⫾ 2.5 mm
Hg, P ⬍ .01; and 17.7 ⫾ 2.0 vs 16.7 ⫾ 2.7 mm Hg, P ⫽
.04) even though treated mean pressures during follow-up
were similar between the 2 groups (14.1 ⫾ 1.9 vs 13.9 ⫾
2.3 mm Hg, P ⫽ .38). However, eyes on brimonidine had
statistically greater IOP fluctuation (1.86 ⫾ 0.6 vs 1.59 ⫾
0.5 mm Hg, P ⬍ .01) and higher peaks (17.0 ⫾ 2.3 vs
16.4 ⫾ 2.6 mm Hg, P ⫽ .03) during follow-up.
Univariate analysis (Tables 2 and 3) revealed the
following variables to be associated with visual field pro-
gression at P ⬍ .25: age, lens status, use of systemic
antihypertensives, use of systemic beta-adrenergic antago-
nists, disc hemorrhage, cup-to-disc ratio, CCT, mean SBP
during follow-up, mean DBP during follow-up, SBP fluc-
tuation, MOPP during follow-up, ocular perfusion pressure
fluctuation, baseline heart rate, and randomization.
To investigate whether an interaction between random-
ization and MOPP significantly influenced the model, an
interaction term (MOPP ⫻ randomization) was included
in the multivariate model. However, this variable did not
reach statistical significance in the model (HR ⫽ 1.03/mm
Hg, 95% confidence interval [CI] ⫽ 0.88 to 1.19, P ⫽ .69).
We also tested the interaction between IOP mean, peak,
and fluctuation and treatment randomization to investi-
gate if the impact of IOP on visual field progression differed
between patients assigned to timolol or brimonidine. We
VOL. 154, NO. 4 RISK FACTORS IN
HR 95% Confidence Interval P Value
0.26 0.12 to 0.55 ⬍.001
1.41 1.05 to 1.90 .022
2.53 1.32 to 4.87 .005
1.21 1.12 to 1.31 ⬍.001
found no significant association between the interaction
terms and progression (mean IOP ⫻ randomization, hazard
ratio [HR] ⫽ 0.75/mm Hg, 95% CI ⫽ 0.535 to 1.076, P ⫽
.12; peak IOP ⫻ randomization, HR ⫽ 0.82/mm Hg, 95%
CI ⫽ 0.62 to 1.08, P ⫽ .17; IOP fluctuation ⫻ random-
ization, HR ⫽ 1.26/mm Hg, 95% CI ⫽ 0.49 to 3.23, P ⫽
.62).
There was significant correlation between the following
pairs of variables: average MOPP vs mean follow-up IOP
(r ⫽ ⫺0.36, P ⬍ .001); average MOPP vs mean follow-up
SBP (r ⫽ 0.75, P ⬍ .001); average MOPP vs mean
follow-up DBP (r ⫽ 0.78, P ⬍ .001); average MOPP vs
MOPP fluctuation (r ⫽ 0.16, P ⫽ .01); and mean fol-
low-up SBP vs mean follow-up DBP (r ⫽ 0.40, P ⬍ .001).
Given this significant association among related variables
and its more significant association with progression in the
univariate analysis, we opted to include MOPP in the
multivariate analysis to circumvent colinearity.
In the multivariate analysis (Table 4), older age (HR ⫽
1.41/decade older, 95% CI ⫽ 1.05 to 1.90, P ⫽ .022), use
of systemic antihypertensives (HR ⫽ 2.53, 95% CI ⫽ 1.32
to 4.87, P ⫽ .005), and lower MOPP during follow-up
(HR ⫽ 1.21/mm Hg, 95% CI ⫽ 1.12 to 1.31, P ⬍ .001)
were associated with increased risk of progression, whereas
randomization to brimonidine was significantly associated
with decreased risk of progression (HR ⫽ 0.26, 95% CI ⫽
0.12 to 0.55, P ⬍ .001).
DISCUSSION
THE PURPOSE OF THIS STUDY WAS TO IDENTIFY RISK FAC-
tors for progression in the Low-pressure Glaucoma Treat-
ment Study. We found a significant association between
the use of topical timolol maleate 0.5% and the risk of
progression in patients with low-pressure glaucoma com-
pared to the use of brimonidine tartrate 0.2%, which was
independent from other known risk factors for glaucoma
progression (eg, disc hemorrhage, older age, and lower
systemic blood pressure) despite similar mean IOP during
follow-up. This finding suggests that brimonidine may
LOW-PRESSURE GLAUCOMA 707
have an effect on IOP-independent mechanisms that
decrease or delay the rate of visual field deterioration in
patients with glaucoma associated with IOPs in the statis-
tically normal range and that this effect is independent of
ocular perfusion pressure.
The differentiation between low- and high-pressure
glaucoma is arbitrary. One of the limitations of this
classification is the fact that it overlooks the continuum of
IOP measurements and sets an arbitrary cut-off value to
define a multifactorial optic neuropathy. It also disregards
the sources of error (limitations of the technique itself and
influence of CCT and corneal curvature, for instance)22,23
and variability (related to the circadian rhythm and
long-term fluctuation)24,25 of IOP measurements. These
limitations notwithstanding, numerous studies have de-
scribed evidence suggesting clinical differences between
patients whose pressure lies above or below this arbitrary
cut-off value.26 –29 For instance, low-pressure glaucoma
appears to be more common among women and myopic
individuals,9,12 may affect the central/paracentral visual
field more often,27–29 and is more commonly associated
with systemic conditions such as migraine and Raynaud
phenomenon;12,30 and disc hemorrhages may be detected
more often.12,17
We determined that a lower MOPP during follow-up
was significantly associated with visual field progression in
our model and this effect was not significantly affected by
other covariates, such as use of systemic antihypertensives
and randomization arm (Table 4). An imbalance between
IOP mechanical stress and blood supply leads to hypoxia,
which may be responsible, at least partially, for axonal
damage and retinal ganglion cell death.30 Even though the
calculation of estimated MOPP is subject to criticism—it
extrapolates the mean arterial pressure measured in the
brachial artery to be the same as that in the ophthalmic
artery and disregards the effects of changes in body position
during the day and night—it appears to be a relatively
robust estimator of the effects of low systemic blood
pressure on the optic nerve.5,30,31 In consonance with our
findings, the Early Manifest Glaucoma Trial (EMGT)5 and
the Barbados Eye Study (BES)32 found a significant asso-
ciation between low systemic blood pressure and the risk of
progressive and incident glaucoma, respectively. Also, the
role of lower systolic perfusion pressure in the EMGT was
significant in the group with lower baseline IOP but not in
the group with higher measurements,5 which supports our
hypothesis that for eyes with statistically low IOP, IOP-
independent risk factors may be more relevant predictors
of progression.
By examining the interaction between randomization
group and MOPP, our data support the notion that the
more detrimental effect of timolol on visual field outcomes
compared with brimonidine in low-pressure glaucoma is
independent of its effect on perfusion pressure, as had been
previously postulated.33,34 It is possible, however, that
overtreatment of systemic hypertension may be injurious
708 AMERICAN JOURNAL
to the MOPP, similarly to what has been reported in
internal medicine.35–37 Patients who are overtreated for
systemic hypertension—sometimes because of the alleged
“white-coat hypertension”—are at increased risk of coro-
nary ischemia and mortality.36 This phenomenon is graph-
ically represented as a “J” curve in which there is an upturn
of cardiac problems and death at both low and high blood
pressure.35 Low blood pressure leads to compensatory
vasoconstriction of peripheral organs and tissues38,39—in
the eye, the retinal and choroidal circulation—and reduc-
tion of the true MOPP, as opposed to the estimated
(brachial) MOPP. An increase in vascular resistance di-
minishes blood flow to the optic nerve head, which is a
watershed zone.40 Nevertheless, it is important to stress
that our study did not aim to investigate the specific role of
systemic antihypertensives on glaucoma progression, as we
did not collect information on the dosage, length of
treatment, and 24-hour blood pressure monitoring of these
patients. Future studies ought to specifically address the
interaction between overtreatment of systemic hyperten-
sion and MOPP and whether there could be a deleterious
effect on glaucomatous neurodegeneration.
In consonance with findings of the randomized clinical
trials in glaucoma,4,5,7,8 older age was a significant predic-
tor of visual field progression in the present study. In the
multivariate analysis, the risk of progression increased by
43% for each decade older. The EMGT also found a more
significant role of older age in the group of patients with
lower baseline IOP—resembling low-pressure glaucoma
patients—when compared to those with more elevated
IOP.5 Once IOP is lowered to a certain level, it is possible
that other IOP-independent factors (such as age) become
more significant. Aging is associated to longer exposure to
exogenous hazards and systemic comorbidities, and may
increase the susceptibility of the optic nerve complex to
IOP stress.
We did not find a significant association between IOP or
CCT and visual field progression in this cohort. This
finding is not likely to be attributable to a confounding
effect of more aggressive treatment of eyes with higher IOP
or decreased CCT, given the standardized treatment pro-
tocol followed in this trial. Nonetheless, the Collaborative
Normal-Tension Glaucoma Study Group12 found a signif-
icant role of IOP even in a population of patients with low
IOP. Our results should not be compared with that trial,
given that their comparison was between treated and
untreated arms, whereas all patients in our study were
treated. Also, we only performed pretreatment diurnal
curves and the role of short- and long-term IOP variability
was not taken into account in our analyses. Despite these
considerations, it is possible that once the IOP is reduced
to low values, as in this study (mean follow-up IOP was 14
mm Hg), the importance of other risk factors may become
either more apparent or important for determining pro-
gression. Moreover, by investigating the interaction be-
tween randomization and mean follow-up IOP on
OF OPHTHALMOLOGY OCTOBER 2012
progression, our findings suggest that it is unlikely that the
different outcomes we observed between patients treated
with timolol or brimonidine were attributable to different
effects of these drugs on daytime IOP. The lack of data on
the effect of each drug on nighttime or early-morning IOP
prevents us from concluding whether the different out-
comes could be attributable to different effectiveness in
dampening the circadian IOP variation. Previous studies
have shown similar effectiveness of both drugs in lowering
the IOP even when assessed with diurnal curves. Also, it
has been shown that both timolol and brimonidine have
limited effectiveness for lowering nocturnal IOP in the
supine position.41– 43 It is particularly interesting that the
brimonidine group had higher untreated mean and peak
IOP at baseline as well as higher peak and fluctuation
during follow-up and still progressed at slower rates than
the timolol group. Despite being statistically significant, it
is controversial whether such small differences (ⱕ1.0 mm
Hg) are clinically significant, especially when looking at
pooled data.
Despite the observed protective effect of brimonidine
compared to timolol in patients with low-pressure glau-
coma, the incidence of adverse reaction to brimonidine
was higher than for timolol. This caused the average
follow-up time in the study to be reduced below that
planned. Development of alternative neuroprotective
agents with fewer adverse effects would be desirable. This
observation notwithstanding, patients on brimonidine
who did not develop significant ocular allergy progressed at
slower rates than those on timolol in the present cohort. In
addition, for those patients who tolerated brimonidine
well, the risk of progression was reduced independently of
other demographic or physiologic factors. Furthermore, for
this ancillary analysis of the Low-pressure Glaucoma
Treatment Study, we selected a subset of patients with at
least 5 visual field tests during follow-up, which ended up
leading to significant baseline differences between treat-
ment groups—which was not observed in our previous
publication including all participants.15 This limitation
notwithstanding, all analyses were adjusted for these po-
tential confounders and we were unable to identify their
significant role in the rates of progression in both the
univariate and multivariate models.
In summary, treatment of low-pressure glaucoma with
topical brimonidine 0.2% preserved the visual field better
than topical timolol 0.5% in the Low-pressure Glaucoma
Treatment Study, despite similar mean IOP during the
study. Lower MOPP and use of systemic antihypertensives
were also independently associated with disease progres-
sion. These findings suggest that the beneficial effect of
brimonidine compared to timolol in the current study was
attributable to factors other than any differences in IOP
control or differences in ocular perfusion, and is consistent
with a neuroprotective effect in the brimonidine arm. This
last hypothesis needs to be confirmed with additional study
before this information can be used to suggest changes to
current glaucoma treatment paradigms. Lastly, MOPP may
be an additional modifiable risk factor that deserves addi-
tional research and clinical attention.

ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF
Interest. Financial disclosures: C.G. De Moraes: grant support, Edith C. Blum Foundation, New York Glaucoma Research Institute; JM Liebmann:
consultant/advisor, Alcon Laboratories, Inc; Allergan, Inc; Diopsys Corporation; Merz Pharmaceuticals, Inc; Optovue, Inc; Quark Pharmaceuticals, Inc;
Topcon Medical Systems; grant support, Carl Zeiss Meditec, Diopsys Corporation, Heidelberg Engineering, National Eye Institute, New York Glaucoma
Research Institute, Optovue, Topcon Medical Systems; D.S. Greenfield: consultant/advisor, Allergan, Inc; Alcon, Inc; Topcon, Inc; Merz; SOLX; grant
support, National Eye Institute, Carl Zeiss Meditec, Optovue, Heidelberg Engineering; R Ritch: consultant/advisor, iSonic, Aeon Astron, Drais
Pharmaceutical, Medacorp; lecture fees: Pfizer, Merck; patents/royalty, Ocular Instruments, Inc.; T Krupin: consultant/advisor, Allergan, Inc. Publication
of this article was supported by funding provided by Allergan, Inc, Irvine, California; the Chicago Center for Vision Research, Chicago, Illinois; Research
to Prevent Blindness, Inc, New York, New York; and Ralph and Sylvia Ablon Research Fund of the New York Glaucoma Research Institute, New York,
New York. Study medications were provided by Allergan, Inc. Dr De Moraes is the Edith C. Blum Foundation Research Scientist, New York Glaucoma
Research Institute, New York, New York. Involved in design and conduct of the study (T.K., R.R., J.M.L., D.S.G.); collection, management, analysis,
and interpretation of the data (T.K., R.R., J.M.L., D.S.G., S.K.G., C.G.D.M.); and preparation, review, or approval of the manuscript (T.K., R.R., J.M.L.,
D.S.G., S.K.G., C.G.D.M.). The institutional review boards at all 13 participating centers approved the prospective study protocol and patients gave
informed consent to participate in this research study. Clinical trial (www.clinicaltrials.gov) ID: NCT00317577.

MEMBERS OF THE LOW-PRESSURE GLAUCOMA STUDY GROUP

University Eye Specialists, Chicago, Illinois. Theodore Krupin, Lisa F. Rosenberg, Jon M. Ruderman, and John W. Yang.
New York Eye & Ear Infirmary, New York, New York. Celso Tello, Jeffrey M. Liebmann, and Robert Ritch.
Wills Eye Hospital, Philadelphia, Pennsylvania. Jonathan S. Myers, L. Jay Katz, George L. Spaeth, Richard P. Wilson, and Marlene R. Moster.
Indiana University, Indianapolis, Indiana. Louis B. Cantor.
Cullen Eye Institute, Baylor College, Houston, Texas. Ronald L. Gross.
Private Practice, Rapid City, South Dakota. Monte S. Dirks.
Brooke Army Medical Center, San Antonio, Texas. Steven R. Grimes.
Bascom Palmer Eye Institute, University of Miami School of Medicine, Palm Beach Gardens, Florida. David S. Greenfield and Harmohina Bagga.
University of Florida–Gainesville, Gainesville, Florida. Mark B. Sherwood.
University of Chicago, Chicago, Illinois. Marianne E. Feitl.
Little Rock Eye Clinic, Little Rock, Arkansas. J. Charles Henry.
Wheaton Eye Clinic, Wheaton, Illinois. David K. Gieser.
Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania. Jody R. Piltz-Seymour.

VOL. 154, NO. 4 RISK FACTORS IN LOW-PRESSURE GLAUCOMA 709

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REPORTING VISUAL ACUITIES

The AJO encourages authors to report the visual acuity in the manuscript using the same nomenclature that was used in
gathering the data provided they were recorded in one of the methods listed here. This table of equivalent visual acuities
is provided to the readers as an aid to interpret visual acuity findings in familiar units.

Table of Equivalent Visual Acuity Measurements

Snellen Visual Acuities

4 Meters 6 Meters 20 Feet Decimal Fraction LogMAR

4/40 6/60 20/200 0.10 ⫹1.0

4/32 6/48 20/160 0.125 ⫹0.9
4/25 6/38 20/125 0.16 ⫹0.8
4/20 6/30 20/100 0.20 ⫹0.7
4/16 6/24 20/80 0.25 ⫹0.6
4/12.6 6/20 20/63 0.32 ⫹0.5
4/10 6/15 20/50 0.40 ⫹0.4
4/8 6/12 20/40 0.50 ⫹0.3
4/6.3 6/10 20/32 0.63 ⫹0.2
4/5 6/7.5 20/25 0.80 ⫹0.1
4/4 6/6 20/20 1.00 0.0
4/3.2 6/5 20/16 1.25 ⫺0.1
4/2.5 6/3.75 20/12.5 1.60 ⫺0.2
4/2 6/3 20/10 2.00 ⫺0.3

From Ferris FL III, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts for clinical research. Am J Ophthalmol 1982;94:91–96.

VOL. 154, NO. 4 RISK FACTORS IN LOW-PRESSURE GLAUCOMA 711