The advanced glaucoma intervention study (AGIS): 4. comparison of treatment outcomes within race

The Advanced Glaucoma Intervention Study (AGIS): 4. Comparison of Treatment Outcomes within Race Seven-year Results The AGIS

Investigators”

Objective: The purpose of this report is to present separately for black and white patients with advanced glaucoma 7-year results of two alternative surgical intervention sequences. Design: A randomized controlled trial. A total of 332 black patients (451 eyes), 249 white patients (325 eyes), and IO patients of other Participants: races (13 eyes) participated. Potential follow-up ranged from 4 to 7 years. Intervention: Eyes were randomly assigned to either an argon laser trabeculoplasty (ALT)-trabeculectomytrabeculectomy (ATT) sequence or a trabeculectomy-ALT-trabeculectomy (TAT) sequence. The second and third interventions were offered after failure of the first and second interventions, respectively. Main Outcome Measures: Average percent of eyes with decrease of visual field (APDVF), average percent of eyes with decrease of visual acuity (APDVA), and average percent of eyes with decrease of vision (APDV) are the outcome measures. Decrease of visual field (DVF) is an increase from baseline of at least 4 points on a glaucoma visual field defect scale ranging from 0 to 20, decrease of visual acuity (DVA) is a decrease from baseline of at least 15 letters (3 lines), and decrease of vision (Dv) is the occurrence of either DVF or DVA. The averages are of percent decreases observed at 6-month intervals from the first 6-month visit to the end of the specified observation period. In both black and white patients throughout 7-year follow-up, the mean decrease in intraocular pressure Results: was greater in eyes assigned to TAT, and the cumulative probability of failure of the first intervention was greater in eyes assigned to ATT. In black patients, APDVF, APDVA, and APDV are less for the ATT sequence than for the TAT sequence throughout the 7 years. In white patients, APDVF also favors the ATT sequence but only for the first year, after which it favors the TAT sequence through the seventh year; APDVA also favors the ATT sequence, but the ATT-TAT difference progressively diminishes over 7 years; and APDV favors ATT over TAT initially, but after 4 years, the advantage switches to and remains with TAT. Conclusions: These data support use of the ATT sequence for all black patients. For white patients without life-threatening health problems, the data support use of the TAT sequence. Ophthalmology 7998; 705: 7 746- 7 764

The current standard of management for newly diagnosed open-angle glaucoma in the United States is to start with medical treatment aimed at reducing intraocular pressure (IOP) below the level associated with optic nerve damOriginally Revision

recetved: September 17, 1997. accepted: December 3 1, 1997.

* The writing team for this report is Douglas E. Gaasterland, MD, Fred Ederer, MA, FACE, E. Kenneth Sullivan, PhD, Paul C. VanVeldhuisen, MS, M. Angela Vela, MD, and Howard Weiss, MD. Members of the Advanced Glaucoma Intervention Study are listed m the Appendtx at the end of this article. Supported by grants from the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services (grants 2 UlO EY06824 through 2 UlO EY06827, 2 UlO EY06830 through 2 UlO EY06835, 2 UlO EY07057, and 7 UlOEY09640). Reprint requests to Douglas E. Gaasterland, MD, University Consultants of Washington, 4910 Massachusetts Avenue, 210; Washington, DC 20016.

1146

Ophthalmtc NW; Suite

age.‘.2 Although some have endorsed surgical alternatives,‘-5 a medical approach is used in the United States for most newly diagnosed patients.’ When, despite progressive escalation of medical treatment, adequate control of IOP is not maintained, the physician recommends surgical intervention, usually laser trabeculoplasty. If the first surgical intervention, even after added medical therapy, fails to control the disease, a second intervention-usually trabeculectomy-is offered; if the second intervention fails despite added medical therapy, a third intervention is offered, and so on. The Advanced Glaucoma Intervention Study (AGIS) was started in 1988 to remedy a deficiency of information regarding progression of glaucoma after medical therapy fails. AGIS is a long-term study of the clinical course and outcomes after surgical therapy for patients with no previous invasive or laser trabecular ocular surgery, who have open-angle glaucoma that is inadequately controlled

The AGIS Investigators

* AGIS

Glaucoma

by medications. We call this stage of the disease “advanced glaucoma.” In addition to clarifying the course of the disease, AGIS was designed to answer questions about advanced glaucoma management, including: 1. How effective in preserving vision are two alternative, randomly assigned, surgical intervention strategies? 2. What are the early and late complication

rates of

glaucoma surgery? 3. Can factors that predict outcome be identified to help the ophthalmologist in planning treatment for the patient?

This is the initial report of AGIS results, with observations through December 31, 1996, and potential followup ranging from 4 to 7 years. Longer term results will be

presented in future communications. Unexpected findings of statistically significant interactions between race and assigned intervention sequence with respect to treatment failure and the major AGIS

visual function outcome variables have prompted us to present the data in this report separately for black and white patients. These divergent results-discovered in the process of analyzing the 7-year results presented in this article, long after patient recruitment and initial interventions were completed-lead to different surgical treatment recommendations advanced glaucoma.

Materials

for black and white patients with

and Methods

The AGIS study design and methods, described in detail elsewhere,617are summarized here. Informed consent was obtained from all enrolled patients, and appropriate institutional review boards approved the AGIS protocol. A principal feature of AGIS is the randomized comparison of two three-step sequences of surgical treatments. In one sequence, designated ATT, the first intervention, argon laser trabeculoplasty (ALT), is followed by trabeculectomy should ALT fail and by a second trabeculectomy (with adjunctive antifibrotic) should the first trabeculectomy fail. In the other sequence, designated TAT, the initial intervention, trabeculectomy, is followed by ALT should the trabeculectomy fail and by a second trabeculectomy (with adjunctive antifibrotic) should the ALT fail. In both sequences, the managing ophthalmologist prescribes glaucoma medical treatment to supplement surgery as appropriate. Management subsequent to failure of the third intervention is left to the discretion of the ophthalmologist. From April 1988 through November 1992, investigators at 11 participating AGIS clinical centers enrolled 789 eyes of 591 patients and randomly assigned the eyes to 1 of the 2 intervention sequences: ATT or TAT. There are 249 white patients (325 eyes), 332 black patients (451 eyes), and 10 patients of other races (13 eyes).

Treatment

Outcomes

within Race

iridotomy. Advanced glaucoma is defined as glaucoma that can no longer be controlled adequately by medications alone in the presence of some glaucomatous visual field loss. Eyes had to be receiving maximum medical therapy (i.e., maximum effective, accepted, and tolerated glaucoma medical treatment), which required that unless contraindicated, not effective, or not accepted by the patient, medications must have been prescribed from each of three groups: miotic or prostaglandin analogue, beta blocker or epinephrine derivative, and carbonic anhydrase inhibitor. Before a medication can be considered not effective or not acceptable, the eye or (in the case of a systemic medication) the patient must be challenged with the medication. Eyes had to meet at least one of nine specified combinations of criteria for consistently elevated IOP, visual field defect due to glaucoma, and optic disc rim deterioration6.* A brief summary of these criteria follows: IOP of 18 mmHg or greater with confirmed optic disc or visual held deterioration, or IOP of 21 mmHg or greater with sufficient, specified visual field defect. The minimum required glaucomatous visual field defect was moderate for eyes with IOP in the low 20s and mild for eyes with IOP of greater than 23. Eligibility based on disease deterioration required, while the eye was continuously receiving maximal medical therapy, a confirmed increase of the glaucoma visual field defect score or documented optic disc deterioration. Eyes had to have a visual acuity score of at least 56 (Snellen equivalent better than 20/80). If both eyes of a patient were eligible, both could be enrolled, but they had to be enrolled simultaneously. When both eyes were eligible, the ophthalmologist specified, before the treatment assignment was issued, the eye to be treated first, which then was randomly assigned to ATT or TAT; the fellow eye was assigned to the other sequence. Glaucoma

Surgical

Treatments

According to study protocol, trabeculectomy” is performed in an operating room with the use of an operating microscope after local or general anesthesia and with the upper nasal quadrant the preferred surgical site and the upper temporal quadrant the next choice. Standard postoperative management is used, including laser suture lysis”’ or releasable sutures” if needed. Since 1993, adjunctive antifibrotic treatment (mitomycin C or 5fluorouracil) has been required for the second trabeculectomy and the first trabeculectomy after previous cataract surgery. Antifibrotic treatment is disallowed for the first trabeculectomy, but exceptions may be approved when the fellow eye has failed a trabeculectomy. Trabeculoplasty is performed in two sessions, 1 to 6 weeks apart. In each session, half the trabecular meshwork is treated with approximately 50 laser applications evenly distributed over 180” of the meshwork in a clockwise fashion, starting at the 6 o’clock meridian in the first session and at the 12-o’clock meridian in the second session. When ALT is the second operation in the sequence, the treatment may be limited by the presence of peripheral anterior synechiae: if the treatable part of the circumference is reduced to less than 240” by peripheral anterior synechiae, ALT is completed in one session; if the treatable circumference is reduced to less than 90” or if ALT is otherwise contraindicated, the procedure is abandoned, and the eye is treated with the third assigned operation, trabeculectomy.

Eligibility To be eligible for the study, patients had to be 35 to 80 years old, and eyes had to have either “advanced” primary openangle glaucoma without previous surgery or “advanced” openangle glaucoma in a phakic eye 4 weeks or more after laser

Cataract

Surgery

Cataract surgery may be performed if the visual defect is ascribed to cataract, the defect is adversely affecting the patient’s lifestyle, and the visual acuity score is less than 65 (Snellen

1147

Ophthalmology

Volume 10.5, Number

equivalent 20150). Cataract operations are not authorized (1) in the interval between the occurrences of treatment failure and the next assigned glaucoma intervention, (2) in the interval between the occurrences of an assigned glaucoma intervention and the next scheduled 3- or 6-month visit, or (3) less than 3 months after the occurrence of an assigned glaucoma intervention. Patients requiring cataract surgery receive conventional cataract surgery without combined trabeculectomy if the IOP has been consistently 17 mmHg or less since the most recent glaucoma intervention, no glaucoma medications currently are prescribed, and the most recent visual field defect score is less than 10. If these three requirements are not met, either conventional cataract surgery or a combined cataract-trabeculectomy procedure may be performed. Cataract operations in general, and combined procedures in particular, are limited to eyes with contrulled glaucoma, unless the study’s Operations Committee has approved a protocol exception for an eye with intervention failure. In AGIS, the intent of allowing a trabeculectomy as part of a cataract operation is to protect against damage from early postoperative pressure spikes in eyes with glaucoma controlled by medical and previous surgical management. A trabeculectomy that is part of a combined procedure is not counted as a step in an AGIS intervention sequence. Antifibrotic treatment is disallowed for conventional cataract surgery and optional for combined procedures.

Failure of Surgical Treatment Glaucoma

to Control

Two kinds of failure of surgical glaucoma treatment, early and late, are defined in AGIS. Early failure occurs within 6 weeks after the first or second session of ALT, or within 6 weeks after trabeculectomy. The occurrence of early failure is determined according to study guidelines7 that involve magnitude of IOP elevation, duration of elevation, amount of visual field loss, amount and type of deterioration of disc rim, and evidence that the IOP elevation has caused, or is likely to cause, additional ocular damage. Late treatment failure, occurring 6 weeks or more after the most recent glaucoma operation, is defined by essentially the same glaucoma criteria as study eligibility (presented above): maximum medical therapy, IOP, glaucoma visual field defect, and optic disc rim deterioration. For late treatment failure due to glaucomatous visual field deterioration or optic disc deterioration, the documented deterioration must be measured from the first examination after the most recent glaucoma intervention at which the eye was on-and since which it has continuously been on-maximum medical therapy.

Study Measurements The following measurements were made at baseline and at all AGIS follow-up visits. Visual Field. Visual field tests are conducted with a Humphrey Visual Field Analyzer I equipped with Statpac 2 software (Zeiss Humphrey Systems, San Leandro, CA) and set for the central 24-2 threshold test, size III white stimulus, and fullthreshold strategy, with the fovea1 threshold test turned on. When visual acuity is insufficient to count fingers at 30 cm or if the visual field test is terminated because of an ocular-related defect, the visual field defect score is recorded as 20. Visual field defect scores range from 0 (no defect) to 20 (end-stage).“.” Visual Acuity. The AGIS refraction and visual acuity examination protocol is essentially that of the Early Treatment Diabetic Retinopathy Study6.“,‘4 with testing distance at 4 m and

1148

7, July 1998

a rear-lighted box replacing the Early Treatment Diabetic Retinopathy Study front-lighted box.” Visual acuity scores range from 0 (a Snellen score of approximately 20/1000) to 100 (approximately 20/10). A score of 85 is approximately 20/20. Intraocular Pressure. Intraocular pressure is measured with a Goldmann applanation tonometer on a slit-lamp biomicroscope. The IOP measurement, after topical anesthesia and fluorescein, is performed, when feasible, by two persons: an operator and a reader. The reading in millimeters of mercury (mmHg) is rounded to the next higher integer. Each measurement is repeated, and if the two measurements differ by 3 mmHg or more, a third measurement is taken. The median of the two or three measurements becomes the IOP determination.

Reference Baseline Values Intraocular pressure and visual field measurements are subject to wide fluctuations. To lessen the effects of regression to and from the mean’” caused by the restriction in range by upper and lower limits of eligibility values, additional baseline “reference” measurements of IOP and visual field were taken at least 1 day after the eligibility measurements but before the initial glaucoma surgery was performed.6 The reference values were not constrained, as were the eligibility values, by imposed upper or lower limits. Changes from baseline in IOP and visual field defect score are measured from the reference values.

Data Collection, Patient Status, and Analysis Data Set The AGIS follow-up visits occur 3 months after randomization, 6 months after randomization, and every 6 months thereafter. In addition, study patients are examined as often as necessary at the discretion of the treating physician. Living study patients are assigned to active or inactive status. Inactive patients have missed the two most recent consecutive 6-month visits, with inactive status beginning at the second missed visit. All other patients are active. When inactive patients return for a subsequent scheduled visit, they become active. The database was closed for the current analysis on December 3 1, 1996. Data for the ten patients who were neither black nor white have been excluded from this report.

Response Variables Visual function (i.e., visual field and visual acuity) is the most important AGIS outcome. In defining the visual function outcome variables, we use the following three events: Decrease of Visual Field (DVF). This is the occurrence in an eye at a 6-month follow-up visit of an increase (worsening) in visual field defect score of 4 or more points from the preintervention baseline reference value. This happens spontaneously because of long-term fluctuation in less than 5% of repeat tests.x Decrease of Visual Acuity (DVA). This is the occurrence in an eye at a 6-month follow-up visit of a decrease (worsening) in visual acuity score of 15 or more letters (3 or more lines on the visual acuity chart) from the preintervention baseline reference value. This loss amounts to a doubling of the visual angle. Decrease of Vision (DV). This is the occurrence in an eye at a 6-month follow-up visit of a DVF or DVA or both. The main visual function outcome variables are defined as follows: Percent of Eyes with Decrease of Vision (PDV). This is the

The AGE

investigators

* AGIS

Glaucoma

percent of eyes at a 6-month follow-up visit for which a DV was observed.Similarly, PDVF and PDVA are the percentof eyesfor which, respectively,a DVF or DVA was observed. Average (APDV).

Percent

of

Eyes

with

Decrease

of

Treatment

Outcomes

within

Race

Table 1. BaselineCharacteristicsof Black and Patients

White

AGIS

and of Their Eyes, by Treatment Assignment (ATT or TAT)

Vision

This is the averageof the PDVS at each 6-month follow-up visit up to and including a specified6-monthfollowup visit. The average percent of eyes with decrease of visual field (APDVF) and the average percent qf eyes with decrease of visual acuity (APDVA) arethe corresponding averagepercent decreasestatisticsof PDVF and PDVA, respectively. Each of thesevariables,in that it is an average,representsthe decrease of vision experienceaccumulatedover the entire interval from the beginningof follow-up through the specifiedvisit. Two other important outcomevariablesare defined asfollows: Sustained Decrease of Vision (SDV). This is the occurrence in aneyeof a DV at threeconsecutive6-monthfollow-up visits. SDVF and SDVA, respectively, are the correspondingoccurrencesof DVF and DVA at three consecutive6-month followup visits. The sustainedevents SDV, SDVF, and SDVA occur at their consummation(i.e., at the third consecutive6-month follow-up visit at which a DV, DVF, or DVA, respectively,was observed).The earliestthat theseeventscan occur is at the 18monthvisit. Time to Intervention Failure. Time to failure of theassigned initial interventionis measured from the dateof randomization.” For the assignedsecond and third surgicaltreatments,time to failure is measuredfrom the date of surgery.

Characteristics of Patients and Eyes

Black Patients

White Patients

Patients No. enrolled Women (o/o) Under age 65 (%) Married (‘S) Completed high school (%) With systemic hypertension With diabetes (‘XI)

332 59 42 44 51 60 27

249 48 35 66 78 39 12

(%)

Eyes No. enrolled Eyes of female patients (‘XI) Mean intraocular pressure (ml&s) Mean visual field defect Mean deviation (dB) Disc notching, to edge (%) Disc notchmg, not to edge (‘31) DISC hemorrhage on txn tissue (%) Mean wsual acmty score Visual acwty score 270 (%) [Snellen cqmvalent 20/40] Mean no. of prescribed glaucoma mcdicattons

ATT

TAT

ATT

TAT

240 61.0

211 60.0

158 52.0

167 49.0

23.7 9.2 11.1 20.0 14.0

23.7 9.2 11.5 23.0 11.0

24.1 7.8 9.7 31.0 5.0

24.8 7.3 9.1 28.0 8.0

1.0 79.7

1.0 78.5

7z

3.0 80.2

89.2

82.0

85.4

880

2.8

2.8

2.5

2.5

Statistical Methods For eye characteristics,the unit of analysiswasthe eye rather thanthepatient.Methodsof statisticalinference(i.e., confidence intervalsand testsof significance)have taken into accountthe positive correlationbetweenpairedeyes(of a singlepatient) as describedbelow. In light of the multiplicity of testsperformed, we usea level of P lessthan 0.01 to designatestatisticalsignificance. For continuousoutcomes(i.e., changefrom baselinein IOP, visual field defect score,and visual acuity score),we usedthe estimatedcorrelationcoefficient for changefrom baselinebetweenpairedeyesto adjustthe estimateof the variancebetween treatmentgroupmeandifferences.We useda chi-squarestatistic that is a hybrid of the McNemar chi-squarestatisticfor paired dataandthe Pearsonchi-squarestatisticfor independentobservations17to take into account the correlation betweenpaired eyes in the percent decreaseof vision (PDV) variablesand a permutationtest” to test for groupdifferencesamongthe averagepercentdecreaseof vision (APDV) variables.We usedthe methodsof Wei, Lin, and Weissfeld’”to take into accountthe paired-eyecorrelationin analyzing the censoredresponsevariablesSDVF, SDVA, SDV, and the initial intervention failure. When the actual date of the event was known (e.g., cataract surgery,patient death),we usedproduct-limit estimates;otherwise, we usedlife-table estimateswith 6-month risk periods correspondingto the patientfollow-up visit schedule. Tests of statistical interaction between assignedtreatment group and racewere performedfor two types of responsevariables: the average of repeated binary responsevariables (APDVF, APDVA, APDV) and censored variables (SDVF, SDVA, SDV, and failure of initial treatment). A permutation test,‘” without covariate adjustments,wasusedfor the average of repeatedbinary variables.Cox regressionmodels,‘9~2” adjusted for selectedbaselinecovariables,were usedto test the treatmentgroup-race interactionfor the censoredvariables.

We pursuedother potential explanationsof the significant treatment-race interaction by including additional interaction termsin theCox regressionmodelsfor sustainedvision decrease and failure of initial intervention. Gender, age at enrollment, presenceof diabetesor hypertension,and sphericalequivalent wereeachintroducedin the regressionmodelsaspotentialinteractingfactorswith interventionsequenceassignment. Statistical adjustmentfor theseterms had little effect on the statistical significanceof the treatment-raceinteraction.

Results Baseline Characteristics Table 1presentssomepersonalandocularbaselinecharacteristics for the 332 black patients(451 eyes) and the 249 white AGIS patients(325 eyes). The black patients,comparedwith the white patients,were morelikely to be female,youngerthan 65 years of age, unmarried,have systemichypertension,and have diabetes.They were lesslikely to have completedhigh school.Table 1 alsocontrastscharacteristicsof eyesrandomly assignedto the two intervention sequences:ALT-trabeculectomy-trabeculectomy (ATT) andtrabeculectomy-ALT-trabeculectomy (TAT). Within each race group, the characteristics of eyes assignedto the two intervention sequences generally are similar; Cox regressionanalysesshow that for blacks and whites, baselinedifferencesin age, gender,diabetes,and systemic hypertensionbetweenrandomizedsequences have no essential effect on the differences in sustainedvision decrease outcomesand failure of initial intervention outcomesreported in this article.

1149

Ophthalmology Table

2. No.

Volume 105, Number

of Inactwe

Patients

and Deaths,

7, July 1998

as of December

31, 1996 One Eye Enrolled

Both Eyes Enrolled

All Patients

Hack patlents All patients Llvmg Deaths All livmg pauents Active Inactive* White patients All panents Lwing Deaths All Iwmg patients Actwc InactIve* * Inactlvc

patients

o/o

N

96

N

%

N

%

332 285 47 285 251 34

100.0 85.8 14.2 100.0 88.1 11.9

119 98 21 98 88 10

100.0 82.4 17.6 100.0 89.8 10.2

121 104 17 104 90 14

100.0 86.0 14.0 100.0 86.5 13.5

92 83 9 83 73 10

100.0 90.2 9.8 100.0 88.0 12.0

249 220 29 220 196 24

100.0 88.4 11.6 100.0 89.1 10.9

76 61 15 61 54 7

100.0 80.3 19.7 100.0 88.5 11.5

82 74 8 74 66 8

100.0 90.2 9.8 100.0 89.2 10.8

91 85 6 85 76 9

100.0 93.4 6.6 100.0 89.4 10.6

are those who missed their

last two scheduled

6-month

study vlslts

those assigned to TAT

P Obtained

Intervention

by Permutation

(mos) ii 36 48 60 72 84

Failures

Intervention failure is failure to control the glaucoma despite surgical intervention and subsequent maximum medical treatment; it does not necessarily involve additional loss of vision. There have been 125 failures (28%) of initial interventions in black patients and 85 (26%) in white patients. For both groups, the rates of first intervention failure are significantly greater in the ATT sequence (i.e., ALT failures) than in the TAT sequence (i.e., trabeculectomy failures) (Fig I). At 5 years, the difference is 13 percentage points for black patients (0.345 for ATT, 0.2 13 for TAT) compared with 28 percentage points for white patients (0.406 for ATT, 0.131 for TAT). So far, after the failed first intervention in the sequence,

Tests for (1) APDV, f or F al‘1ure of AssIgned

Test*

APDVF, Initial

I’ Obtained

“Awerage Percent wrth Decrease” Vmubfe~

Follow-up visit

Treatment-Race Interaction SDVF, and SDVA, and (3)

between black and white pa-

as follows (Table 3): APDVF at 48, 60, 72, and 84 months; APDVA at 24 and 72 months; APDV at 24, 36,48, 60, 72, and 84 months; SDV, SDVF, and SDVA; and rate of failure of assigned initial intervention.

Interactions between race and treatment indicate that the difference in treatment outcomes between eyes assigned to ATT and

of [Black-White] for SDV,

differed

tients. Testsfor interactionwere significantat P less than 0.01

Race Interactions

3. Results

TAT

N

As of database closure for this analysis, December 3 1, 1996, 4 years had elapsed since 100% of the patients were enrolled, 5 years since 84% were enrolled, 6 years since 67% were enrolled, and 7 years since 45% were enrolled. Approximately 14% of the black patients and 12% of the white patients had died by December 31, 1996. On this date, 12% of the living black patients and 11% of the living white patients were inactive (Table 2). The percentages of patients at 48, 60, 72, and 84 months after enrollment were 7.5% (40 of 435), 9.7% (42 of 434), 11.5% (38 of 330), and 13.5% (28 of 20X), respectively. The death rate was higher in patients with both eyes enrolled than in patients with one eye enrolled, even after adjustment for race, age, gender, hypertension, and diabetes (P = 0.03). Among patients with one eye enrolled, the death rate was higher, but not significantly so, for those assigned to ATT than for those assigned to TAT.

Table

ATT

“Swturned

and APDVA Intervention

from Cox Proportional Dccrense”

by Follow-up

Hazards

Varrables

APDV

APDVF

AI’DVA

Adjustment

SDV

SDVF

SDVA

0.3564 0.0084 0.0060 0.0052 0.0024 0.0012 0.0024

0.4516 0.0252 0.0104 0.0040 0.0012 0.0000 0.0008

0.2832 0.0068 0.0196 0.0336 0.0128 0.0048 0.0268

Unadlusted Adlusted?

0.0036 0.0019

0.0007 0.0014

0.0320 0.0091

Time,

Regression Fdure

lnirial

(2)

of

lnterPienrron

0.0019 0.0012

* 2500 permutations t Adjustment score.

1150

was made for SLX baseline

variables:

age, gender,

presence of hypertension,

presence

of dmbeces, waual field defect score, and wwal

acurry

The AGE Inoestigutors * AGIS Glaucoma Treatment Outcomes within Race 0.6

Black Patients

White Patients

I

0.5

0.5

1

..... . ;z 2 2 o.4 ifi I-

....... qz 0.4

J

8 c 0.37 iii 2 & 0.2CL

--A

/

I-

0.3 i””

,.---. I , . . . . .

0.2

0.1 -

.- . . . . -.-.. . ..A

0.1 . . . ..----

o.o-l’m 0

’ 12

1

’ 24

’

1 36

’

FOLLOWUP Figure 1. Cumulative probabihty < 0.001) for white patients.

’ 40

1

’ 60

’

’ 72

’

’ 04

I

0.0 0

12

MONTH

of fadurc

of awgned

mwal

mterventmn.

Adjusted

chi-square

36 FOLLOWUP

Figure

2. Mean

change from baseline

40

60

72

84

0

MONTH m mtraocular

I1

equals 7.2 (P = 0.007)

standard

I,

1

60

72

I,

04

MONTH for black

patwnts

amI

32.2

(I’

12

ATT TAT

24

36 FOLLOWUP

pressure (t2

I

40

------------_______----------------------------------. White Patients

‘.“” ‘.’

24

I

36

of 47) in TAT; white patients, 9% (6 of 64) in ATT and 19% (4 of 21) in TAT. In 20 cases (15 in blacks and 5 in whites), there was a medical contraindication (e.g., excessive peripheral anterior synechiae involvement precluded ALT). In 18 cases (14 in blacks and 4 in whites), the patient

---------_________-_____________________---------Black Patients

12

I

,-----

FOLLOWUP

there have been 96 second assigned interventions in black patients and 75 in white patients. Approximately 18% (38 of 210) of eyes with a failed initial glaucoma intervention have not received the assigned second intervention as follows: black patients, 22% (17 of 78) in ATT and 26% (12

0

24

i-” *

. ..--.

. . . . ..-.-e....

48

60

72

84

MONTH

errors).

J151

Ophthalmology

Volume

“1 0

8 24

12

0

“I 36

FOLLOWUP

u 46

1’ 60

7, July 1998

4

Black Patients

-2-1

10.5, Number

White Patients

1

‘1’ 72

-2’ 64

MONTH

0 0

11 12

“1 24

1 36

FOLLOWUP

Figure 3. Mean change from basehne m wsual field defect score (+2 standard errors). An tncrease mdtcates worsening

has refused additional surgical intervention. In 1 case, there was a clinic error. Failure rates are higher for second than for first interventions, and, as in the case of the first interventions, the rates are higher for ALT than for trabeculectomy in both race groups, although thus far not significantly so. There have been too few third interventions to allow a meaningful assessment of failure rates.

Intraocular

Pressure

In both black and white patients during the first 84 months of follow-up, the mean decrease in IOP from baseline is greater in eyes assigned to TAT than in those assigned to ATT (Fig 2). This treatment effect appears to be greater in white patients (averaging approximately 2 mmHg) than in black patients (averaging approximately 1 mmHg), with the effect in white patients being particularly large in the first year after the initial intervention (range, 3-4.5 mmHg).

Visual Field Defect Score In black patients, despite the greater mean IOP decrease (Fig 2), TAT eyes experienced a greater worsening of visual field than did ATT eyes (Fig 3); average visual field defect score even improved in ATT eyes during the first 30 months of follow-up, after which it worsened. In eyes of white patients, conversely, the mean visual field changes after the first 15 months are concordant with the pressure changes: the visual field worsening is less in eyes assigned to TAT (Fig 3), which experienced greater mean IOP decreases (Fig 2).

Visual Acuity

Score

Visual acuity progressively worsened over 84 months of followup in black and white patients, both in eyes assigned to ATT

1152

r 46

I

“1’

r 60

72

’ 04

MONTH of the wsual field.

and to TAT (Fig 4). In black patients, the worsening was consistently greater in eyes assigned to TAT just as it was for visual field. In white patients, the greater visual acuity worsening in TAT eyes occurred only during the first 48 months; thereafter, the worsening was greater in ATT eyes. The pattern for change in mean visual acuity in white patients is also similar to that for visual field, except that the crossover for visual acuity changes occurs later (at 48 months) than for visual field changes (at 15 months).

Average Percent of Eyes with Decrease of Visual Field, Visual Acuity, and Vision We remind the reader that unlike the percent decrease of vision statistics PDVF, PDVA, and PDV, which are measures of decrease of vision at a specified follow-up time, the average percent decrease of vision statistics APDVF, APDVA, and APDV provide the average decrease of vision experience from the beginning of follow-up to the specified time (e.g., 84 months). The outcomes for the variable APDVF, as indicated by the significant treatment-race interaction (Table 3), are different in black and white patients (Table 4, Fig 5). In black patients, APDVF is less for the ATT sequence than for the TAT sequence at all follow-up visits. Although none of the seven probability values in Table 4 reach the 0.01 level, the first four values range between 0.01 and 0.05. In white patients, APDVF also favors the ATT sequence, but only for the first year; thereafter, this statistic favors TAT by a progressively increasing margin (from 2-9 percentage points), with the differences significant at 6 and 7 years (Table 4). For black patients, APDVA (Table 5, Fig 6) favors the ATT sequence even more strongly than did the corresponding visual field statistic. The differences between ATT and TAT in APDVA, all significant at P less than 0.0 1, range from 10.6

The AGIS Investigators * AGIS Glaucoma Treatment Outcomes within Race Black

5

Patients

White

Patients

-5

-10 -

ATT TAT

-15

t

l-

24

12

0

36 FOLLOWUP

Figure

4. Mean

48

60

72

-20

84

1

0

12

MONTH

24

36

48

FOLLOWUP

change from hasehne in visual acuity SCOW (t2

standard

to 14.0 percentage points; for white patients, APDVA also consistently favors ATT, although the ATT-TAT difference diminishes over time from IO. 1% at 6 months to 2.5% at 84 months; the differences are significant (P < 0.01) only for the first 2 years.

60

72

84

MONTH

errors).

With decrease q~vision (Dv) denoting a decrease of either visual field or visual acuity APDV for black patients, consonant with the visual field and visual acuity results, is greater for TAT than for ATT by an amount that is consistently large (range, 9.3%- 14.2%) and statistically significant (P < 0.01)

Table 4. Percent of Eyes with Decrease of Visual Field (PDVF) and A verage Percent of Eyes with Decrease of Visual Field (APDVF) Black

Scheduled

Visit

12 mos ATT TAT 24 ma ATT TAT 36 mos ATT TAT 48 mm ATT TAT 60 mos AT-ITAT 72 mos ATT TAT 84 mos ATT TAT * P ohtamed

White

Average %I with

No. of Eyes

% with Decreare of Vi& F&I (PDVF)

Decrease Of Visual Field (APDVF)

226 202

11.5 16.8

10.1 15.3

214 194

13.1 20.1

204 183

Patients

Average wth

%

P*

No. of Eyes

% with Decrease of Visual Field CPDVF)

-5.2

0.0432

152 163

10.5 13.5

10.7 13.0

11.5 17.4

-5.9

0.0148

139 156

15.1 10.9

13.5 11.8

1.7

0.5080

20.1 22.4

13.2 18.7

-5.5

0.0248

131 149

22.1 14.1

16.3 12.6

3.7

0.1632

186 173

18.8 23.1

14.6 199

-5.3

0.0300

127 145

30.7 21.4

19.5 13.9

56

0.0444

138 128

26.1 25.0

16.2 20.8

-4.6

0.0652

104 118

33.7 20.3

22.3 15.4

69

0.0124

96 91

27.1 28.6

17.8 22.3

-4.5

0.0916

82 97

40.2 23.7

25.3 16.7

8.5

0.0044

55 58

27.3 32.8

18.7 23.4

-4.6

0.0996

52 57

38.5 26.3

26.4 17.6

8.7

0.0060

and

Assigned Intervention Sequence

Patients

from a permutatmn

test comparing

Dtfference

in APDVF

ATT-TAT

the two mtetventmn

sequences

(2500 permutations).

;;;r;,e$

Difference

IAPDVF)

ATT-TAT

-2.4

m APDVF I’*

0 3964

Ophthalmology

Volume

105, Number 7, July 1998 50:

Black Patients

White Patients

45: 40:

25:

0

12

24

36

48

FOLLOWUP

60

72

04

0

12

24

MONTH

36

48

FOLLOWUP

60

72

64

MONTH

5. Average percent of eyeswtth decrease of mual field (APDVF).

Figure

through

7 years of follow-up

(Table 6, Fig 7). For white initially, but between 42 and 48 months, the two curves cross and the advantage shifts to, and remains with, TAT. None of the differences are statistically significant.

patients, APDV

Table

5. Percent

of Eyes with

Decrease

Black

Scheduled Visit and Assigned Intervention Sequence

12 mos ATT TAT

Sustained Decrease of Visual Field, Visual Acuity, and Vision

also favors ATT

of Visual

Acuity Acuity

In black patients, the cumulative probability of the event sustained decrease of visual field (SDVF), which, by defini(PDVA) (APDVA)

and

4.0

Percent

of Eyes with

White

Patients

Average % % wtth with Decrease Differencein Decreaseof of VISual APDVA Acuity No. of Visual Acuity Eyes (PDVA) (APDVA) A7’T-TAT P* 227

Average

% with Decreaseof

Decrease

of Visual

Patients

Average % wtth Decrease of Visual

No. of

VWUI~ Acuq

Acurty

Eyes

(PDVA)

(APDVA)

Dtfferencein APDVA ATT-TAT

P*

4.2

202

18.3

3.3 14.8

-11.5

0.0000

153 163

7.8 14.1

12.4

-8.2

0.0000

215 194

9.3 27.8

5.7 19.7

-14.0

0.0000

138 155

11.6 15.5

7.1 13.1

-6.0

0.0096

204 184

18.6 26.1

8.4 21.4

-12.8

0.0000

132 150

13.6 19.3

8.6 14.2

-5.6

0.0128

85 72

21.1

11.4 23.6

129

30.2

-12.2

0.0000

146

18.6 24.0

10.8 16.2

-5.4

0.0240

139 129

25.9 30.2

24.7

-11.3

0.0000

106 119

23.6 16.8

12.8 16.2

-3.4

0.1412

97 93

19.6 33.3

14.8 25.9

-11.1

0.0000

83 98

25.3 24.5

15.2 17.4

-2.2

0.3668

57 59

28.1 32.2

15.9 26.5

-10.6

0.0000

54 59

22.2 27.3

17.1 19.6

-2.5

0.3512

24 mos

ATT TAT 36 mos A-M-

TAT 48 mos

ATT TAT 60 mos

ATT TAT

13.5

72 mos

ATT TAT 84 mos

ATT TAT * P obtamed

1154

from a permutation

test comparing

the two interventmn

sequences (2500

permutauons).

The AGlS 50:

Investigators * AGIS

Glaucoma

Treatment

Outcomes

50

Black Patients

within

Race

White Patients

45: 40:

30: 5i 8

: 25:

:

: 20:

0-l

’

1

’

12

0

“1

18

24

36 FOLLOWUP

Figure

6. Average

percent

”

0

48

60

“1

72

84

6. Percent

of eyes wth

decrease of visual acutty

of Eyes with

Decrease

of Vision

Black

Scheduled Visit and Assigned Intervention

No. of

Sequence

Eyes

12 mm ATT TAT 24 mos A?T TAT 36 mos ATT TAT 48 mos ATT TAT 60 mos ATT TAT 72 mos ATT TAT 84 mos AT TAT * P obtamed

24

% with Decrease Vism (PDVJ

48

72

84

(PDV)

sequence. The difference is statistically significant (P < 0.01). In black patients, the cumulative probability of the visual acuity event SDVA was significantly lower for eyes in the ATT sequence (P < 0.001); in white patients, the

and Average

Percent

of Eyes with

Decrease

of Vision

(APDV)

White Patients

%

dth Decrease of Vision (APDV)

60

MONTH

(APDVA)

Patients

Average

of

36 FOLLOWUP

tion, cannot occur until the 18-month follow-up visit (refer to the Methods section), was greater in eyes assigned to the TAT sequence but not statistically significantly so (Fig 8). In white patients, conversely, eyes in the TAT sequence had a lower probability of the event than eyes in the ATT

Table

12

0

MONTH

Average Difference ATT-TAT

%

P*

No. of Eyes

% with Decrease of V~on (PDV)

wth Decrease of Vtsion (APDV)

m APDV

Drfference ATT-TAT

m APDV P*

227 202

14.1 27.7

12.5 24.5

-12.0

0.0000

153 163

15.7 23.3

13.6 21.5

-8.0

0.0144

215 194

19.5 38.1

15.5 29.7

-14.2

0.0000

139 156

22.3 22.4

18.1 21.2

-3.2

0.3040

204 184

32.8 37.5

19.3 31.5

-12.1

0.0004

132 150

29.5 28.7

21.5 22.8

-1.3

0.6600

a7 74

32.6 38.5

22.6 33.6

-11.0

0.0004

129 146

40.3 35.6

25.4 25.1

0.4

0.9008

139 130

40.3 42.3

24.9 35.1

-10.2

0.0004

107 119

43.0 32.8

28.8 26.6

2.1

0.4916

91 93

35.1 44.1

26.6 36.8

-9.8

0.0008

83 98

53.0 38.8

32.6 28.6

4.0

0.2140

57 59

38.6 40.7

27.8 37.1

-9.3

0.0008

54 59

48.1 49.2

34.8 31.0

3.8

0.2800

from a permutation

test comparmg

the two Intervention

sequences (2500

permutations).

Ophthalmology 50:

Volume

105, Number 50

Black Patients

45: 40;

7, July 1998

‘1

White Patients

45 40 i I

J

35:

35:

30:

30:

5 : 8 25: % :

25:

20:

20:

15:

15:

10:

10:

5:

0

12

24

36

40

FOLLOWUP

Figure

7. Average

percent

of eyes wth

60

72

84

0

12

24

MONTH decrease

36

48

FOLLOWUP of vmm

60

72

04

MONTH

(APDV).

difference favored ATT more often than TAT, but the overall difference is not statistically significant (P = 0.250) (Fig 9). For the endpoint, SDV, which combines SDVF and SDVA, the cumulative probability favors ATT for black patients (P < O.OOl), but for white patients, no clear difference emerges (P = 0.530) (Fig 10).

Number of Prescribed Glaucoma Medications In eyes assigned to initial trabeculectomy for both black and white patients, the average number of prescribed glaucoma medications decreased sharply from approximately 2.5 at baseline to approximately 0.5 at the 3-month follow-up visit. In eyes assigned to initial ALT, the decrease was modest from approximately 2.5 to

0.6

Black Patients

White Patients

0.5

qAA’: 0.4

0.3

0.2

0.1

0.0 0

12

24

36

40

FOLLOWUP Figure

8. Cumulative

(I’ = 0.002)

for whtte

probability patients.

60

72

84

l-

0

12

24

MONTH

of summed

36

FOLLOWUP decrease

of wsual

field

(SDVF).

Adjusted

chl-square

equals

48

60

72

84

MONTH

2.4 (P = 0.121)

for black

patients

and

9.3

The AGIS Investigators

- AGIS

Glaucoma

Treatment 0.6

Black Patients

Outcomes

1

within

Race

White Patients

.r

._-______.

12

24

36 FOLLOWUP

48 MONTH

Figure 9. Cumulative probabihty of sustamed 0.83 (P = 0.363) for white patients.

60

0

72

of Cataract

24

36 FOLLOWUP

decrease of wsual acmty

between 2.0 and 2.5 (Fig 11). Thereafter, in both black and white patients, the large ATT-TAT difference in mean numbers of medications gradually reduced to approximately 0.5 at 84 months. Probability

12

Surgery

There have been 127 cataract operations in black patients (54, ATT: 73, TAT) and 109 cataract operations in white patients

(SDVA).

Adjusted

chl-square

equals 21.4 (I < 0.001)

a----.

60

72

84

for black patients

and

(47, ATT; 62, TAT). For both black and white patients, the cumulative probability of cataract surgery is greater for TAT eyes than for ATT eyes (Fig 12). The difference is statistically significant for blacks (P < 0.001) but not for whites (P = 0.097). Risk of cataract surgery in ATT eyes appears to be lower in blacks than in whites; in TAT eyes, the risk appears similar in the two race groups. As listed in Table 7, the percent of enrolled eyes that 0.6

Black Patients

48 MONTH

White Patients

0.5

0.4

0.3

0.2

0.1

0.0 0

12

24

36

48

FOLLOWUP Figure 10. Cumulauve probability = 0.470) for white patients.

60

72

0

84

MONTH

of sustained

12

24

36 FOLLOWUP

decrease of vision

(SDV).

Adjusted

chi-square

equals 13.1 (P < 0.001)

48

60

72

04

MONTH for black patients

and 0.52 (I’

Ophthalmology Black

Volume 10.5, Number 4-

Patients

White

3-

,

12

0

24

36

48

FOLLOWUP

7, July 1998

60

.

6-e-e 0.. e-a

“’

72

04

,

.

0

Patients

ATT TAT

.

12

.

.

.

24

.

.

36

MONTH

.

48

FOLLOWUP

.

*.

60

72

,

04

MONTH

Figure 11. Mean nutnber of prescribed glaucotna me&cations.

needed and received a cataract operation in the 4 study subgroups (2 race groups, 2 intervention sequences) ranges from 23% to 37%. The percent of the cataract operations in the four subgroups that were combined procedures ranges from 23% to 57%, and a small number of these procedures (range,

0.6

Black

2-7 operations in the subgroups) were performed under protocol exception for eyes with a surgically untreated glaucoma intervention failure. The large majority (77%-870/o) of combined procedures was in eyes that had not failed the preceding glaucoma surgery.

0.6-

Patients

White

Patients

0.5-

0.4-

0.3-

0.2-

0.1 -

0

12

24

36

40

FOLLOWUP

Figure 12. Cunulatwe patients.

probabihty

60

72

64

0.0+-r:. 0

-’ 12

MONTH

of cataract

surgery.

8 24

1

u 36

g

FOLLOWUP Adjusted

chi-square

equals 10.5 (P = 0.001)

for black patwnts

0 48

b

’ 60

11 72

1 84

MONTH and 4.0 (P = 0.045)

for white

The AGIS Investigators Table

7. No.

of Conventional

* AGIS

Cataract

Glaucoma

Operations

Treatment

and Combined

Outcomes

within

Cataract-Trabeculectomy

Procedures

Black Patients

White

An

No. of eyes enrolled With cataract operation* With conventional? cataract operation only With combined cataract-trabeculectomy procedure No. of eyes with cataract operation ConventIonal? Combined with trabeculectomy No. of eyes with combined cataract-trabeculectomy procedure With “controlled” glaucoma$ After failed intervention, but before next programmed intervention9 * With

and without

t Without

combined

Race

TAT

Patients

ATT

TAT

N

%

N

%

N

%

N

%

240 54 23 31 54 23 31

100.0 22.5 9.6 12.9 100.0 42.6 57.4

211 73 48 25 73 48 25

100.0 34.6 22.7 11.8 100.0 65.8 34.2

158 47 24 23 47 24 23

100.0 29.7 15.2 14.6 100.0 51.1 48.9

167 62 48 14 62 48 14

100.0 37.1 28.7 8.4 100.0 77.4 22.6

31 24

100.0 77.4

25 21

100.0 84.0

23 20

100.0 87.0

14 12

100.0 85.1

7

22.6

4

16.0

3

13.0

2

14.3

trabeculectomy. trabeculectomy.

3: Procedure

allowed

by study protocol.

8 Procedure

allowed

after approved

exception

to study protocol.

Discussion Glaucoma affects blacks more often and more severely than whites. In the Baltimore Eye Survey the prevalence of open-angle glaucoma in blacks was three to four times as great as in whites,2’ and prevalence of blindness from the disease was six times as great.22 The prevalence among blacks in the Caribbean23*24 was found to be even greater than in Baltimore, and the high Baltimore blackwhite blindness ratio is consistent with data from U.S. blindness registries.25 In AGIS (Table 1) and other clinical studies,26,27visual field defects at baseline were more severe in blacks than in whites. The principal aim of AGIS, started in 1988, was to assess the effects of sequential surgical interventions for eyes of patients with open-angle glaucoma after the failure of medical therapy. A subsidiary aim, given that to determine the disease occurs more frequently in blacks than in whites, was whether there is a racial difference in prognosis. The interactions of race with treatment outcome and with failure of initial intervention were not postulated but rather discovered in the course of data analysis. We considered the possibility that these interactions were fundamentally interactions with iris pigmentation rather than with race, but our analysis (not shown) of treatment outcomes in white patients according to either dark or light iris color provided no support for the iris pigmentation hypothesis. The principal purpose of this article is to compare, separately within black and white patients, the outcomes of the randomized assignments. Although it is not the purpose here to compare black and white patients with respect to treatment-specific outcomes, a few such comparisons are made in this report. These comparisons, to be the subject of a separate article, will, as they must,

take into account black-white differences in baseline characteristics (e.g., age, severity of visual field defect). The AGIS methods of trabeculectomy and argon laser trabeculoplasty are standard in the United States. The AGIS postsurgical management, including topical antiinflammation medications,28 suture lysis” or releasable sutures,” and adjunctive antifibrotics,29 has adhered to the community standards in practice at the time of the surgical intervention. Routine use of antifibrotics in AGIS began in 1993 after all initial trabeculectomies had been completed. Adjunctive antifibrotics were used during 2 of 379 trabeculectomies that were assigned first AGIS interventions and during 19 of 119 trabeculectomies that were second AGIS interventions (after a failed ALT). The AGIS protocol allows cataract surgery when there has been sufficient visual acuity loss attributable to progression of lens opacity, provided the most recent glaucoma intervention has not failed. When filtering surgery is combined with cataract surgery, the combined procedure is counted as a variant of cataract surgery and not as an intervention in the AGIS glaucoma sequences. Among glaucoma subspecialists, there is no standard definition of glaucoma intervention failure. In many published reports, it is defined as failure to achieve IOP reduction to less than 22, less than 21, or less than 20 mmHg; some add as another criterion the failure to achieve a reduction of at least 20% from the presurgical level.30 Other studies consider optic nerve function or structure, in addition to IOP reduction, in defining intervention failure. The AGIS investigators agreed to define failure of a glaucoma surgical intervention to occur when glaucoma status deteriorates sufficiently for the eye, despite resumption of maximum medical glaucoma treatment, to again meet the study’s glaucoma-related eligibility criteria. We have applied this failure definition uniformly throughout

Ophthalmology

Volume 105, Number

the study, allowing only a few exceptions. The AGIS failure rates for laser trabeculoplasty and trabeculectomy are lower than most rates reported in the literature.30-46 When failure occurs, AGIS ophthalmologists recommend to the patient the next surgical intervention in the sequence. In a limited number of cases, trabeculoplasty as the second assigned intervention has not been possible because of peripheral anterior synechiae formation after previous invasive surgery (either trabeculectomy or, rarely, cataract surgery). Thus far, we have had too few failures of AGIS second interventions to allow meaningful interpretation of these failure rates. A number of studies have indicated that cataract development is accelerated after glaucoma filtering surIn 48 eyes after filtering surgery, gery. 30,33,34.38,44*45,47,48 Rollins and Drance38 reported a 44% 5-year incidence of visual acuity deterioration due to cataract of at least 2 Snellen lines or to less than 6/120 (20/400). Greve and associates33 reported cataract progression in 13 (45%) of 29 eyes within 10 years after filtering surgery. Sugar,47 with an average follow-up of 11 years after trephination, reported a cataract incidence of 38%. The magnitude of the excess cataract risk is not easily assessed from these data. Estimates from the Framingham Eye Study indicate that among persons in the general population 65 to 70 years of age, a typical age for patients with advanced glaucoma, the 5-year incidence of cataract, defined as lens opacity accompanied by best-corrected visual acuity of 20/30 or worse, is approximately 5% to 8%, whereas the 5-year incidence of lens opacity, with or without visual acuity deficit, is approximately 23% to 31%.49 In AGIS patients, cataract undoubtedly depresses visual functionvisual acuity probably more than visual field. The effect of cataract and cataract surgery, with and without concomitant trabeculectomy, on the outcome of glaucoma management is complex.50s5’ In AGIS, trabeculectomies performed as part of combined procedures were not counted as steps in the glaucoma intervention sequences. Nevertheless, these procedures do tend to affect glaucoma. Did these procedures strongly influence the visual field outcome observed in AGIS? The data in Table 7 indicate that they did not. First, only 12% of eyes enrolled in AGIS had these procedures. Second, glaucoma was in control in most eyes (87%) that received trabeculectomies combined with cataract extraction. Third, in black patients, the proportion of eyes that received these combined procedures was approximately the same in the two intervention sequences (12% and 13%); in white patients, if these combined procedures were effective in preventing glaucomatous visual function loss, eyes in the ATT sequence would have benefited more because a larger proportion of eyes in this sequence (14.6%) than in the TAT sequence (8.4%) received these combined procedures. Despite such possible benefit, after 12 to 18 months of follow-up, visual field preservation in white patients was better in the TAT sequence. The primary AGIS response variables are the three average percent decrease of vision variables: APDVF, APDVA, and APDV. In the initial AGIS protocol, the specified primary response variables were the three sus-

1160

7, July 1998

tained decrease of vision variables, SDVF, SDVA, and SDV, the consummation of which required persistence of the decrease for two consecutive 6-month follow-up visits. When these variables were found to lack stability, the persistence requirement was increased to three consecutive 6-month follow-up visits. With this change, instability was improved but not eliminated: 33% of eyes were found to “recover” from visual field events (SDVF) and 47% from visual acuity events (SDVA). (Recovery indicates sufficient visual function improvement after an event so that the vision loss criterion for the event is no longer met.) Further, 87% and 57% of eyes, respectively, “relapsed” after visual field and visual acuity event recovery. Consequently, we selected the average percent decrease variables as the primary response variables. These variables, which cumulate vision experience over the entire study period, are relatively insensitive to the fluctuations observed in the “sustained” variables. The AGIS results favor the ATT sequence for black patients in whom both visual field and visual acuity are better preserved in eyes in the ATT sequence despite the lower IOP in the TAT sequence. The large advantage in average percent of eyes with decrease of vision (APDV) is sustained over 7 years of follow-up (Table 6, Fig 7), indicating that the cumulative advantage will continue for at least the next few years. These data clearly support the use of the ATT sequence in black patients, the current standard management for advanced glaucoma. In white patients, the mean visual field defect score changes favor the ATT sequence during the first 12 to 18 months and thereafter favor the TAT sequenceby a progressively increasing margin (Fig 3). The early mean visual acuity score changes in white patients also favor the ATT sequence, with the early period for this effect lasting 4 years, after which the meanvisual acuity changes favor the TAT sequence(Fig 4). The cumulative effects of these changes over time are measured by the average percent decrease of vision statistics in Figure 5 for APDVF, Figure 6 for APDVA, and Figure 7 for APDV. The APDVF data favor the ATT sequencefor the first 12 to 18 months but thereafter favor the TAT sequenceby an increasing margin. The APDVA data favor the ATT sequencethroughout 7 years of follow-up by a progressively decreasing margin, and the data for APDV, a combination of APDVF and APDVA, favor the ATT sequence for nearly the first 4 years and then favor the TAT sequence by a progressively increasing margin. Based on these data, it is our judgment that white patients without life-threatening health problems be offered the TAT sequence. This recommendation for white patients differs from current standard management.’ In discussing the surgical treatment alternatives with white patients with advanced glaucoma, the physician should take into account, in addition to the patient’s health, the need for medications and compliance with the medication schedule after glaucoma surgery and the comparative risks of developing cataract, vision loss, and treatment failure. Clearly, these are complex issues. We emphasize that all eyes enrolled in AGIS had no previous invasive ocular surgery, so that all were phakic.

The AGIS

Investigators

* AGIS

Glaucoma

Therefore, inferences drawn directly from the AGIS results should be limited to phakic eyes. In both black and white patients, the mean baseline IOP is essentially the same in the ATT and TAT subgroups, whereas the mean IOP reduction from baseline during the first 84 months of follow-up is larger in the TAT sequence than in the ATT sequence (Fig 2). Glaucoma treatment in AGIS and elsewhere is based on the hypothesis that IOP reduction protects against worsening of the visual field. If the hypothesis is true, then eyes in the TAT sequence should have better visual field preservation. Indeed, this is found in white patients after the first 15 months of follow-up (Fig 3). However, in the eyes of black patients throughout 84 months of follow-up, visual field deterioration was greater in the TAT sequence despite greater IOP reduction (Fig 3); the average visual field defect score in eyes of black patients in the ATT sequence actually improved from baseline during the first 30 months of follow-up. The lack of concordance of visual field preservation with mean reduction of IOP in black patients suggests that in these patients, factors other than IOP may play a role in determining the integrity of peripheral visual function. Such factors have been hypothesized.52 It is possible that visual function in black patients could be better preserved than in the AGIS TAT sequence through routine use of adjunctive antifibrotics with the initial trabeculectomy. Adjunctive antifibrotics have been found to improve the pressure-lowering effect of initial trabeculectomy;s3-55 the clinician should be mindful of the potential for increases in the risk of complications associated with adjunctive antifibrotics.5sB56 Future analyses of AGIS data may shed light on the role of the magnitude of IOP reduction in visual function preservation. The ATT and TAT sequences differ, by design, in only the first and second interventions, with trabeculectomy as the third intervention in both sequences. Currently, with potential follow-up in AGIS ranging from 4 to 8 ‘/* years, the probability of an eye having failed both the first and second interventions is small, ranging between 4.4% and 7.0% depending on intervention sequence and race. Thus, few eyes have had as many as two intervention failures. Additional follow-up is needed for a more complete picture of the effects of these intervention sequences. The following important issues about advanced glaucoma management remain to be addressed by AGIS: l

l

The newly discovered interaction of visual function outcome with race is particularly important. We need to determine whether current trends will continue. For example, in black patients, the visual field advantage of assignment to the ATT sequence appears to be decreasing (Figs 3, 5, 8). In white patients, the visual field advantage of assignment to the TAT sequence appears to be increasing (Figs 3, 5, 8), and the visual acuity advantage of the ATT sequence appears to be decreasing (Figs 4, 6, 9). There is a lack of information about rates of failure of second and subsequent glaucoma interventions. Is the failure rate higher when trabeculectomy is preceded by failure of ALT, as has been found in a

Treatment

l

Outcomes

within

Race

retrospective data analysis?57 Thus far in AGIS, there have been too few second and third intervention failures for a meaningful comment on this issue. AGIS will provide information about (1) longer term preservation of visual function; (2) a comparison of the impact of large and small reductions of IOP on vision; (3) the occurrence of and risk factors for bleb encapsulation, vision loss, and second and subsequent glaucoma surgical intervention failures: and (4) the impact of cataract and cataract surgery, with and without filtration, on the course of glaucoma.

The interaction of race and treatment found in the current study indicates that the planning and analysis of future studies of glaucoma treatment should take race into account.

Appendix:

AGIS Centers and Investigators

Participating

Current Investigators, Who Participated for

Institutions, Investigators Two or More Years and Former Clinical

Centers:

Emory

University, Atlanta, GA: Reay H. Brown, MD (CD); Allen Beck, MD (CI); Mary Lynch, MD (CI); Donna Leef, MMSc, COMT (CC)(CM); Kathy Moore (T); John Closek, COT (T); Twyla Marsh, COA (T); Juanita Banks (T). Past participating personnel: M. Angela Vela, MD (CD); Johnny Gunsby, COT; Kathy Lober, COA; Candace Stepka. Georgetown University, Washington, DC: Douglas E. Gaasterland, MD (CD); Suzanne Plavnieks, COT (CC)(CM); Melissa Kellogg, COA (T). Satellite facility: Frank Ashburn, MD (SD); Karen Schacht, COT (SC). Past participating personnel: Elizabeth Burt, COT; Ellen Coyle, COMT (CC); Mary Hundley, COT; Susan Lauber, MA (CC); Karl Michelitsch, COMT (CC) (deceased); Anne Rae, COT; Lynn Vayer, COT (SC). Medical College of Virginia, Richmond, VA: Robert C. Allen, MD (CD); Amy Sporn, OD (CC)(CM); Sharon Hoyle, COT. Past participating personnel: C. Kay Fendley, COT (CC)(CM). Ohio State University, Columbus, OH: Paul A. Weber, MD (CD); Robert Derick, MD (CI); Kathryne McKinney, COMT (CC)(CM); Diane Moore, COA (T); Billi Romans (T). Satellite facility: N. Douglas Baker, MD (SD); Fred Kapetansky, MD (CI); David Lehmann, MD (CI); Becky Gloeckner, COT (SC)(T); Mary Cassady, COA (T); Kris Coleman, COT (T). Past participating personnel: Yvonne Satterwhite (T); Lori Simmons; Lisa J. Sharf, COA. Piedmont Hospital, Atlanta, GA: M. Angela Vela, MD (CD); Thomas S. Harbin, Jr, MD (CI); Montana Hooper, COT (CC)(CM); Stacy Goldstein, (CC)(CM); Julie Wright, COT (T); June LaSalle, COA (T); Gail Degenhardt (T); Stephanie Ann Bridgman (T). Past participating personnel: Randall R. Ozment, MD (CI); Linda Butler, COT; Anne Eckel, COA; Anja Martin, COA; 1161

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Volume 105, Number

Dana Nummerdor; Marianne Perry, COT; Celeste Session, COA; Lisa Wille. Sinai Hospital/Detroit, Southfield, MI: Marshall N. Cyrlin, MD (CD); Patricia S. Corbin (CC)(CM). Past participating personnel: Roselyn Fazio, BS, COT (CC). University of Illinois, Chicago, IL: Jacob T. Wilensky, MD (CD); Kim Lindenmuth, MD (CI); David Hillman, MD (CI); Catherine A. Nail, COMT (CC)(CM); Jennifer Hatton, COT (T). Satellite facility: Sriram Sonty, MD (SD); Catherine A. Nail, COMT (SC). Past participating personnel: Eve J. Higginbotham, MD (CD); Gary Scholes, MD (CI); Gloria Hopkins, LPN; Julie Fiene, COT; Diane Frohlichstein, COT; Valeria Gates, OT; Loreen Pappas, COT; Donna Rathbone, COT; Marlem Tadelman, COT: Rosanna Uva, COT (CC). University of Michigan, Ann Arbor, MI: Paul R. Lichter, MD (CD); Terry J. Bergstrom, MD (CI); Robert M. Schertzer, MD (CI); Sayoko E. Moroi, MD, PhD (CI); Carol Standardi, RN, CRNO (Co-CC)(CM); Carol Rundle, COT (Co-CC)(T); Lynette Abt, COT (T); Terri Van Heck, COT (T). Past participating personnel: Gregory L. Skuta, MD (CD); Eve J. Higginbotham, MD (CD); Desiree Aaron, COA; Judith Birk, COA; Joyce Dederian, COA; Linda Kruscke, COA; Barbara Michael, COT; Renee Papierniak-Dubiel; Donna Wicker, OD; Jennifer Ziehm-Scott, COA. University of Virginia, Charlottesville, VA: Bruce Prum, MD (CD); Steven A. Newman, MD (CI); Cindi Berghuis, COT (CC)(CM); Carolyn Harrell, COA (T); Christine Evans, COT (T); Lil Shoffstall-Tyler, COA (T); Christi Harris, COA (T); Terri Voight, COA (T). Past participating personnel: Louis J. Schott, MD (CI); John R. Nordlund, MD, PhD (CI); Robert Fornili, OD (CC); James Chisholm, COA; Ellen Murphy, COA.

Washington

Hospital

Center,

Chevy Chase, MD:

Arthur L. Schwartz, MD (CD); Howard Weiss, MD (CI); Anne Boeckl, MS (CC)(CM); Karen Carmody, COT (T). Satellite facility: Anne Boeckl, MS (SC): Lois Maloney, COT (T). Past participating personnel: Mark Morris, MD (CI); Maria Cirone, MD (CI); John Gurley, MD (CI); Scott Wehrly, MD (CI); Stephen Pappas, MD (CI); Maureen O’Dea, MD (CI); Cathy Reed, COMT (CC); Cindy V. Witol, COA (CC); Janet Browning, COT; Elaine Harris; Patrick Lopez, COT; Richard Mercer; Victoria Monks, COA; Kathy Vawter, COA. Wills Eye Hospital, Philadelphia, PA: L. Jay Katz, MD (CD); George L. Spaeth, MD (CI); Richard P. Wilson, MD (CI); Jonathan Myers, MD (CI); Annette Terebuh, MD (CI); Fillis Samuel, COT (CC)(CM); Alaine Meli (T). Past participating personnel: Sue Kao, MD (CI); Coleen C. Beckershoff. Yale University, New Haven, CT: Eydie Miller, MD (CD); Maureen Roche, COMT (CC)(CM); Gail Grottole (T); Anne Leone, COT (T). Past participating personnel: Charles Tressler, MD (CI); Joseph Caprioli, MD (CD). Coordinating Center: The EMMES Corporation, Potomac, MD: E. Kenneth Sullivan, PhD (Director); Fred Ederer, MA, FACE (Epidemiologist); Paul C. VanVeldhuisen, MS (Statisti-

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cian); Lie-Ling Wu, MS (Statistician); Marline Bradford (Data Coordinator); Susan Raitt, MA (Administrative Coordinator). Past participating personnel: Anne S. Lindblad, PhD (Deputy Director); James D. Knoke, PhD (Deputy Director); Gary Entler, COT (Protocol Monitor); Carol Smith, MPH (Protocol Monitor); Marsha Denekas, MLT (Data Coordinator); Katherine L. Tomlin, MA (Administrative Coordinator); Elaine Stine (Alternate Interviewer); Elizabeth L. Wagner, MPH (Data Coordinator); Tamara Voss, BA (Administrative Coordinator). Sponsor: National Eye Institute: Mary Frances Catch, PhD (NE1 Representative); Carolyn Grimes, Grants Management Specialist. Past participating personnel: Richard L. Mowery, PhD (NE1 Representative); Frances Goff (Grants Management Specialist); Gaye Lynch (Grants Management Specialist). Study Groups: Study Co-Chairmen: Douglas E. Gaasterland, MD; Fred Ederer, MA, FACE.

Policy and Treatment Effects Monitoring Board (PATEMB): Curt D. Furberg, MD, PhD (Chairman); John E. Connett, PhD; Matthew D. Davis, MD; David K. Dueker, MD; Sylvan B. Green, MD; Sanford Leikin, MD; Paul F. Palmberg, MD, PhD; Ex officio members: Fred Ederer, MA, FACE, Douglas E. Gaasterland, MD; Mary Frances Catch, PhD. Past participating personnel: Marvin Schneiderman, PhD (deceased); The Rev. Canon Michael P. Hamilton; Richard L. Mowery, PhD (Ex officio). Operations Committee: Fred Ederer, MA, FACE; Douglas E. Gaasterland, MD; E. Kenneth Sullivan, PhD; Paul C. VanVeldhuisen, MS; Arthur L. Schwartz, MD (consultant). Past participating personnel: Anne S. Lindblad, PhD; James D. Knoke, PhD. Steering Committee: Permanent members: Fred Ederer, MA, FACE; Douglas E. Gaasterland, MD; Arthur L. Schwartz, MD; Aaron Kassoff, MD (consultant); Mary Frances Catch, PhD. Elected investigator members: Marshall N. Cyrlin, MD (1988); M. Angela Vela, MD (1988- 1989); Joseph Caprioli, MD (1988- 1990); Eve J. Higginbotham, MD (1989- 1991); Gregory L. Skuta, MD (1990-1992); L. Jay Katz, MD (1991-1993); Paul A. Weber, MD (1992-1994); Robert C. Allen, MD (19931995); Jacob T. Wilensky, MD (1994- 1996); Eydie Miller, MD (19951997); Reay Brown, MD (19961998); Bruce Prum, MD (1997- 1999). Elected Clinic Coordinator members: Donna Leef, MMSc, COMT (1988); Kathryne McKinney, COMT (1989); Cathy Reed, COMT (1990); Rosanna Uva, COT (199 1); Fillis Samuel, COT (1992); Maureen Roche, COMT (1993); Carol Standardi, RN, CRNO (1994); Ellen Coyle, COMT (1995); Anne Boeckl, MS (1996); Carol Rundle, COT (1997). Past participating member: Richard L. Mowery, PhD. Training and Certification Faculty: Fred Ederer, MA, FACE; Douglas E. Gaasterland, MD; Aaron Kassoff, MD (Consultant); L. Jay Katz, MD; Donna Leef, MMSc, COMT; Gregory L. Skuta, MD; Carol Standardi, RN CRNO; Fillis Samuel, COT. Past participating personnel: Anne S. Lindblad, PhD; Cathy Reed, COMT; Coleen

The AGIS

lnvestigutors

* AGIS

Glaucoma

C. Beckershoff; Gary Entler, COT; Elizabeth L. Wagner, MPH. (Abbreviations: CD = Clinic Director; CI = Co-Investigator; CC = Clinic Coordinator; CM = Clinic Monitor; SD = Satellite Director; SC = Satellite Coordinator: T = Technician.)

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38. Rollins DF, Drance SM. Five-year follow-up of trabeculectomy in the management of chronic open angle glaucoma. In: Symposium on Glaucoma. New Orleans Academy of Ophthalmology. St. Louis: CV Mosby Co., 198 1; 295-300. 39. Schwartz AL, Love DC, Schwartz MA. Long-term followup of argon laser trabeculoplasty for uncontrolled openangle glaucoma. Arch Ophthalmol 1985; 103: 1482-4. 40. Shingleton BJ, Richter CU, Bellows AR, et al. Long-term efficacy of argon laser trabeculoplasty. Ophthalmology 1987;94:1513-8. 41. Shingleton BJ, Richter CU, Dharma SK, et al. Long-term efficacy of argon laser trabeculoplasty. A lo-year followup study. Ophthalmology 1993; 100:1324-9. 42. Spaeth GL, Baez KA. Argon laser trabeculoplasty controls one third of cases of progressive, uncontrolled, open angle glaucoma for 5 years. Arch Ophthalmol 1992; 110:491-4. 43. Stewart WC, Reid KK, Pitts RA. The results of trabeculectomy surgery in African-American versus white glaucoma patients. J Glaucoma 1993;2:236-40. A long-term 44. Tijrnqvist G, Drolsum LK. Trabeculectomies. study. Acta Ophthalmol 1991;69:450-4. 45. Wilensky JT, Chen TC. Long-term results of trabeculectomy in eyes that were initially successful. Trans Am Ophthalmol Sot 1996;94: 147-59. 46. Wise JB. Ten year results of laser trabeculoplasty. Does the laser avoid glaucoma surgery or merely defer it? Eye 1987; 1:45-50. 47. Sugar HS. Postoperative cataract in successfully filtering glaucomatous eyes. Am J Ophthalmol 1970;69:740-6.

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