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Reduction of Intraocular Pressure and Glaucoma Progression
Results From the Early Manifest Glaucoma Trial
Anders Heijl, MD, PhD;
M. Cristina Leske, MD, MPH;
Bo Bengtsson, MD, PhD;
Leslie Hyman, PhD;
Boel Bengtsson, PhD;
Mohamed Hussein, PhD;
for the Early Manifest Glaucoma Trial Group
Arch Ophthalmol. 2002;120:1268-1279.
ABSTRACT
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Objective To provide the results of the Early Manifest Glaucoma Trial, which compared
the effect of immediately lowering the intraocular pressure (IOP), vs no treatment
or later treatment, on the progression of newly detected open-angle glaucoma.
Design Randomized clinical trial.
Participants Two hundred fifty-five patients aged 50 to 80 years (median, 68 years)
with early glaucoma, visual field defects (median mean deviation, -4
dB), and a median IOP of 20 mm Hg, mainly identified through a population
screening. Patients with an IOP greater than 30 mm Hg or advanced visual field
loss were ineligible.
Interventions Patients were randomized to either laser trabeculoplasty plus topical
betaxolol hydrochloride (n = 129) or no initial treatment (n = 126). Study
visits included Humphrey Full Threshold 30-2 visual field tests and tonometry
every 3 months, and optic disc photography every 6 months. Decisions regarding
treatment were made jointly with the patient when progression occurred and
thereafter.
Main Outcome Measures Glaucoma progression was defined by specific visual field and optic
disc outcomes. Criteria for perimetric progression were computer based and
defined as the same 3 or more test point locations showing significant deterioration
from baseline in glaucoma change probability maps from 3 consecutive tests.
Optic disc progression was determined by masked graders using flicker chronoscopy
plus side-by-side photogradings.
Results After a median follow-up period of 6 years (range, 51-102 months), retention
was excellent, with only 6 patients lost to follow-up for reasons other than
death. On average, treatment reduced the IOP by 5.1 mm Hg or 25%, a reduction
maintained throughout follow-up. Progression was less frequent in the treatment
group (58/129; 45%) than in controls (78/126; 62%) (P =
.007) and occurred significantly later in treated patients. Treatment effects
were also evident when stratifying patients by median IOP, mean deviation,
and age as well as exfoliation status. Although patients reported few systemic
or ocular conditions, increases in clinical nuclear lens opacity gradings
were associated with treatment (P = .002).
Conclusions The Early Manifest Glaucoma Trial is the first adequately powered randomized
trial with an untreated control arm to evaluate the effects of IOP reduction
in patients with open-angle glaucoma who have elevated and normal IOP. Its
intent-to-treat analysis showed considerable beneficial effects of treatment
that significantly delayed progression. Whereas progression varied across
patient categories, treatment effects were present in both older and younger
patients, high- and normal-tension glaucoma, and eyes with less and greater
visual field loss.
INTRODUCTION
STARTING IN THE 1960s, epidemiological studies demonstrated that normal-tension
glaucoma was much more common than previously thought and that ocular hypertension,
or elevated intraocular pressure (IOP) without glaucomatous visual field defects
or optic disc cupping, was more common than glaucoma.1-3 Subsequent
studies showed that relatively few patients with ocular hypertension developed
signs of glaucomatous damage during follow-up periods of up to 20 years, even
if the condition was left untreated.4-8 The
earlier concept that basically equated elevated IOP with glaucoma became obsolete,
resulting in uncertainty of the effects of glaucoma treatment.
Given this background, several randomized trials were initiated in the
early 1980s to evaluate the relationship between glaucoma and the reduction
of IOP.9-12 The
relationship was studied somewhat indirectly by investigating whether IOP
reduction could reduce the incidence of glaucoma damage in patients with ocular
hypertension. At that time, conducting a study to address the subject more
unequivocally (ie, a carefully designed randomized trial of patients with
glaucoma that included an untreated control arm) would probably have been
considered unethical.
Controversy continued regarding when, how aggressively, and whether
or not to treat,13 and the uncertainty of treatment
effects was outlined in a report presented to the National Leadership Commission
on Health Care.14 The development and widespread
use of computerized perimetry and the improved understanding of early optic
disc changes in glaucoma had demonstrated a complex relationship between IOP
and glaucoma damage. Researchers and professional organizations emphasized
a new glaucoma concept in which the disease was described as an optic neuropathy,
with IOP as only one of several risk factors.15-16 This
view has now become the standard, and modern glaucoma definitions often do
not even mention IOP.17-18
When our trial was planned in the early 1990s, several controlled studies
using timolol maleate in patients with ocular hypertension had been in progress
for many years but had not shown that such treatment effectively prevented
glaucoma damage. Given the relatively low incidence of this damage in patients
with ocular hypertension, the sample sizes and statistical power of these
trials were probably insufficient. Only 1 controlled trial involving treated
and untreated patients with glaucoma had been published, and with negative
results.19 The Collaborative Normal-Tension
Glaucoma Study (CNTGS) was under way at that time.20-21 In
1993, Rossetti et al22 concluded in a systematic
literature review that "[p]racticing ophthalmologists should be aware that
the effectiveness of pressure-lowering agents in the treatment of primary
open angle glaucoma is still to be determined," and that controlled trials
with functional endpoints and sufficient duration were urgently needed.
Because the effectiveness of such treatment had never been shown in
a randomized clinical trial, several clinical implications influenced glaucoma
management: What price in terms of adverse effects, inconvenience, and cost
could be considered acceptable when treatment effects were uncertain? Efforts
to detect cases of glaucoma that remained undetected (approximately 50%)2-3,23-25 could
hardly be advocated because an effective treatment for a particular disease
is considered a prerequisite for screening.26-28 The
need for knowledge in this area was clear. The development of improved methods
for computerized visual field testing and recognition of mild glaucoma progression
enhanced the feasibility of such trials. Hence, a randomized study with a
control arm, in which patients underwent follow-up without treatment as long
as progression did not occur, would not expose study patients to unacceptable
risks.
The Early Manifest Glaucoma Trial (EMGT) began in 1992. It is a controlled
clinical trial evaluating the effectiveness of reducing IOP in patients with
newly detected, previously untreated glaucoma. The study design and baseline
data were reported in 1999.29
The purpose of our article is to report the EMGT results pertaining
to the primary aim of the trial, namely to compare the effect of immediate
therapy to lower the IOP, vs no treatment or later treatment, on the progression
of newly detected open-angle glaucoma as measured by increasing visual field
loss or optic disc changes.
METHODS
Our previously published article29 contains
a detailed description of the study methods. The following is a condensed
description, which should enable the reader to understand and interpret the
results.
INCLUSION AND EXCLUSION CRITERIA
Study patients had newly detected, previously untreated open-angle glaucoma.
All patients fulfilled the following eligibility criteria:
- A diagnosis of early manifest open-angle glaucoma,
including primary open-angle glaucoma, normal-tension glaucoma, or exfoliation
glaucoma.
- Reproducible glaucomatous visual field defects
in at least one eye.
- Age between 50 and 80 years.
To determine eligibility, glaucomatous visual field defects were documented
with computerized static perimetry using the Full Threshold 24-2 program of
the Humphrey perimeter. Eligibility required a classification of "outside
normal limits" involving the same visual field area at 2 initial postscreening
visits using the glaucoma hemifield test 30-31 of
the Statpac II program for computer-assisted visual field interpretation.32 A "borderline" classification was acceptable only
if obvious localized glaucomatous optic disc cupping was present in an area
corresponding to the visual field defect.
Exclusion criteria were as follows:
- Advanced visual field defects (mean deviation [MD]
worse than -16 dB)33 or a threat to fixation,
defined as differential light sensitivity of 10 dB or worse at either or both
test points closest to the point of fixation in both the upper and lower hemifields.
If both eyes were eligible, the MD had to be better than -10 dB in at
least one eye.
- Visual acuity less than 0.5 (Monoyer-Granström),
corresponding to 20/40, in any eye.
- Mean IOP greater than 30 mm Hg or any IOP greater
than 35 mm Hg in at least one eye.
- Any condition precluding reliable results of perimetry
or optic disc photography, the use of study interventions, or 4 years of follow-up.
- Cataractous lens changes exceeding gradings of
N1, C2, or P1 according to the Lens Opacities Classification System (LOCS)
II.34
The study was conducted according to the tenets of the Declaration of
Helsinki. All subjects gave informed consent, and the study was approved by
the Ethics Committee of the University of Lund (Lund, Sweden) and the Committee
on Research Involving Human Subjects at the State University of New York at
Stony Brook.
RANDOMIZATION, TREATMENT, AND MASKING
Eligibility was independently confirmed at the data center. Eligible
patients were randomized evenly between treatment and nontreatment groups
according to a permuted block randomization scheme stratified by the clinical
and satellite centers. All eyes randomized to treatment received a full 360°
trabeculoplasty plus betaxolol hydrochloride eye drops at a dose of 5 mg/mL
(Betoptic; Alcon, Fort Worth, Tex) twice daily. Eyes stayed in their allocation
arms unless significant progression occurred. If, however, the IOP in treated
eyes exceeded 25 mm Hg at 2 consecutive follow-up visits or 35 mm Hg in control
eyes, latanoprost eye drops at a dose of 50 µg/mL (Xalatan; Pharmacia,
Uppsala, Sweden) were given once daily. When definite progression occurred,
patients were informed and options were discussed; decisions on subsequent
clinical management were made with their cooperation and following the usual
patterns of glaucoma treatment.
As part of the quality control protocol for the trial, all study personnel
completed a training period according to the manual of procedures prior to
data collection, which was followed by a formal certification process implemented
by the data center. Regular site visits and data audits were conducted. Study
outcomes were determined either through numerical, predetermined objective
criteria (visual field tests) or by masked graders at the disc photography
reading center. Study personnel measuring visual acuity, IOP, and visual fields
were masked to patients' study group, but patients and treating physicians
were not masked. An independent Data Safety and Monitoring Committee (DSMC),
which includes members from both Sweden and the United States, has been responsible
for monitoring all aspects of the trial since its inception. The DSMC meets
yearly to review patient safety, evaluate data quality and the results of
interim analyses, and supervise the overall conduct of the study.
PATIENT VISITS
The protocol required 2 postscreening visits preceding the 2 baseline
visits. These early visits were used to substantiate the diagnosis, ascertain
eligibility, minimize the effects of perimetric learning, and provide information
about the trial. Both baseline examinations included visual field testing
and the measurement of IOP (Goldmann applanation tonometry). After eligibility
was confirmed at the second baseline visit, informed consent was obtained
and patients were randomized. Patients received follow-up at 3-month intervals.
A recent medical and ophthalmologic history, including adverse events and
compliance, was obtained at each visit. Examinations included visual acuity
testing with Monoyer-Granström standard decimal charts following subjective
refraction, Goldmann applanation tonometry, computerized visual field testing
(Humphrey 30-2 Full-Threshold program), ophthalmoscopy, and slitlamp examination
with lens classification using the LOCS II system.34 Optic
disc photographs were obtained every 6 months.
ADDITIONS TO THE STUDY PROTOCOL
To further assess differences in nuclear clinical LOCS II gradings34 between study groups, the DSMC approved a proposal
to obtain nuclear lens photographs with slitlamp cameras specifically adapted
for this purpose. After standardization and certification of the photographers,
lens photographs were obtained twice: (1) between December 1999 and March
2000, and (2) between March 2001 and July 2001. The 2 sets of slitlamp photographs
were evaluated concurrently, following a random order, at a reading center
at the Department of Ophthalmology, University of Wisconsin–Madison.
The graders were masked and applied a standardized system.35
Further additions to the protocol once the study began included visual
function-related quality-of-life assessment with the National Eye Institute's
Visual Function Questionnaire36 and corneal
pachymetry measurements.37
OUTCOMES
The study outcome was progression of either glaucomatous visual field
defects or optic disc cupping, each according to predetermined objective criteria.
For each patient, one or both eyes could be included in the study, based on
eligibility at baseline. A patient was considered to have progression when
the first eligible eye met progression criteria.
To determine visual field progression, all follow-up results of visual
field tests were compared with an average of those from the 2 baseline tests
from the same eye using glaucoma change probability maps (GCPMs). These maps
differentiate between significant progression at P<.05
and random test-retest fluctuations at each of 74 test point locations in
the visual field. The EMGT used pattern deviation GCPMs based on pointwise
pattern deviations from the age-corrected normal threshold values38 rather than the standard total deviation GCPMs. Pattern
deviation maps limit the effects of increasing homogeneous loss of differential
light sensitivity, such as the loss caused by progressive cataract. Definite
EMGT visual field progression was defined as at least 3 test points showing
significant progression, as compared with baseline, at the same locations
on 3 consecutive GCPMs. These criteria have been shown to be highly sensitive
indicators of early visual field progression (A.H., M.C.L., B.B., B.B., and
M.H., for the EMGT Group, unpublished data, 2002).
To determine optic disc progression, baseline and follow-up photographs
were compared at the disc photography reading center using flicker chronoscopy.39-40 The protocol was designed to yield
highly specific outcomes. Two graders masked to study group and photograph
order independently judged each pair of photographs. If a suspected or definite
change was found, a second set of photographs was judged. If a consensus was
reached that flicker chronoscopy indicated change (sometimes after adjudication),
a nonflicker side-by-side comparison by a third independent grader decided
if definite optic disc progression was present. A previously described quality
control system evaluated the validity and reproducibility of the gradings,
as well as grading drift, based on a standard set of photographs.29
STATISTICAL ANALYSIS
The sample size calculations were based on assuming 4-year progression
rates of 40% in the treatment group and 60% in the control group, a significance
level of 5%, 2-tailed tests, and an attrition rate of 15%, thus providing
at least 80% statistical power to detect differences in progression between
trial arms. The statistical analysis plan has previously been described in
detail.29 This article includes comparisons
of the primary outcome of glaucoma progression between the treatment and control
groups. We followed an intent-to-treat analytic strategy, with all patients
analyzed according to their original group assigned by randomization. Comparisons
of glaucoma progression were based on assessing visual field or optic disc
changes that met the prespecified EMGT criteria while accounting for follow-up
times. Analyses were patient based; for those with 2 eligible eyes, the event
time to progression was defined by the first progression in either eye. Survival
analysis and life-table methods41 were used
to (1) estimate the proportion of progressions by study group, and (2) test
for a significant difference in these rates between groups using the log-rank
test. The estimated difference in 4-year progression rates between groups
and 95% confidence intervals were derived from the life-table analyses and
calculated as binomial events. Survival curves were also plotted for all patients,
stratified according to the prespecified covariates of IOP (<21 mm Hg or
 21 mm Hg) and exfoliation ("yes" or "no") as well as MD and age (less
than median values or equal to or greater than median values).
Univariate comparisons between treatment and control groups (eg, in
baseline characteristics or numbers progressing) were based on t tests for continuous variables if normality assumptions were justified
(otherwise, nonparametric methods were used), and on the  2 test
or Fisher exact test for categorical variables. In addition, progression across
time by study group was compared while stratifying according to the prespecified
covariates mentioned previously. The generalized estimating equations method42 was used to adjust for the correlation of lens status
among different follow-up visits for the same eyes. We also compared visual
field changes between the 2 study arms using linear regression analyses of
both MD and number of highly significantly depressed test point locations
(P<0.5%) according to the pattern deviation probability
maps. As reported in detail elsewhere, additional multivariate statistical
analyses using Cox proportional hazards models43-44 were
performed to evaluate factors related to glaucoma progression, including treatment.
These analyses estimated the magnitude of treatment effects (for each millimeter
of mercury of IOP reduction) and explored possible non–IOP-related effects
of treatment while controlling for other significant variables (M.C.L., A.H.,
M.H., B.B., L.H., and E. Komaroff, PhD, unpublished data, 2002).
RESULTS
RECRUITMENT AND RETENTION
Recruitment has previously been described in detail.29 A
large population screening of 44 243 residents aged 57 to 76 years was
conducted between October 1992 and January 1997 in the cities of Malmö,
Sweden, and Helsingborg, Sweden, to recruit for the trial. Most trial participants
(84.7%) came from this screening, whereas a smaller number were referred from
other ophthalmologists. A flowchart is shown in Figure 1. The randomization period began in January 1993 and ended
in April 1997. Of the 255 patients randomized, 129 were allocated to treatment
and 126 were controls. Only 3 patients in each group were lost to follow-up
for reasons other than death (n = 22); that is, 6 living patients no longer
received follow-up as of September 1, 2001, the time of database closure for
this study. The remaining 227 patients exceeded the originally selected minimum
follow-up period of 4 years, with follow-up times comparable between study
groups and ranging from 51 to 102 months (for the treatment group, mean ±
SD = 67.0 ± 20.4 months; median = 66 months; for the control group,
mean ± SD = 69.7 ± 20.8 months; median = 69 months). The number
of patient study years was similar in the 2 groups: 720 in the treatment group
and 732 in the control group.
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Figure 1. Patient flowchart. Most study
patients were recruited from a population-based mass screening. Attrition
rates were low, and follow-up is indicated as of September 2001.
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BASELINE CHARACTERISTICS
The mean age of the patients was 68 years; 66% were women, almost all
patients were white,29 and 132 (52%) had a
baseline IOP less than 21 mm Hg. The baseline characteristics of the 2 study
groups (Table 1) were comparable,
and none of the observed parameters differed significantly between groups.
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Table 1. Baseline Characteristics of All Study Patients by Study Group*
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IOP CHANGES AFTER BASELINE
The mean IOP in the treatment group decreased from 20.6 mm Hg at baseline
(Table 1) to 15.5 mm Hg at the
3-month follow-up visit, for a reduction of 25% that was maintained throughout
the follow-up period; the median change was 0.2% from 3 months until progression
or the last visit (for nonprogressed eyes). The reduction was larger (29%)
in eyes with a baseline IOP of 21 mm Hg or greater than in eyes with a baseline
IOP less than 21 mm Hg (18%). Results were similar when considering changes
in IOP from baseline to each visit until progression or the last visit. The
mean ± SD difference from baseline to all visits was -4.5 ±
3.4 mm Hg in treated eyes; the corresponding values were -6.8 ±
3.0 mm Hg for eyes with a baseline IOP of 21 mm Hg or greater and -2.7
± 2.4 mm Hg in eyes with a baseline IOP less than 21 mm Hg. By self-report,
treated patients indicated using treatment "most of the time" at 96.8% of
visits. The mean IOP reduction in the treatment group from the baseline readings
(average of 2 visits) to the reading obtained just before laser trabeculoplasty
a few weeks later, when patients were receiving betaxolol, was 2.7 mm Hg;
the IOP reduction from that reading to the 3-month visit was 2.4 mm Hg. The
protocol-defined cutoff point for extra treatment in the treated patients
(>25 mm Hg) occurred infrequently (4 patients, or 3%), whereas no untreated
patients reached the 35 mm Hg limit requiring topical medication before progression.
In the control group, IOP values were unchanged (20.9 and 20.8 mm Hg
at baseline and the 3-month visit, respectively), with small changes thereafter
(median change = 0.0% from 3 months until progression or the last visit).
The mean ± SD difference from baseline to all visits, censored for
progression, was 0.0 ± 1.9 mm Hg.
MAIN OUTCOMES
By September 1, 2001, the proportion of patients who showed definite
visual field and optic disc progression was larger in the control group than
the treatment group: 78 (62%) of 126 vs 58 (45%) of 129, respectively (P = .007) (Table 2).
All patients with progression met the visual field outcome criteria with 1
exception, who met the optic disc criterion only. In accordance with the specific
EMGT criteria to define optic disc progression, few of these outcomes were
observed.
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Table 2. Progression by Study Group*
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Life-table analyses show that the separation between study groups appeared
early and was maintained during the entire follow-up period; they also show
that progression increased considerably with time, in the treatment group
as well as the control group (Figure 2).
Progression was more common in the control group at any point during follow-up;
in other words, progression occurred earlier in controls than in the treatment
group. Whereas the median time to progression (using the Kaplan-Meier cumulative
survival function) was 48 months in controls, it was 66 months in treated
patients, indicating a delay in progression caused by treatment. According
to the life-table results at 48 months, which was the minimum planned period
of follow-up, 62 controls (49%) had progressed compared with 39 (30%) in the
treatment group (difference = 19%; 95% confidence interval, 7%-23%; P = .004). The differences between study groups and apparent
treatment effects were also observed when stratifying according to the baseline
covariates (Figure 3). All of these
curves show a clear and persistent separation between treatment and control
groups, and the covariates were significantly related to progression in multivariate
analyses (M.C.L., A.H., M.H., B.B., L.H., and E. Komaroff, PhD, unpublished
data, 2002). In these analyses, each millimeter of mercury of decreased IOP
was related to an approximately 10% lowering of risk, and the results showed
no significant treatment effects beyond those related to IOP reduction.
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Figure 2. Progression across time of all
patients by study group. The cumulative probability of patients with progression
was larger in the control group than the treatment group (P = .007). The number of patients at risk for glaucoma progression
in the treatment group and control group are shown below the x-axis.
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Figure 3. Progression across time stratified
according to baseline covariates: patients with an intraocular pressure less
than 21 mm Hg (A) and 21 mm Hg or greater (B), with exfoliation (C) and without
(D), with mean deviation values better than -4.5 dB (E) and worse (F),
and who are younger than 68 years (G) and 68 years or older (H). The numbers
of patients at risk for glaucoma progression in the treatment group and control
group are shown below the x-axes. These numbers decrease significantly with
length of follow-up and were small from the beginning in the exfoliation group.
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The regression analyses of MD and number of highly significantly depressed
test point locations (P<.5%) in pattern deviation
probability maps yielded differences between study groups similar to those
based on EMGT-defined progression criteria. Although the regression analyses
may underestimate true progression because of sustained, low-grade perimetric
learning, these results show significantly slower visual field deterioration
in patients allocated to treatment than in control patients (Table 3). The mean change in visual field loss from baseline to
the end of follow-up, as expressed by the MD, was a worsening by 2.24 dB in
the treatment group and 3.90 dB in the control group. A separate analysis
has shown that the amount of visual field deterioration needed to reach EMGT-defined
visual field progression is associated with a worsening in MD by 2.26 dB (A.H.,
M.C.L., B.B., B.B., and M.H., for the EMGT Group, unpublished data, 2002).
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Table 3. Change of Mean Deviation Values and Number of Highly Significant
Test Point Locations Until Time of Progression in Progressed Eyes or Until
Last Visit in Nonprogressed Eyes, by Study Group*
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ADVERSE EVENTS AND SELF-REPORTED ADVERSE EFFECTS
As seen in Table 4, few
systemic and ocular conditions were identified; however, both occurred more
commonly in the treatment group. Cataract surgery was performed in 8 patients,
6 of whom were in the treatment group. Ocular adverse effects of treatment
were generally mild, with redness, dryness, and erythema reported by 11 patients,
blurred vision by 8 patients, and other symptoms, mainly transient discomfort,
by 12 patients. Visual acuity decreased with time and was not significantly
different between study groups (visual acuity at 4 years of follow-up [Monoyer-Granström]:
mean ± SD = 0.87 ± 0.18 in the treatment group vs 0.90 ±
0.16 in the control group; P = .82).
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Table 4. Adverse Events and Self-reported Conditions by Study Group*
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Data-monitoring analyses indicated an unexpected increased incidence
of nuclear opacities evident in the LOCS II clinical gradings. The percentages
of LOCS II gradings of 2 or higher by study group during the initially planned
4-year follow-up period are shown in Figure
4. There was a clear and significantly more rapid development of
nuclear opacities in the treatment group, without similar changes observed
for cortical and posterior subcapsular lens gradings. The results of analysis
using generalized estimating equations indicated a significant increase in
clinical nuclear opacities with time (P = .02) and
treatment (P = .002).
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Figure 4. Lens Opacities Classification
System (LOCS) II scores of 2 and higher by study group during the first 48
months of follow-up.
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Lens photographs were taken to further evaluate these clinical findings,
but a high percentage of controls had received treatment by that time: 34.5%
(41/119) at the first round of photographs and 45.9% (50/109) at the second
round. The intent-to-treat analyses of these lens photogradings were inconclusive,
although more eyes in the treatment group (8) were ungradable because of cataract
or cataract surgery than in controls (2). In multivariate analyses including
these eyes and evaluating associations with treatment (independent of study
group and controlling for age, sex, and follow-up time), lens photograding
scores were related to treatment (P = .004).
More patients died in the treatment group than in the control group:
15 of 22 (Figure 1). This difference,
although not statistically significant (P = .08),
was observed within the first few years of follow-up. The patterns of cause-specific
mortality were not unusual, with most deaths due to cardiovascular diseases
(eg, myocardial infarction or stroke) or malignancies (eg, liver cancer or
stomach cancer) in both trial arms; most deaths occurred in men.
DATA QUALITY
The rate of missed visits was 5.9% and was similar between study groups.
Protocol deviations at follow-up were infrequent and were mainly due to the
noncompletion of data items (29, or 0.5% of visits) and nonscheduling or noncompletion
of additional visits according to protocol (33, or 0.6% of visits). Only 0.2%
of data entries on study forms required editing. Unmasking of the technicians
to study group occurred in 81 visits (1.5%) involving 31 treated patients
and 17 controls. The evaluations of optic disc gradings confirmed the high
specificity of the protocol, with no false-positive gradings in 12 cycles
of masked readings of a quality control set of photographs. Reproducibility
of flicker gradings varied throughout the quality control cycles and among
graders, with most  statistics in the "fair" to "good" range for both
intragrader agreement (medians ranged from = 0.50-0.73 among graders)
and intergrader agreement (median of all comparisons of grader pairs:
= 0.63).
REVIEW BY THE DSMC
No patient safety issues were identified by the DSMC, and the trial
has continued as planned. In May 2000, the results suggested favorable subclinical
treatment effects, and the DSMC recommended that the investigators share this
information with enrolled patients and continue the study according to protocol
until all patients had completed at least 4 years of follow-up. After receiving
such information and discussing clinical management options, all patients
continued follow-up in their assigned study groups.
COMMENT
Modern evidence-based medicine recognizes that the best proof of treatment
effectiveness comes from randomized controlled trials that are not only well
designed and executed but also thoroughly and accurately reported. Beginning
in 1996, a series of statements were published by the Consolidated Standards
of Reporting Trials (CONSORT) Group to increase and ensure the quality of
such reports.45 Our article follows the recently
updated CONSORT guidelines.46
EFFECTS OF TREATMENT ON GLAUCOMA PROGRESSION
The EMGT showed clear beneficial effects of treatment on delaying the
onset of progression, with lower rates of progression in the treatment group
than the control group (Table 2 and Table 3; Figure 2). Differences between treated and untreated patients also
remained when results were further stratified according to various baseline
characteristics: IOP level, degree of visual field damage, patient age, or
presence of exfoliation (Figure 3). Despite these clear treatment effects, a large percentage of treated eyes
showed progression during the follow-up period.
The median time to progression was 18 months longer in the treatment
group than the control group. This observation should not be interpreted to
mean that the only benefit of treatment (as used in the EMGT) is to delay
glaucoma progression by 18 months. Instead, the finding means that the amount
of disease worsening necessary to trigger the EMGT-defined progression criteria
took an average of 18 months longer in treated patients than controls. This
article provides data just up to the time of the initial EMGT outcome, but
it is likely that the difference in glaucoma progression between study groups
would have increased if the initial allocation to treatment or no treatment
had remained unchanged even after this outcome.
The IOP reduction achieved by the EMGT treatment was substantial and
was not associated with adverse effects as significant as those typically
encountered after filtering surgery and documented in the CNTGS.20-21 There
was no difference in visual acuity loss across time between the 2 study groups,
despite the fact that treatment was associated with an increased incidence
of cataract in the EMGT.
Time to progression varied greatly among treated patients as well as
untreated ones and was sometimes rather short. This indicates that the standardized
treatment was insufficient in many rapidly progressing patients. On the other
hand, many patients, even untreated ones, showed no progression after 6 or
more years of follow-up. Because the EMGT visual field progression criterion
is a sensitive indicator of deterioration, careful follow-up may allow treatment
to be deferred in some patients, as suggested by Drance et al47:
"[I]t might be prudent not to treat most patients with normal-tension glaucoma
until the rate of the disease in the particular individual had been established
over a period of observation." The EMGT thus supports today's emphasis on
individualized treatment, and we expect that after further analyses, EMGT
data will be found useful for tailoring follow-up and treatment to individual
patients.
ADVERSE EVENTS
In our opinion, only 2 types of adverse events deserve comment: cataract
and mortality. During recruitment, the EMGT used a standardized system of
lens classification to ascertain lens status so that patients with cataractous
changes were excluded from the trial. This design feature and the absence
of glaucoma surgery in the treatment protocol resulted in a low frequency
of cataract surgery at follow-up (n = 8, or 3%) compared with the rates reported
in other glaucoma trials. Continued monitoring of clinical lens gradings in
the EMGT led to the detection of an increase in nuclear opacities in the treatment
group (Figure 4), which was paralleled
by a higher frequency of cataract surgery in that group (Table 4).
Analysis of nuclear photograding scores also showed associations with
treatment, but the difference in scores between groups was not confirmed in
intent-to-treat analyses. The latter result is difficult to interpret because
many of the controls were receiving treatment at the time the lens photographs
were taken.
It is well known that glaucoma filtering surgery is associated with
a marked rise in cataract incidence and that topical irreversible cholinesterase
inhibitors caused cataract. The reports of the CNTGS have emphasized the frequent
occurrence of cataract surgery in its treated group20-21;
cataracts were also common in the Advanced Glaucoma Intervention Study (AGIS).48-49 The CNTGS is the only other glaucoma
study besides ours that permits a comparison in cataract rates between treated
and untreated arms. Although it did not show a significant difference in cataract
rates between the medically treated patients and untreated controls, numbers
were small; the mean time to cataract development was actually lower in the
medical treatment group. The use of topical IOP-lowering medications was strongly
related to an increased incidence of nuclear lens opacities in the Barbados
Eye Studies.50 The Ocular Hypertension Treatment
Study51 (OHTS) reported "a slight excess of
cataract surgery" in the medication group: 6.4% (52/806) vs 4.3% (35/813)
in the observation group (P = .06), a result consistent
with EMGT observations.52
Everything considered, we deem it likely that therapeutic IOP reduction
can be linked with cataract formation.
The difference in death rate between groups is worth attention. The
rate observed in the treated patients was as expected according to the population
statistics of Sweden,53 whereas the control
group had a considerably lower value. Furthermore, there was no difference
in cause-of-death patterns between the 2 groups. The OHTS reports similar
death rates in treated and untreated patients: 3.2% and 3.5%, respectively.52 For these reasons, it is likely that the observed
mortality differences in the EMGT were caused by chance.
POSSIBLE MECHANISMS
In the EMGT, all patients received standardized treatment, and no effort
was made to meet specific target IOPs. This design allowed an unbiased quantification
of treatment effects related to IOP reduction, which was strongly related
to glaucoma progression. The magnitude of this dependence on IOP change was
impressive: an estimated 10% decrease in risk of progression with each millimeter
of mercury of IOP reduction. Our results do not suggest that the outcome differences
between study groups were due to non–IOP reduction effects; for example,
to possible intrinsic vasoactive or neuroprotective properties of the topical
medications used in this study.
Even though the EMGT clearly supports the beneficial effect of IOP reduction
on open-angle glaucoma, these results do not prove that elevated IOP is the
primary cause of glaucoma. The true causes of the disease may be a set of
more fundamental malfunctions, some of which may lead to elevated IOP (defined
as either a statistically high pressure level or a level that is not tolerated
by the individual patient while falling within the normal range). However,
the fact that IOP reduction slows progression indicates that IOP levels are
important in the course of the disease.
COMPARISON WITH OTHER TRIALS
Since the start of the EMGT, data have become available that are of
value when examining the overall evidence for the effect of IOP reduction
on open-angle glaucoma.20-21,48, 51, 54 In
general, available results have been interpreted to indicate that all modalities
of IOP reduction slow the progression of glaucomatous optic atrophy, but to
an unknown extent.20-21,52, 55-56 Even
recent evidence remains conflicting. A nonrandomized analysis of data from
the AGIS provided evidence that effective IOP reduction is of great importance
for disease progression.55 In the Collaborative
Initial Glaucoma Treatment Study56 (CIGTS),
however, aggressive medical therapy and initial surgery resulted in indistinguishable
rates of visual field progression despite differences in IOP reduction, and
the intent-to-treat analysis of the CNTGS showed no difference between treated
and untreated arms.21 Thus, up to now, uncertainty
has remained regarding the effect of IOP reduction on glaucoma progression.
Recently, researchers have agreed that conclusive evidence should come from
trials specifically designed to address this issue.55
Most important is the CNTGS, in which 140 patients with normal-tension
glaucoma were randomized either to nontreatment as controls or to have the
IOP lowered by 30% from baseline. The clinical course and visual field and
optic disc outcomes of both groups were then compared. Although the intent-to-treat
analyses of the CNTGS found no significant differences between treated and
untreated arms,21 these negative results have
largely been ignored in the ophthalmic community. Our results show that the
conclusion of the CNTGS (that IOP reduction decreases glaucoma progression
in normal-tension glaucoma20) is correct but
that treatment effects can be achieved without a rigid IOP goal or serious
adverse effects.
Although trials involving patients with ocular hypertension address
a somewhat different subject, they deal with the same fundamental question
of the relationship between IOP and glaucoma damage. It is therefore appropriate
to include the results from such studies in the discussion of overall evidence.
Earlier controlled studies of patients with ocular hypertension had diverging
results9-12 and
together failed to demonstrate a statistically significant beneficial effect,22 but their study power was usually low. The OHTS currently
provides conclusive data showing positive effects of IOP reduction in decreasing
the frequency of glaucoma damage in patients with ocular hypertension. The
incidence of glaucoma damage differed significantly between treated patients
and untreated controls, amounting to 4.4% and 9.5%, respectively, after 60
months of follow-up.52 The overall evidence
that lowering the IOP reduces the risk of further visual field progression
in glaucoma must now be regarded as very strong.
STRENGTHS AND LIMITATIONS
Interpretation of the EMGT results must consider several methodologic
strengths of the trial. That only 2.4% of patients were lost to follow-up
for reasons other than death indicates a very high motivation among patients
and personnel to conduct the study according to protocol. Consequently, we
are able to report the study results with few missing data items.
Data on both visual field and optic disc outcomes were obtained by masked
observers following standardized and unbiased methods. Visual field criteria
were defined using modern statistical programs for visual field analysis and
were therefore numerical and objective. Glaucoma change probability maps provided
early yet specific detection of visual field progression. These maps were
based on pattern deviation rather than total deviation, strongly reducing
any confounding effects of progressing lens opacities on visual field outcomes.38 The number of significantly progressing test point
locations and the reproducibility of such progressed locations required to
reach a visual field endpoint were specified prior to the EMGT, based on retrospective
studies of a large number of clinical visual field series. These visual field
progression criteria were not changed during the study; they permitted immediate
objective recognition of tentative and definite perimetric progression based
on printouts that could be judged while the patient was still in the clinic.
This feature allowed immediate scheduling of extra visits when tentative progression
was found, as well as discussions of visual field progression and treatment
alternatives with the patient when definite progression occurred and thereafter.
The computer-assisted visual field analysis also obviated the need for a visual
field reading center.
Because glaucoma cases were newly detected and previously untreated,
no residual effects of previous drug therapy or surgery were possible. Most
patients were identified through a screening of a large population group of
relevant age in a designated geographical area, and the screening examination
included a majority of invited citizens. This knowledge is valuable when deriving
conclusions on glaucoma management from the results of this study and particularly
when assessing the implications of the EMGT results on glaucoma screening.
Interpretation of the EMGT results must also consider potential limitations
of the study. One such limitation is that the study involved a specific, homogeneous
patient population: almost all patients were white. This certainly limits
the generalizability of the study results to other populations. Patients also
had relatively early glaucoma, so our study results cannot provide quantitative
data pertaining to patients with high IOP levels (>30 mm Hg) or advanced visual
field loss. Another necessary limitation was that the initial randomization
to treatment or no treatment was maintained only as long as progression did
not occur; this shortened the ascertainment period of the glaucoma's natural
history, which was a secondary EMGT aim. The study, therefore, does not include
long-term follow-up of untreated patients beyond EMGT progression.
The EMGT used a new criterion to define visual field progression, which
was unchanged throughout the entire study. The EMGT definition allowed the
detection of small amounts of progression, an important safety aspect of the
trial. This criterion was based on knowledge gathered during the 1980s on
the nature of random variability in glaucomatous visual fields57 and
permitted an earlier separation between treatment arms than more conventional
criteria (eg, linear regression of MD values or changes in numbers of test
point locations developing significant or absolute visual field loss). However,
the EMGT visual field criterion is not as intuitively comprehensible as other
simpler criteria. To address this issue and to provide a basis for a later
article that will present clinically useful conclusions from the study results,
we have compared the EMGT criterion with other criteria in a separate report
(A.H., M.C L., B.B., B.B., and M.H., for the EMGT Group, unpublished data,
2002).
The EMGT's visual field progression criterion showed excellent sensitivity
and specificity in a comparison of the performance of such criteria used in
the EMGT, AGIS, and CIGTS. In this pilot study, the EMGT criteria detected
progression in 20 of 20 series of visual fields from EMGT patients who had
been deemed to have definite progression by 2 independent glaucoma experts.
Progression was sustained in 90.8% of visits following the visit when definite
progression was first found. Specificity was determined from another 20 series
of visual fields that had been classified as stable by the same experts. It
was found to be high; none of the 20 stable visual fields were falsely labeled
as progressing with the EMGT's criterion (A.H., M.C.L., B.B., B.B., and M.H.,
for the EMGT Group, unpublished data, 2002).
IMPLICATIONS OF STUDY RESULTS
The EMGT is the first randomized study providing a long-term comparison
of progression between treated and untreated patients with primary open-angle
glaucoma, normal-tension glaucoma, and exfoliation glaucoma that shows a definite
positive effect of IOP reduction. This information is valuable because treatment
effects in chronic open-angle glaucoma have been largely unknown, and there
is very little information about the natural history of glaucoma.
Although these results provide quantitative data directly applicable
to most patients with glaucoma, our eligibility criteria led to a study population
with earlier disease than a typical clinical glaucoma population.58 At the population screening, 19% of patients with
newly detected early manifest glaucoma were ineligible for the EMGT because
their IOP exceeded the inclusion criteria (mean IOP >30 mm Hg or any IOP >35
mm Hg), and an additional 10% could not participate because the visual field
damage exceeded our limits for inclusion. The EMGT results provide little
information directly pertaining to patients with advanced glaucoma and high
IOP levels; however, as mentioned earlier, future analyses will likely show
that the current results are indeed applicable to such patients.
The EMGT data have important clinical implications. The results not
only confirm previous beliefs that IOP reduction is beneficial but also provide
new knowledge on rates of disease progression, with and without treatment,
in patients with various characteristics. Our results therefore strengthen
the rationale for current standard clinical management. In addition, they
afford a basis for increased efforts to achieve earlier detection of the disease
and for tailoring the clinical management of glaucoma to the needs of the
individual patient. The latter issues are worth special consideration and
will be addressed separately.
AUTHOR INFORMATION
Submitted for publication June 24, 2002; final revision received August
1, 2002; accepted August 5, 2002.
This study was supported by grants U10EY10260 and U10EY10261 from the
National Eye Institute, Bethesda, Md, and grant K2002-74X-10426-10A from the
Swedish Research Council, Stockholm.
Drugs were donated by Alcon Laboratories Inc, Fort Worth, Tex, and Pharma |
