LANDMARK STUDIES

SECTION EDITOR: RONALD L. FELLMAN, MD

Take-Home
Messages From the
Advanced Glaucoma
Intervention Study
BY LEON W. HERNDON, MD, AND DANIEL B. MOORE, MD

I tasked Leon W. Herndon, MD, and Daniel

B. Moore, MD, with a difficult assignment: to
answer questions about the Advanced Glaucoma “This study was designed to
Intervention Study (AGIS). This study is one of evaluate two sequences of
the most complex landmark glaucoma studies surgical treatments in patients
ever produced, with countless articles stemming from the
data. Drs. Herndon and Moore did an admirable job of with medically uncontrolled
addressing the questions and explaining the reasons. They open-angle glaucoma.”
summarize that a lower IOP helps to slow down field loss,
but how to reduce IOP in each individual patient may need
to be modified by countless factors that are addressed in OAG despite maximum medical therapy between 1988
this article. and 1992 at one of 11 participating clinical centers.2
—Section Editor Ronald L. Fellman, MD Eligible participants were between 35 and 80 years of
age; were diagnosed with OAG in a phakic eye; were on
What question was the AGIS designed to maximum effective, accepted, and tolerated glaucoma
answer? medical therapy; had undergone at least one automated
Although it has long been established that patients field test before the eligibility visual field test; met at
with advanced glaucoma require aggressive therapy,1 least one of nine combinations of criteria for consistent-
prior to the AGIS, little was known about the long-term ly elevated IOP, glaucomatous visual field defect, and
outcomes or effectiveness of surgical treatments in optic disc rim deterioration; had a visual acuity score of
these patients. This study was designed to evaluate two 56 or better (approximate Snellen equivalent, 20/80);
sequences of surgical treatments in patients with medi- had a visual field score between 1 and 15; and had an
cally uncontrolled open-angle glaucoma (OAG). The eye that was treatable with either argon laser trabeculo-
main outcome measures were visual acuity and progres- plasty (ALT) or trabeculectomy.
sion of visual field loss. The investigators also reported Visual acuity, gonioscopy, and fundoscopy were each
on IOP, complications, time to treatment failure, and assessed once, visual field testing was assessed twice, and
the need for adjunctive medications. IOP was assessed three times at baseline. Next, eyes were
randomly assigned to one of two sequences of escalat-
How was the study designed to answer the ing therapy: trabeculectomy, followed by ALT, followed
question? by a second trabeculectomy (TAT) or ALT, followed by
AGIS was a prospective, multicenter, randomized trial trabeculectomy, followed by another trabeculectomy
that enrolled 591 patients (789 eyes) with uncontrolled (ATT).

20 GLAUCOMA TODAY MAY/JUNE 2013

 Failure was defined as an eye on maximum medical
therapy that met the study’s eligibility criteria for ele-
vated IOP, visual field defects, and optic disc rim dete-
rioration. The use of intraoperative antimetabolites was
evolving during the study period; prior to 1990, anti-
metabolites were not used during trabeculectomy,
whereas 5-fluorouracil has been used postoperatively
since 1990 and mitomycin C intraoperatively since 1991.
IOP was measured 1 and 4 weeks after each opera-
tion, and visual acuity, visual fields, and IOP were
assessed 3 and 6 months after enrollment and then
biannually thereafter. Data collection closed March 31,
2001.3 Because the investigators did not a priori ran-
domize patients stratified by race, there are unequal
numbers of patients and eyes in the four arms of the
trial. The large sample size, however, makes it possible
to statistically compare the results when stratified by
race.

With regard to baseline characteristics

(AGIS 3) for the study group, what were the
most important differences between black
and white patients? Interestingly, disc hem-
orrhages were more common in whites, but
glaucoma was more severe in blacks. Why
might this occur, considering that disc hem-
orrhages are usually associated with worsen-
ing glaucoma?
Race in the AGIS was characterized as white, black,
Hispanic, or other, either by self-report or by study per-
sonnel. Of the 581 patients in AGIS 3, 57% were black.
This group of patients was younger and had more sys-
temic hypertension and diabetes than white patients.
Black patients also had significantly worse visual field
defects on average than white patients, although IOP
and visual acuity were similar between the two groups.
There were only four black patients (all women) who had
an observed disc hemorrhage (0.9%), whereas 12 white
patients (5 men, 7 women) had disc hemorrhages (3.7%).4
The difference in the rate of disc hemorrhages
between the two races did not reach statistical signifi-
cance, but it is an interesting comparison nonethe-
less. Visual field loss has been reported to occur at an
accelerated rate after disc hemorrhages are identified,5
but the severity of baseline visual field damage does
not seem to be a risk factor for the development of
disc hemorrhages.6 Although the investigators did not
report on specific characteristics of the patients with
disc hemorrhages, it is worth noting that variables
such as the average IOP or vertical cup-to-disc ratio
were similar between the two groups. Optic disc hem-
LANDMARK STUDIES

orrhages have been reported over a wide age range, AGIS 5 revealed that bleb encapsulation
but advanced age has been reported as a risk factor for occurred after filtration surgery in 18.5% of
visual field progression in patients with disc hemor- eyes with previous ALT and in 14.5% of eyes
rhages.5 It is possible, therefore, that the significantly without ALT. Is bleb encapsulation less of a
older age of the white patients in this study con- problem with selective laser trabeculoplasty,
tributed to the finding. Also, as this study evaluated or is bleb encapsulation more a function of
patients with advanced glaucoma, it is important to limbus-based filtration, which is now less
search for and appropriately consider this finding in all common?
of our glaucoma patients, regardless of the severity of AGIS 5 reported on the incidence of encapsulated
the disease. blebs after trabeculectomy in eyes with and without
previous ALT, and the investigators assessed the risk
What are the most important clinical points factors for developing an encapsulated bleb.9 They
regarding the comparison of treatment out- found that male gender and high school graduation
comes in AGIS 4? Even though IOP decreased without further formal education were statistically sig-
the most with filtration surgery in both nificant risk factors for bleb encapsulation.
treatment groups, white patients fared bet- ALT is more destructive to the trabecular tissue than
ter with this treatment modality. What is selective laser trabeculoplasty. One report documented
the most likely cause of this? Could this be elevated levels of TGF-beta 2 in the aqueous of patients
because 21% of filters failed in blacks versus with pseudoexfoliation after ALT prior to undergoing
only 13% in whites? trabeculectomy than without prior ALT therapy, and it
AGIS 4, which reported on the 7-year results of found that the former were more prone to bleb scar-
the study, is full of acronyms and figures. In essence, ring.10 It is possible, therefore, that selective laser tra-
the investigators found that, in both black and white beculoplasty causes less inflammation than ALT, and as
patients, the mean IOP was lower in eyes assigned to the such, bleb encapsulation may be less of a concern with
TAT sequence, and the cumulative failure of initial ther- that procedure.
apy was higher with the ATT sequence. When evaluating
the preservation of visual field and acuity, black patients AGIS 7 reported the relationship between
fared better with ATT, whereas white patients had a IOP control and visual field deterioration.
lower cumulative decline with TAT (the first 15 months What are the most important findings about
slightly favored ATT). Despite a greater mean reduction this relationship? Do the overall AGIS data
in IOP with the TAT sequence, black patients experi- suggest that diabetic patients are more
enced more rapid visual field deterioration with this likely to have trabeculectomy failure or just
sequence compared with ATT. The average visual field overall treatment failure? Should glaucoma
defect score actually improved in black patients with the specialists tell diabetic patients that it might
ATT sequence during the first 30 months of follow-up. be hard to control their glaucoma?
Black patients had a higher rate of failure with filtra- AGIS 7 evaluated the relationship between IOP and
tion surgery than did white patients. The reasons for visual field progression over 6 or more years.11 The
this finding are likely multifactorial, but one impor- investigators found with post hoc analysis that eyes with
tant consideration is that an antifibrotic agent was an early average IOP greater than 17.5 mm Hg had sig-
used in only 0.5% of primary filtering surgeries in the nificant worsening of visual field progression compared
AGIS.7 Broadway et al8 obtained conjunctival biopsies with eyes that had an IOP of less than 14 mm Hg. This
at the time of filtration surgery from 90 patients with difference was even more pronounced after 7 or more
glaucoma; 45 patients were black, and 45 were white. years of follow-up compared with 2 years. Furthermore,
Conjunctiva from black patients was found to con- eyes observed at 100% of follow-up visits to have an
tain a greater number of macrophages and a smaller IOP of less than 18 mm Hg over 6 years had little to no
number of both mast and goblet cells compared with change in visual field progression, whereas eyes with an
that of white patients. There was a tendency for the IOP of less than 18 mm Hg at fewer than 50% of visits
conjunctiva from black patients to contain more fibro- had significant field deterioration. This difference was
blasts. A greater number of conjunctival macrophages worse after 7 or more years of follow-up compared with
and possibly fibroblasts in black patients may partially 2 years.
explain the tendency for a lower success rate with fil- Eyes with an IOP of 17.5 mm Hg or greater had a
tration surgery in this group of patients. higher prevalence of diabetes compared with those

22 GLAUCOMA TODAY MAY/JUNE 2013

that had an IOP between 14 and 17.5 mm Hg or
14 mm Hg and lower. Black patients were more likely to
have diabetes compared with white patients.4 Diabetic
patients did not have a significantly higher rate of bleb
encapsulation,9 and diabetes was an independent risk
factor for cataract progression.12
AGIS 11 reported on the association between pre- and
postintervention risk factors for treatment failure with
trabeculectomy or ALT. Diabetes was associated with
an almost threefold risk of trabeculectomy failure as a
first or second intervention but not with ALT failure.13
Although these results are compelling, they must be
interpreted with caution for several important reasons.
First, numerous advances have been made in trabeculec-
tomy surgery since the study, including the increased use
of releasable sutures, suture lysis, and antifibrotic agents.
For example, as mentioned earlier, antifibrotics were used
in 0.5% of trabeculectomies as an initial intervention in
AGIS and increased to 90% when it was used as the third
intervention.7 Second, the investigators stratified diabetic
patients into an “either/or” category; the disease and its
influence on glaucoma is likely more complicated than
this distinction. Regardless, patients with diabetes need
special consideration, and given these and other data, it
is not unreasonable to counsel these patients about the
difficulties of managing their
glaucoma.

AGIS 9 reemphasizes that, when medical

therapy fails to control glaucoma, black
patients are better off starting with ALT
therapy and white patients are better off
starting with trabeculectomy. Have these
data changed the way you manage patients?
Do you think adjunctive antifibrotic therapy
would improve the results of filtration sur-
gery in blacks?
AGIS 9 evaluated treatment outcomes in black versus
white patients up to database closure (between 7 and
11 years after enrollment). The investigators found the
first intervention failed significantly less often in black
patients compared with white patients who underwent
the ATT sequence. Black patients had a significantly
higher rate of failure, an IOP equal to or greater than
18 mm Hg, and a decline in visual field progression than
white patients who underwent the TAT sequence.14
What this report does not discuss is the rate of compli-
cations associated with trabeculectomy as the initial sur-
gical procedure. Given the invasive nature of trabeculec-
tomy and its associated complications, we do not recom-
mend trabeculectomy as a surgical option for either black
or white patients before laser trabeculoplasty is offered.
LANDMARK STUDIES

One of the disadvantages of the AGIS is the limited use rarely forgetting to take their medications, other
of antifibrotic agents during trabeculectomy, particularly research has found that patients often greatly exagger-
as a primary intervention. The extended use of these ate compliance.16
agents has been associated with better results in black
patients15 and is largely the standard of care in our What is the take-home message from this
practice. landmark study?
Surgeons need to collate countless variables when
Thirty percent of black patients who had tailoring individualized treatment for patients with
laser therapy first required a second inter- advanced glaucoma. Two important messages from the
vention, and only 18% required a second AGIS are worth particular consideration: (1) disparate
intervention with a trabeculectomy first. Yet, treatment outcomes are associated with race, and (2)
the AGIS’ analysis supports laser treatment regardless of treatment modality, lower IOP is associ-
first. Why is this? ated with slower visual field progression. n
AGIS 9 reported on 9 years of follow-up with the
intent of determining whether the treatment-specific Section Editor Ronald L. Fellman, MD, is a glaucoma
clinical course of advanced glaucoma differed between specialist at Glaucoma Associates of Texas in Dallas and
black and white patients. Due to the numerous tests of clinical associate professor emeritus in the Department
statistical significance used in the study, the investiga- of Ophthalmology at UT Southwestern Medical Center in
tors considered P < .01 significant and values between Dallas. Dr. Fellman may be reached at (214) 360-0000;
.01 and .05 to be of borderline significance. The eyes of [email protected].
black patients had lower failure rates with initial ALT Leon W. Herndon, MD, is an associate pro-
and higher failure rates with initial trabeculectomy com- fessor of ophthalmology at the Duke University
pared with white eyes, which was of borderline signifi- Eye Center in Durham, North Carolina.
cance. Specifically, 30% of black patients’ eyes and 39% Dr. Herndon may be reached at
of white patients’ eyes underwent a second interven- (919) 684-6622; [email protected].
tion in the ATT sequence compared with 18% of black Daniel B. Moore, MD, is a clinical associate
patients’ eyes and 13% of white patients’ eyes in the TAT at the Duke University Eye Center in Durham,
sequence.14 Based on these data alone, black patients North Carolina. Dr. Moore may be reached at
had a lower rate of failure than did white patients with [email protected].
ALT first, but this finding seems less convincing when the
rate of failure between the two primary interventions in 1. Grant WM, Burke JF Jr. Why do people go blind from glaucoma? Ophthalmology. 1982;89:991-998.
2. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 1. Study design and methods and baseline
black patients’ eyes are compared. characteristics of study patients. Control Clin Trials. 1994;15:299-325.
The investigators argue that their data support ALT 3. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 9. Comparison of glaucoma outcomes in
black and white patients within treatment groups. Am J Ophthalmol. 2001;132:311-320.
first in black patients’ eyes based on several additional 4. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 3. Baseline characteristics of black and white
measures. The researchers determined that the odds of patients. Ophthalmology. 1998;105:1137-1145.
achieving an IOP of less than 18 mm Hg was borderline 5. Prata TS, De Moraes GC, Teng CC, et al. Factors affecting rates of visual field progression in glaucoma patients with optic
disc hemorrhage. Ophthalmology. 2010;117:24-29.
significant and that the risk of visual field loss was signifi- 6. Diehl DL, Quigley HA, Miller NR, et al. Prevalence and significance of optic disc hemorrhage in a longitudinal study of
cantly greater in blacks compared with whites in the TAT glaucoma. Arch Ophthalmol. 1990;108:545-550.
sequence. There was also a trend for a sustained decline in 7. Beck AD. Review of recent publications of the Advanced Glaucoma Intervention Study. Curr Opin Ophthalmol.
2003;14:83-85.
visual field and visual acuity in black patients compared to 8. Broadway D, Grierson I, Hitchings R. Racial differences in the results of glaucoma filtration surgery: are racial differences in
white patients in the TAT sequence, but this did not reach the conjunctival cell profile important? Br J Ophthalmol. 1994;78(6):466-475.
statistical significance. Taken as a whole, the investigators 9. Schwartz AL, Van Veldhuisen PC, Gaasterland DE; the AGIS Investigators. The Advanced Glaucoma Intervention Study
(AGIS): 5. Encapsulated bleb after initial trabeculectomy. Am J Ophthalmol. 1999;127:8-19.
state the TAT sequence is worse for black patients than 10. Wimmer I, Weige-Luessen U, Picht G, Grehn F. Influence of argon laser trabeculoplasty on transforming growth factor-
white patients, and the researchers suggest ALT first in beta 2 concentration and bleb scarring following trabeculectomy. Graefes Arch Clin Exp Ophthalmol. 2003;631-636.
11. The AGIS Investigators. The Advanced Glaucoma Intervention study (AGIS): 7. The relationship between control of
black patients. intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130:429-440.
An additional important finding of AGIS 9 was a 12. The AGIS Investigators. The Advanced Glaucoma Intervention Study: 8. Risk of cataract formation after trabeculectomy.
significantly greater number of prescribed medications Arch Ophthalmol. 2001;119:1771-1780.
13. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 11. Risk factors for failure of trabeculectomy
for black patients in both the ATT and TAT sequences and argon laser trabeculoplasty. Am J Ophthalmol. 2002;134:481-498.
compared with white patients. The investigators 14. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 9. Comparison of glaucoma outcomes in
acknowledged that different rates of compliance might black and white patients within treatment groups. Am J Ophthalmol. 2001;132:311-320.
15. Shin DH, Hughes BA, Song MS, et al. Primary glaucoma triple procedure with or without adjunctive mitomycin.
contribute to the race-specific outcomes. Although Prognostic factors for filtration failure. Ophthalmology. 1996;103:1925-1933.
almost 90% of enrolled AGIS patients self-reported 16. Kass MA, Gordon M, Morley RE, et al. Compliance with topical timolol treatment. Am J Ophthalmol. 1987;103:108-193.

24 GLAUCOMA TODAY MAY/JUNE 2013