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Factors for glaucoma progression and the effect of treatment - The Early
Manifest Glaucoma Trial

Article  in  Archives of Ophthalmology · February 2003

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 CLINICAL SCIENCES

Factors for Glaucoma Progression

and the Effect of Treatment
The Early Manifest Glaucoma Trial
M. Cristina Leske, MD, MPH; Anders Heijl, MD, PhD; Mohamed Hussein, PhD; Bo Bengtsson, MD, PhD;
Leslie Hyman, PhD; Eugene Komaroff, PhD; for the Early Manifest Glaucoma Trial Group

Objective: To assess factors for progression in the Early
Manifest Glaucoma Trial (EMGT), including the effect
of EMGT treatment.
Setting/Participants: Two hundred fifty-five open-
angle glaucoma patients randomized to argon laser tra-
beculoplasty plus topical betaxolol or no immediate treat-
ment (129 treated; 126 controls) and followed up every
3 months.
Methods: Progression was determined by perimetric and
photographic optic disc criteria. Patient-based risk of pro-
gression was evaluated using Cox proportional hazard
regression models and was expressed as hazard ratios (HR)
with 95% confidence intervals (95% CI).
Results: After 6 years, 53% of patients progressed. In
multivariate analyses, progression risk was halved by treat-
ment (HR = 0.50; 95% CI, 0.35-0.71). Predictive base-
line factors were higher intraocular pressure (IOP) (ie,
the higher the baseline IOP, the higher the risk), exfo-
liation, and having both eyes eligible (each of the latter
2 factors doubled the risk), as well as worse mean de-
viation and older age. Progression risk decreased by about
10% with each millimeter of mercury of IOP reduction
from baseline to the first follow-up visit (HR=0.90 per
millimeter of mercury decrease; 95% CI, 0.86-0.94). The
first IOP at that visit (3 months’ follow-up) was also re-
lated to progression (HR = 1.11 per millimeter of mer-
cury higher; 95% CI, 1.06-1.17), as was the mean IOP at
follow-up (HR=1.13 per millimeter of mercury higher;
95% CI, 1.07-1.19). The percent of patient follow-up vis-
its with disc hemorrhages was also related to progres-
sion (HR=1.02 per percent higher; 95% CI, 1.01-1.03).
No other factors were identified.
Conclusions: Patients treated in the EMGT had half of
the progression risk of control patients. The magnitude
of initial IOP reduction was a major factor influencing out-
come. Progression was also increased with higher base-
line IOP, exfoliation, bilateral disease, worse mean devia-
tion, and older age, as well as frequent disc hemorrhages
during follow-up. Each higher (or lower) millimeter of mer-
cury of IOP on follow-up was associated with an approxi-
mate 10% increased (or decreased) risk of progression.
Arch Ophthalmol. 2003;121:48-56

From the Department of
Preventive Medicine, Stony
Brook University School of
Medicine, Stony Brook, NY
(Drs Leske, Hussein, Hyman,
and Komaroff); and the
Department of Ophthalmology,
Malmö University Hospital,
Malmö, Sweden (Drs Heijl
and Bengtsson).
A list of the members of the
Early Manifest Glaucoma Trial
Group appears on page 55.
T
HE FACTORS related to the
progression of open-angle
glaucoma (OAG) have been
evaluated in many studies,
with variable findings
reported.1-11 This variability may be ex-
plained by differences in study design,
methods of data collection, specific
factors evaluated, or approaches used for
statistical analyses. Some studies have been
based on retrospective analyses of pa-
tient data, which are subject to various
limitations, while others have provided
stronger evidence by evaluating risk fac-
tors prospectively. In addition, the num-
ber and type of patient characteristics stud-
ied have ranged widely—from a broad
spectrum of variables to only a few data
items. At times, the level of intraocular
pressure (IOP) has been used to select pa-
tients for study, with some reports focus-
ing only on “high pressure” or “normal
pressure” in patients with glaucoma, and
in others, including a continuum of IOP.
It is not surprising, therefore, to find that
studies have reached different conclu-
sions regarding the relative importance of
factors influencing outcome.
The role of IOP-lowering treatment
on progression was recently assessed in
the Early Manifest Glaucoma Trial
(EMGT).12,13 The EMGT is a randomized
clinical trial designed to evaluate the effect
of immediate treatment on glaucoma pro-
gression, as compared with no initial treat-
ment or later treatment. All EMGT pa-
tients had early and previously undetected
glaucoma with visual field defects, and
most were identified through a large
(N=44243) population-based screening in
Malmö and Helsingborg, Sweden. Study
participants were randomized to argon la-

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48

©2003 American Medical Association. All rights reserved.

ser trabeculoplasty plus betaxolol, or to no immediate
treatment. Patients were examined every 3 months for
at least 4 years, and glaucoma progression was deter-
mined through specific visual field and optic disc crite-
ria, as described in detail elsewhere.12-14 The EMGT thus
allows a prospective evaluation of factors for progres-
sion, following a standardized protocol, within the con-
text of a randomized trial comparing treated and con-
trol arms.
The rationale and specific details of the EMGT de-
sign have been reported, as have the major results of the
trial.12,13 The EMGT showed that treated patients had sig-
nificantly lower rates of progression than controls, and that
immediate IOP-lowering treatment significantly delayed the
progression of OAG.13 This article adds to these main re-
sults by presenting multivariate analyses that jointly evalu-
ate the effect of treatment and patient-related factors on pro-
gression. This matter has been difficult to assess
conclusively, since most glaucoma clinical trials have evalu-
ated the effect of different modes of treatment, rather than
of treatment itself.15-20 In the Collaborative Normal Ten-
sion Glaucoma Study (CNTGS), which was limited to pa-
tients with a median IOP of 20 mm Hg or less, the intent-
to-treat analyses yielded no differences between treated and
untreated patients, but a significant effect of treatment was
reported after censoring for cataract outcomes.19 The role
of other characteristics affecting glaucoma progression has
been reported for patients in the untreated arm of that
study,10 but not for treated patients.
The first aim of this article is to estimate and evalu-
ate the magnitude of the treatment effect in EMGT, while
controlling for other factors. This aim was achieved by
comparing progression rates in both study groups dur-
ing at least 4 years of follow-up, while adjusting for other
variables possibly related to progression. In addition to
providing a quantitative measure of the IOP-lowering
effect of EMGT treatment, further analyses explored pos-
sible interactions with treatment.
The second aim is to identify clinically relevant fac-
tors that are independently related to glaucoma progres-
sion in EMGT. This aim was achieved by evaluating the
role of demographic, systemic, familial, and ocular fac-
tors on EMGT progression. The intent was to provide pre-
dictive information on the risk of progression according
to specific patient characteristics at baseline. The pos-
sible role of longitudinal changes in clinical findings at fol-
low-up was also examined, as the results could contrib-
ute to our understanding of the factors influencing
glaucoma progression.
METHODS
OVERVIEW
Details on the study design have been described elsewhere.12
The trial setting included a clinical center (Malmö University
Hospital, Malmö), a satellite clinical center (Helsingborg Hos-
pital, Helsingborg), a data center (School of Medicine at Stony
Brook, Stony Brook, NY), and a disc photography reading cen-
ter (Lund University Hospital, Lund, Sweden). The study is regu-
larly monitored by a Data and Safety Monitoring Committee,
which oversees all aspects of the trial. Funding was provided
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49
©2003 American Medical Association. All rights reserved.
by the National Eye Institute (Bethesda, Md) and the Swedish
Research Council (Stockholm).
Briefly, men and women aged 50 to 80 years who had newly
diagnosed, previously untreated, early manifest OAG were eli-
gible for inclusion. The OAG diagnosis (including chronic simple
glaucoma, normal-tension glaucoma, and exfoliative glaucoma)
required repeatable glaucoma visual field defects in at least one
eye that were not explained by other causes, and that were as-
sessed by computerized perimetry.21-23 Patients with the follow-
ing were excluded: (1) advanced visual field defects; (2) visual
acuity worse than 0.5; (3) mean IOP greater than 30 mm Hg, or
any IOP greater than 35 mm Hg in at least one eye; (4) lens opaci-
ties24 or any condition precluding reliable visual field or disc pho-
tography, or use of study treatments or 4-year follow-up. The
EMGT protocol includes 4 prerandomization visits (ie, 2 post-
screening visits and 2 baseline visits), as well as laser treatment
visits for the treated patients. All patients have follow-up visits
every 3 months, with data being collected by trained and certi-
fied EMGT examiners, following a standardized protocol.
OUTCOME MEASURE AND UNIT OF ANALYSIS
Progression, as defined by EMGT, is evaluated by standard-
ized, independently determined criteria that are based on pe-
rimetry or optic disc assessment. Perimetric criteria were ob-
jectively determined and defined as significant changes from
baseline in at least 3 of the same progressing points in 3 con-
secutive visual fields, as assessed by pattern deviation–based
Glaucoma Change Probability Maps.25 As was necessary for the
design of the trial, these criteria were designed to be highly sen-
sitive to detect visual field changes—an aim that was achieved.14
Optic disc progression was evaluated at a masked reading cen-
ter and was based on photographic criteria designed to have high
specificity. These criteria required clear change on an optic disc
follow-up photograph, as detected by flicker chronoscopy and
confirmed by side-by-side gradings in 2 consecutive visits. Pro-
gression as EMGT defines it, is patient-specific, occuring when
at least one eye meets progression criteria. For patients with
one eligible eye at baseline, only that eye was considered in the
analyses. For patients with 2 eligible eyes at baseline, time of
progression for the first progressing eye was used in life-table
and multivariate analyses.
For univariate analyses, the unit of analysis was based on
the patient for person-based covariates (eg, age and sex), and
based on the eye for eye-based covariates (eg, exfoliation sta-
tus and IOP). The multivariate analyses strictly used the per-
son as a unit of analysis; for patients with 2 eligible eyes, the
following selection criteria were used. If one eye progressed first,
then that eye was considered for the analyses. If neither eye pro-
gressed (or if both progressed at the same time), then the worse
of the 2 eye-based covariate measurements at baseline was con-
sidered (eg, IOP, mean deviation [MD], disc hemorrhages, and
exfoliation). To evaluate the potential effects of the “worse-
eye” selection criteria on the results, an additional approach
was to randomly select one eye of patients with 2 eligible non-
progressing eyes (or 2 eyes progressing at the same time), rather
than the eye with the worse measurement. This selection scheme
yielded results indistinguishable from those using our initial
selection criteria. The results of patient-based analyses were also
compared with those obtained by eye-based analyses, account-
ing for intereye correlation.26 Again, the results were essen-
tially the same as those from the patient-based analyses, with
similar hazard ratio (HR) magnitudes.
STATISTICAL METHODS
Univariate analyses were based on summarizing percent pro-
gression according to a specific variable (eg, IOP at baseline)
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and did not include simultaneous adjustment for other covari-
ates. The Pearson ␹2 test was used to test for a significant differ-
ence in percent progression for categorical variables, and the t test
was used for differences in progression on continuous variables.
Based on the constancy of the HR throughout follow-up time,
multivariate analyses used Cox proportional hazard models,27 with
Breslow adjustment for ties in time to progression,28 to (1) model
the hazard (follow-up specific conditional probability of progres-
sion) of the treated group as a constant multiple of the hazard in
the control group, while (2) simultaneously adjusting for other
study covariates. Criteria for model selection were guided by:
(1) the findings of the univariate analysis (eg, Pⱕ.20); (2) simul-
taneous adjustment for important covariates; and (3) identifica-
tion of the most parsimonious, clinically interpretable, and sta-
tistically fitting model, which involved using backward, forward,
and stepwise variable selection algorithms in SAS.29 The model
selection also included testing for interaction between the study
groups and the different levels of each covariate.
As a first step, the main effects (independent) models were
pursued to define the baseline factors that were significantly
associated with progression of glaucoma. All 3 model-
selection criteria identified the same variables for inclusion in
the final model. As a second step, longitudinal changes in IOP,
and clinically assessed disc hemorrhages at follow-up visits were
also evaluated while adjusting for significant baseline factors.
As a third step, 2-factor interaction models were fit using those
factors identified as significantly associated with glaucoma pro-
gression. Results are expressed as HRs with 95% confidence in-
tervals (CIs). Analyses conducted separately in each study group
yielded the same conclusions.
COVARIATES FOR MULTIVARIATE ANALYSES
Study covariates were selected based on their potential clini-
cal importance and statistical association with glaucoma pro-
gression. In addition to study group (treated or control), other
baseline factors were evaluated. Demographic variables were
age, sex, and clinical center.
Ocular variables were number of eligible eyes, IOP (aver-
age of 2 baseline Goldmann measurements), perimetric MD (av-
erage of 2 baseline fields), exfoliation (dilated examination),
and refractive error (automated refractor); clinically observed
disc hemorrhages (dilated examination); and central corneal
thickness (ultrasonic pachymeter; measured after baseline13).
Medical and family history variables were casual systolic
and diastolic blood pressure measurements; hypertension (sys-
tolic ⬎160 mm Hg or diastolic ⬎95 mm Hg, or use of antihy-
pertensive medications) self-reported history of cardiovascu-
lar disease, use of hypertension medications, low blood pressure,
migraine, Raynaud disease, smoking, and family history of glau-
coma (in either parent or any sibling).
The follow-up covariates evaluated were: (1) initial IOP
change from baseline to the first follow-up visit (IOP at base-
line minus IOP at 3 months’ follow-up); (2) IOP at the first fol-
low-up visit (IOP at 3 months’ follow-up); (3) later IOP change
beyond the first follow-up visit (IOP at 3 months’ follow-up
minus IOP at progression [for those who progressed] or at the
end of follow-up [for those who did not progress]); (4) mean
follow-up IOP (average IOP at all follow-up visits until pro-
gression or until the end of follow-up); and (5) percent of all
patient visits with clinically assessed disc hemorrhages until
progression or until the end of follow-up.
RESULTS
The 255 patients enrolled in EMGT had a median age of
68 years, and 66% were female. As reported previously,
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50
©2003 American Medical Association. All rights reserved.
both groups were balanced at baseline with regard to ma-
jor variables.13 Retention was excellent, with 227 of 255
patients (89%) completing follow-up through Septem-
ber 2001. At that time, the median length of follow-up
was 6 years and was similar in both groups. Death was
the major reason for losses to follow-up (n=22); only 6
patients (2%) were lost to follow-up for other reasons.
Of the EMGT-designated visits, 99% were fully com-
pleted, and the missed-visit rate was very low at only 5%
(289/5744 patients).
Overall, 53% (136/255) of the patients progressed,
and 47% (119/255) did not progress during the fol-
low-up period. Table 1 presents univariate compari-
sons of percent progression according to several patient
characteristics; the study groups were balanced at base-
line in all the factors presented. Progression was signifi-
cantly lower in the treated group than the control group
(45% vs 62%; HR=0.60). Patients above the median age
had a higher percentage of progression, as did patients
with higher median IOP, worse median MD, exfolia-
tion, and both eyes eligible for the trial. Analyses based
on continuous variables and evaluated as such, gave simi-
lar results as analyses based on median values. No sig-
nificant associations (P ⬍.05) were found with the other
factors evaluated.
Table 2 presents results of multivariate analyses
evaluating associations of EMGT progression with the
baseline factors presented in Table 1. Study group (treated
vs control) was significantly associated with progres-
sion (P⬍.001). In analyses based on the hazard func-
tion, which adjusts for censoring and other covariates,
the treated group had half the risk of progression
(HR=0.50) as compared with controls.
An IOP at or above the median at baseline in-
creased the risk of progression (HR=1.70), as well as the
presence of exfoliation (HR=2.31) and having 2 eligible
eyes at baseline (HR=1.93). Increased progression risks
were also found in patients with worse median baseline
MD (HR = 1.55) and patients above the median age
(HR=1.43). Similar estimated treatment effects were found
when we repeated these analyses using continuous val-
ues of IOP, MD, and age, rather than median values. In
these analyses, the risk of progression increased by 5%
with each millimeter of mercury of higher baseline IOP
(HR=1.05; 95% CI, 1.01-1.10). Results were also con-
sistent with the higher progression of patients with worse
MD and older age (MD: HR=1.03 per 1 dB [decibel] of
worse MD; [95% CI, 0.98-1.09]); age: HR=1.01 per 1 year
of age; [95% CI, 0.98-1.05]). No significant relation-
ships were found with other factors in Table 1. In addi-
tion, no statistically significant interactions were found
with treatment.
Patients randomized to treatment had a substantial
lowering of IOP. At the first follow-up visit after ran-
domization (3 months’ follow-up), there was an average
reduction of 5.1 mm Hg, or 25% from baseline in the
treated group, with no changes in the control group.13
After this visit, the difference in IOP between groups was
generally maintained over time. Both in treated and con-
trol patients, average differences of less than 1 mm Hg
were observed between the IOP at the first follow-up visit
and the IOP at the time of progression (for those who
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Table 1. Treatment Assignment and Baseline Factors Evaluated Among 255 EMGT Patients by Progression Status*

No. of Patients Univariate Hazard Ratio

Variable (Percent Progressed) (95% CI) P Value†
Progressed 136 (53) ... ...
Treatment assignment
Treatment 129 (45)
0.60 (0.42-0.84) .003
Control 126 (62)
Demographic factors
Age, y
ⱖ68 135 (57)
1.42 (1.01-1.98) .05
⬍68 120 (49)
Sex
Female 169 (54)
0.97 (0.68-1.39) .87
Male 86 (52)
Ocular factors
Intraocular pressure, mm Hg
ⱖ21 123 (63)
1.67 (1.19-2.35) .003
⬍21 132 (45)
Mean deviation, dB
ⱕ−4.0 128 (59)
1.46 (1.04-2.05) .03
⬎−4.0 127 (47)
Central corneal thickness, µm
⬍548.4 108 (62)
1.25 (0.89-1.78) .20
ⱖ548.4 112 (55)
Exfoliation
Yes 23 (83)
3.15 (1.93-5.15) ⬍.001
No 232 (50)
Both eyes eligible
Yes 61 (72)
1.92 (1.34-2.75) ⬍.001
No 194 (47)
Disc hemorrhages
Yes 35 (57)
1.32 (0.82-2.12) .26
No 220 (53)
Refractive error, D
ⱕ−1 31 (55)
0.97 (0.58-1.61) .99
⬎−1 224 (53)
Medical and family history
Systolic blood pressure, mm Hg
⬎160 42 (43)
0.69 (0.42-1.14) .15
ⱕ160 213 (55)
Diastolic blood pressure, mm Hg
⬎95 34 (47)
0.79 (0.47-1.34) .39
ⱕ95 221 (54)
Hypertension§
Yes 98 (51)
0.89 (0.63-1.27) .53
No 157 (55)
Cardiovascular disease history
Yes 30 (53)
1.07 (0.63-1.80) .81
No 225 (53)
Hypertension medication
Yes 62 (53)
1.06 (0.71-1.56) .78
No 193 (53)
Low blood pressure history
Yes 8 (38)
0.78 (0.25-2.45) .67
No 247 (54)
Raynaud disease history
Yes 22 (68)
1.49 (0.87-2.55) .15
No 233 (52)
Migraine history
Yes 25 (68)
1.37 (0.82-2.28) .23
No 230 (52)
Current smoker
Yes 24 (50)
0.75 (0.41-1.36) .34
No 201 (59)
Prior smoker
Yes 99 (62)
1.13 (0.80-1.60) .47
No 126 (55)
Glaucoma family history
Yes 50 (52)
0.98 (0.64-1.50) .91
No 205 (54)

Abbreviations: CI, confidence interval; D, diopters; dB, decibels; EMGT, Early Manifest Glaucoma Trial.
*For all variables, the second listed variable is the reference group.
†Wald ␹2 statistic.
‡Thickness was measured after baseline.
§Indicates hypertension is systolic (⬎160 mm Hg) or diastolic (⬎95 mm Hg), or a history of antihypertensive treatment.

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progressed) or the end of follow-up (for those who did
not progress). For that reason, we separately evaluated
associations with each of the follow-up IOP variables de-
fined in the “Methods” section (ie, the initial IOP change
[baseline minus 3 months’ follow-up]; the 3 months’ fol-
low-up IOP itself, representing the posttreatment base-
line IOP; the later IOP change [beyond the IOP at 3
months]; and the mean IOP at follow-up). Table 3 pre-
sents the results of each of these multivariate analyses,
evaluating the association between EMGT progression
and those measures of longitudinal changes in IOP after
baseline, while controlling for IOP, exfoliation, number
of eligible eyes, MD, and age.
The first row of Table 3 substantiates that progres-
sion is related to the magnitude of initial IOP change from
baseline to the first follow-up visit. This initial change
in IOP was strongly and inversely associated with pro-
gression. Thus, an IOP reduction of 1 mm Hg from base-
line decreased the risk of progression by about 10% in
these analyses.
The second row of Table 3 similarly indicates that
progression was strongly associated with the initial IOP
reached after treatment or with no treatment (IOP at 3
months’ follow-up). This IOP, which reflected the ef-
fects of study group assignment and of baseline IOP, was
a significant predictor of progression, with an estimated
11% higher risk for every millimeter of mercury higher
IOP—a result consistent with the estimate presented in
the first row of Table 3. The later IOP change was not a
significant factor when accounting for the 3 months’ IOP.
The latter result would be expected, given the small
changes in IOP after the initial follow-up visit.
Table 2. Baseline Factors Associated With Progression
in the Early Manifest Glaucoma Trial*
Hazard Ratio
Variables Reference (95% CI)
Study group Control 0.50 (0.35-0.71)
Intraocular pressure, mm Hg ⬍21 1.70 (1.18-2.43)
Exfoliation None 2.22 (1.31-3.74)
No. of eligible eyes 1 1.96 (1.36-2.82)
Mean deviation, dB ⬎−4 1.58 (1.10-2.28)
Age, y ⬍68 1.47 (1.04-2.09)
Abbreviations: CI, confidence interval; dB, decibels.
*Progression analysis used Cox proportional hazard model. P values based
on Wald ␹2 statistic.
The third row of Table 3 further confirms that the
mean follow-up IOP achieved after baseline is related to
progression, with an estimated 13% higher risk per each
millimeter of mercury higher IOP.
In all these analyses, baseline IOP was not signifi-
cantly associated with progression. When study group
was added to the model, results were essentially the same,
although study group was no longer retained as a sig-
nificant factor.
The final row of Table 3 presents results that exam-
ine associations with disc hemorrhages observed during
follow-up, while controlling for the mean IOP during the
follow-up period and the significant variables. The per-
cent of patient visits with disc hemorrhages was strongly
related to progression, with a 2% increase in risk for ev-
ery percentage point.
COMMENT
SYNOPSIS
Several baseline factors were independently related to
EMGT-defined progression (Table 2). Treated patients
had half the risk of progressing of control patients, in-
dicating the efficacy of EMGT treatment. Other factors
included a higher IOP at baseline, the presence of exfo-
liation, having 2 eyes eligible for the trial, worse median
MD, and older median age. No other baseline factors
evaluated were related to progression in these analyses.
Progression was closely linked to the magnitude of the
initial IOP reduction with treatment. The initial change in
IOP (from baseline to the initial follow-up visit) was strongly
associated with progression, with about a 10% lowering of
the risk with each mm Hg of IOP reduction (Table 3). Con-
sistent with and related to this finding, the IOP level achieved
after this initial change (ie, the 3-months IOP) was also a
strong predictor of progression (Table 3), as was the mean
P IOP at follow-up (Table 3), with about a 10% higher risk
Value with each mm Hg of higher IOP. In analyses that included
⬍.001 the posttreatment IOP, neither baseline IOP nor later change
.004 in IOP were significantly related to progression. While in-
.003 terpretation of these nonsignificant findings must con-
⬍.001 sider the high degree of dependence among all these fac-
.01 tors, the results support the major prognostic importance
.03
of the IOP achieved after the initial reduction, represent-
ing the posttreatment baseline (Table 3, row 2). Frequent
disc hemorrhages at follow-up were also an independent
factor for progression (Table 3).

Table 3. Intraocular Pressure and Disc Hemorrhages After Baseline as Factors for Progression in the Early Manifest Glaucoma Trial*

Variables Reference Hazard Ratio (95% CI) P Value

Intraocular pressure, mm Hg
Initial change in IOP (baseline IOP–3-mo IOP) Continuous (per mm Hg decrease) 0.90 (0.86-0.94) ⬍.001
IOP at first follow-up visit (3-mo IOP) Continuous (per mm Hg increase) 1.11 (1.06-1.17) ⬍.001
Mean IOP at follow-up (mean IOP at all follow-up visits) Continuous (per mm Hg increase) 1.13 (1.07-1.19) ⬍.001
Disc hemorrhages
Percent of visits with disc hemorrhages Continuous (per % increase) 1.02 (1.01-1.03) .001

Abbreviations: CI, confidence interval; IOP, intraocular pressure.

*Progression analysis used Cox proportional hazard models, with results obtained from 4 separate models adjusting for baseline IOP, exfoliation number of
eligible eyes, mean deviation, and age. Intraocular pressure at first follow-up also adjusts for later changes in IOP, and percent of visits with disc hemorrhages
adjusts for mean follow-up IOP. P values based on Wald ␹2 statistic.

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 IOP AND TREATMENT EFFECTS
ON PROGRESSION
The multivariate analyses have quantified the magnitude
of the IOP-lowering effect of treatment, which halved the
risk of EMGT progression after adjusting for baseline IOP
and other variables (Table 2). These analyses thus contrib-
ute to the main results of the trial13 and provide new quan-
titative information on the effect of IOP-lowering treat-
ment to reduce progression in early OAG, while accounting
for other relevant factors. As such, it addresses the main
study question regarding the effect of IOP reduction on pro-
gression. Such knowledge can be obtained only from rig-
orous randomized trials with an untreated control arm that
were designed to evaluate this issue.30,31 To our knowl-
edge, the EMGT provides the first estimate that meets these
criteria. The previous estimates of treatment efficacy in glau-
coma have been based on nonrandomized studies with vari-
ous limitations32 or on randomized trials comparing vari-
ous treatments,15,16,19 which addressed a different research
question.
Of the 2 previous randomized glaucoma trials that
measured treatment effects directly by including an un-
treated control arm, the first had a small sample size and
yielded negative results.33 The second trial was the
CNTGS, which randomized 145 patients (average IOP
⬍20 mm Hg at baseline) to “treatment” or “no treat-
ment.” The intent-to-treat analyses, which are most com-
parable to the main EMGT analyses,13 did not directly
show an effect of treatment.18 Visual field progression de-
veloped at similar rates in the pressure-lowered and un-
treated arms (22/66 [33%] vs 31/79 [39%], respectively).
Significant differences favoring treatment were detected
only after additional analyses censoring for cataract (8/66
[12%] vs 21/79 [26%]). The CNTGS results, therefore,
did not yield a measure of treatment effects that is com-
parable to the EMGT results.
In the Collaborative Initial Glaucoma Treatment
Study (CIGTS), the role of IOP lowering on progression
was not clearly established, as medically treated pa-
tients had visual field outcomes similar to surgically treated
patients, yet IOP was 3 mm Hg lower in the latter group.34
Other comparisons within clinical trials, although not
based on intent-to-treat analyses, have provided sugges-
tive evidence that IOP lowering induced by treatment de-
creases progression. In the other CNTGS report17 (not
based on intent-to-treat), the course of treated patients
was followed from the time they achieved a 30% reduc-
tion in IOP (mean±SD=210±158 days after randomiza-
tion), to the course of control patients followed up since
randomization. These results indicated that treated pa-
tients reached progression less frequently than controls
(7/61 [12%] vs 28/79 [35%]), supporting a favorable treat-
ment effect.
The Advanced Glaucoma Intervention Study (AGIS)
investigated the issue using nonrandomized compari-
sons of patients achieving different levels of IOP reduc-
tion,31 finding a consistent association between lower IOP
and decreased visual field progression. Few changes in
AGIS field scores were seen in patients who achieved re-
ductions to IOP of less than 14 mm Hg early in the study
(predictive analyses), as well as in patients who main-
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53
©2003 American Medical Association. All rights reserved.
tained an IOP lower than 18 mm Hg throughout fol-
low-up (associative analyses). In AGIS, the IOP achieved
in the early follow-up period was positively correlated
with subsequent IOP levels. The results of these analy-
ses are very similar to our findings of a strong associa-
tion between progression and initial changes in IOP af-
ter baseline (Table 3), as well as the IOP level reached at
the first follow-up visit (Table 3), and the mean IOP af-
ter baseline (Table 3). We evaluated these factors sepa-
rately, as they are very closely linked. Since the baseline
IOP, the reduction in IOP, and IOP at 3 months’ fol-
low-up are all interdependent, they will compete for sta-
tistical significance if entered jointly into a model; hence,
careful interpretation is needed for lack of associations
in the various models. Still, the IOP achieved after the
initial reduction emerged as a major predictor of future
progression, indicating the importance of the initial
changes following EMGT treatment.
The AGIS results are also consistent with our ob-
servation that IOP was relatively stable after the first fol-
low-up visit. For this reason, later changes in IOP were
not related to progression after accounting for the IOP
level reached at the first follow-up visit (Table 3). Fur-
ther follow-up of EMGT patients is needed to evaluate
this issue, particularly since later visits in AGIS were not
as highly correlated with the initial posttreatment IOP
as were earlier visits (eg, r=0.63 at 24 months vs r=0.35
at 96 months). Additional data on IOP will be provided
in a future EMGT report.
Further support for the magnitude of the estimated
EMGT treatment effect comes from the Ocular Hyper-
tension Treatment Study (OHTS).35 This trial random-
ized ocular hypertensives to IOP-lowering treatment or
to no treatment, and compared the development of OAG
in both study groups. After 5 years, the cumulative prob-
ability of developing glaucoma was 4.4% in the treat-
ment group vs 9.5% in the untreated group, for an HR
of 0.40, which is similar to the HR of 0.50 that was found
in our EMGT analyses. While the OHTS is addressing a
different research question among ocular hypertensives
and not glaucoma patients, and while it has a somewhat
shorter follow-up period, its results are highly consis-
tent with EMGT findings.
EXFOLIATION
Most (83%) of the 23 patients with exfoliation at base-
line progressed (Table 1), and this condition was a ma-
jor factor predicting glaucoma progression (Table 2).
While known to have a wide geographic distribution,36
the prevalence of exfoliation is reported to be particu-
larly high in Scandinavia, accounting for more than half
of the OAG cases in a population study in Sweden.37 In
contrast, exfoliation was present in fewer than 10% of
EMGT patients—a fact most likely related to the study’s
eligibility criteria for early glaucoma. Another impor-
tant reason for the low frequency in EMGT is age, given
the late age of onset of exfoliation, with prevalences usu-
ally reported in individuals older than 60 years,38 as it is
seen rarely in persons younger than 50 years.38 Despite
this relatively low frequency, exfoliation emerged as an
important and independent predictor of progression,
WWW.ARCHOPHTHALMOL.COM
which more than doubled the risk. This increased risk
was an expected finding, being consistent with the more
severe clinical course of exfoliation glaucoma.39 Since per-
sons with this type of glaucoma have higher IOP than
others,40 their increased risk could be attributed, at least
in part, to the elevated IOP. In fact, 20 of the 23 EMGT
patients with exfoliation had an IOP of 21 mm Hg or more.
It is important to emphasize, however, that the strong
association with exfoliation was present while control-
ling for IOP. As such, exfoliation itself seems to confer a
greatly increased risk.41 Vascular factors may be the pos-
sible mechanisms contributing to this increased progres-
sion, given the reports of altered hemodynamics in pa-
tients with exfoliation glaucoma.42-44
ELIGIBLE EYES
Having 2 eligible eyes in the study was also a strong pre-
dictor of glaucoma progression, increasing the risk just
under 2-fold. Progression was observed in 72% of the pa-
tients with bilateral disease, as opposed to 47% of those
with one eye eligible (Table 1). Such patients had both
eyes at risk for progression since the beginning of the
study, and thus, they had a higher probability of pro-
gression than other patients. Patients with manifest bi-
lateral visual field defects at enrollment might also have
a more aggressive disease than patients with only one eye
eligible. While EMGT patients with 2 eligible eyes had
similar age and IOP to those with one eligible eye, their
average MD was worse by 2.17 dB, suggesting more vi-
sual field damage for these patients.
MEAN DEVIATION
Patients in EMGT generally had mild visual field loss,
with a median MD of −4 dB. Those with MD worse than
this level were at increased risk of progression as com-
pared with patients with better MD. However, MD has
not been always associated with subsequent progres-
sion.9 The EMGT results are consistent with those of pre-
vious studies, which also found that the extent of initial
visual field damage is related to subsequent damage.2,34
Possibly, a worse MD in newly identified patients in our
population screening may indicate a less favorable dis-
ease course.
AGE
Older patients showed an increase in their risk of pro-
gression as compared with younger patients. Several stud-
ies have reported similar results, such as CIGTS, which
found older age to be associated with increased visual field
scores at follow-up,9,34 while in other studies, such as
CNTGS, age was not associated with progression.2,10,11
DISC HEMORRHAGES
Disc hemorrhages are a well-known sign of glaucoma
damage,45-47 and their presence during follow-up is re-
lated to progression. 48-50 While EMGT results con-
firmed these observations, they are offered with the ca-
veat that our report is based on clinical assessment of disc
(REPRINTED) ARCH OPHTHALMOL / VOL 121, JAN 2003
54
©2003 American Medical Association. All rights reserved.
hemorrhages. This method is subject to interobserver
variation and may lead to considerable underascertain-
ment, as compared with standardized photographic as-
sessment of disc hemorrhages, which will be the subject
of a future EMGT report.
Because of the limitations of the method of assess-
ment, it is difficult to interpret the lack of an association
with the presence of disc hemorrhages at baseline, which
was recorded in 12% to 13% of the patients.13 To assess
their role during follow-up, we attempted to quantify this
variable by evaluating the percentage of patient visits with
disc hemorrhages. As the percentage of patient visits with
disc hemorrhages increased, the risk of progression cor-
respondingly increased so that each percentage point im-
plied a 2% higher progression risk. Frequent disc hem-
orrhages at follow-up were confirmed as an important
sign and conferred a worse prognosis.
OTHER FACTORS
Although many variables were evaluated, no additional
factors, other than those reported here, were found in
our main patient-based analyses or our eye-based analy-
ses. Of interest, with the exception of age, all the factors
associated with progression were eye related (Table 1).
In an investigation of progression factors, which was re-
stricted to patients in the untreated arm of the CNTGS,
progression was related to female gender, migraine, and
Raynaud disease.10 None of those factors were signifi-
cant in EMGT, a divergence that could be due to the dif-
ference in study populations. Migraine and Raynaud dis-
ease are both considered to be manifestations of
vasospasm, which has been related to glaucoma in pre-
vious studies. However, EMGT patients reporting any of
these conditions did not overlap (more than expected by
chance). While they showed a nonsignificant trend to
higher progression in univariate analyses, neither mi-
graine nor Raynaud disease were significant factors in the
multivariate analyses.
In the OHTS, factors related to the onset of OAG were
older age, larger cup-disc ratios, higher IOP, greater pat-
tern standard deviation, and thinner central corneal mea-
surements.51 Of these variables, age, IOP, and visual field
damage were also significantly related to glaucoma pro-
gression in EMGT, but not to central corneal thickness
(Table 1). The latter result could be explained by the many
differences in study populations between OHTS and EMGT,
including IOP levels and age.
STRENGTHS AND WEAKNESSES
Randomized clinical trials provide the strongest evi-
dence to assess the effects of treatment. The EMGT was
carefully designed to meet this goal and assess the ex-
tent to which IOP-lowering treatment affected the pro-
gression of newly diagnosed, early OAG. The visual field
and optic disc criteria to assess progression were pre-
defined and did not change during the study, as well as
being independently determined and confirmed. The de-
tection of the early stages of field progression, a neces-
sary safety feature, was achieved. The EMGT perimetric
criterion has high sensitivity14 and detected visual field
WWW.ARCHOPHTHALMOL.COM
 Early Manifest Glaucoma Trial Group
Clinical Center
Department of Ophthalmology, Malmö University Hospi-
tal, Malmö, Sweden: Anders Heijl, MD, PhD (study di-
rector); Bo Bengtsson, MD, PhD (screening director);
Karin Wettrell, MD, PhD (ophthalmologist; 1992-
2000); Peter Åsman, MD, PhD, (ophthalmologist); Boel
Bengtsson, PhD (investigator; since 2001); Margareta
Wennberg, BA (clinic coordinator); Gertie Ranelycke
(technician); Monica Wollmer, RN (technician); Gu-
nilla Lundskog, RN (technician); Katarina Magnusson
(secretary).
Data Center
Department of Preventive Medicine, State University of New
York at Stony Brook: M. Cristina Leske, MD, MPH (di-
rector); Leslie Hyman, PhD (deputy director); Mo-
hamed Hussein, PhD (senior biostatistician); Qimei He,
PhD (biostatistician; since 2001); Eugene Komaroff, PhD
(biostatistician; since 2001); Ling-Yu Pai, MA (data man-
ager); Lisa Armstrong (assistant data manager; since
1999).
Satellite Clinical Center
Department of Ophthalmology, Helsingborg Hospital, Hel-
singborg, Sweden: Kerstin Sjöström, MD (director); Lena
Brenner, MD (ophthalmologist); Göran Svensson, MD
(ophthalmologist); Ingrid Abrahamson, RN (head nurse);
Nils-Erik Ahlgren, RN (technician); Ulla Andersson, RN
(technician); Annette Engkvist, RN (technician); Lilian
Hagert (secretary/clinic coordinator).
Disc Photography Reading Center
Department of Ophthalmology, Lund University Hospital,
Lund, Sweden: Anders Bergström, MD (director; since
1997); Catharina Holmin, MD (director; 1993-1997);
Anna Glöck, RN (photograder); Catharina Dahling Wes-
terberg, RN (photograder); Inger Karlsson, RN (center
coordinator).
National Eye Institute, Bethesda, Md
Carl Kupfer, MD (director; until 2000); Donald Ever-
ett, MA (program director).
Steering Committee
Bo Bengtsson, MD, PhD; Donald Everett, MA; Anders
Heijl, MD, PhD; Leslie Hyman, PhD; M. Cristina Leske,
MD, MPH.
Data Safety and Monitoring Committee
Curt Furberg, MD, PhD (chairman); Richard Brubaker,
MD; Berit Calissendorff, MD, PhD; Paul Kaufman, MD;
Maureen Maguire, PhD; Helge Malmgren, MD, PhD.
changes in EMGT patients earlier than other measures
of progression.13 To facilitate interpretation, separate
analyses have estimated the amount of visual field loss
associated with EMGT-defined progression.14
Thorough attention was given to the overall con-
duct of the trial, as well as to ensuring high retention.
Few patients were lost to follow-up, rigorous quality con-
trol protocols were implemented, extensive monitoring
of study activities was conducted, and data quality was
high throughout the study.13 An expert data safety and
(REPRINTED) ARCH OPHTHALMOL / VOL 121, JAN 2003
55
©2003 American Medical Association. All rights reserved.
monitoring committee met regularly to provide inde-
pendent oversight of the trial. We also made efforts to
address potential methodologic issues in our statistical
analyses, with similar results obtained from patient-
based and eye-based approaches. For these reasons, we
believe that EMGT provides firm evidence to answer its
main study questions.
As in all trials, it is necessary to assess the general-
izability of EMGT results. The study was based on pre-
viously undetected patients with early glaucoma field de-
fects, who were mainly identified by a population-based
screening. Since EMGT patients were newly diagnosed
and had early disease, results are not directly applicable
to patients with a more advanced stage of the disease, but
it is likely that our results also apply to patients with more
advanced disease.13 The study was conducted in Swe-
den and predominantly involved white people, so that
appropriate caution is needed when extending EMGT re-
sults to other populations. Interpretation of the results
must also consider the specific protocols for treatment
and follow-up in EMGT, which are not necessarily ap-
plicable to all clinical situations.
CONCLUSIONS
The EMGT provides conclusive evidence to confirm that
reduction in IOP lowers the risk of progression in early
OAG. Furthermore, the analyses reported here estimate
that the pressure reduction achieved in EMGT decreases
the risk in half. The magnitude of the initial IOP reduc-
tion achieved after treatment emerged as a strong predic-
tor of progression. Since on average, no marked differ-
ences existed between the IOP achieved after the initial
reduction and subsequent IOP levels, the mean fol-
low-up IOP was similarly related to progression.
Our analyses also identified clinical characteristics
other than IOP, which were important and independent
factors for progression. The trial also provides solid sci-
entific evidence on the effectiveness of treatment to re-
duce glaucoma progression in a randomized clinical trial,
which is needed to support the value of early detection
and subsequent treatment of persons with glau-
coma.52-56 These data have not been available in the past
and have led to considerable uncertainties, not only in
the clinical domain, but also pertaining to the rationale
and merits of glaucoma screening,55-57 a topic that we plan
to address separately. The results of the EMGT, there-
fore, have clinical and public health implications.
Submitted for publication July 3, 2002; final revision re-
ceived August 22, 2002; accepted September 26, 2002.
This study was supported by grants U10EY10260,
U10EY10261, and K2002-74X-10426-10A from the
National Eye Institute (Bethesda, Md) and the Swedish
Research Council (Stockholm).
Corresponding author and reprints: M. Cristina Leske,
MD, MPH, Department of Preventive Medicine, Stony Brook
University School of Medicine, Health Sciences Center,
L3 086, Stony Brook, NY 11794-8036 (e-mail: cleske
@notes.cc.sunysb.edu).
WWW.ARCHOPHTHALMOL.COM

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