The advanced glaucoma intervention study (AGIS): 1. Study design and methods and baseline characteristics of study patients

The Advanced Glaucoma Intervention Study (AGIS): 1. Study Design and Methods and Baseline Characteristics of Study Patients The AGIS Investigators

ABSTRACT: Medical therapy has been the standard initial treatment for open-angle glau-

coma. When some visual field has been lost and maximum tolerated and effective medical therapy does not succeed in controlling the disease, the patient is considered to have advanced glaucoma, and the first of a potential sequence of surgical treatments is usually indicated. Little is known about the long-term course and prognosis of advanced glaucoma or about the long-term effectiveness of sequential surgical treatments in controlling the disease and preventing vision loss and blindness. The Advanced Glaucoma Intervention Study was designed to study, in advanced glaucoma, the long-term clinical course and prognosis, and, in a randomized trial, the comparative outcomes of two sequences of surgical treatments. Toward these goals, 789 eyes in 591 patients were enrolled at 11 clinical centers between 1988 and 1992. Follow-up will continue until 1996. Eyes were randomly assigned to one of two sequences of surgical treatments. One sequence begins with argon laser trabeculoplasty (ALT), is followed by trabeculectomy, an incisional surgical filtering procedure, should ALT fail to control the disease, and by a second trabeculectomy should the first trabeculectomy fail. The other sequence begins with trabeculectomy, is followed by ALT should the trabeculectomy fail, and by a second trabeculectomy should ALT fail. The main outcome of interest is visual function (visual field and visual acuity). Other important outcomes are intraocular pressure, complications of surgery, time to treatment failure, and extent of need for additional medical therapy. We present in this paper the rationale, objectives, design and methods of the study, and the baseline characteristics of study patients and eyes. KEY WORDS: Clinical trial desig n, open-angle glaucoma, laser surgery, trabeculectomy, visual acuity, visual fields INTRODUCTION The A d v a n c e d G l a u c o m a I n t e r v e n t i o n S t u d y (AGIS) is a l o n g - t e r m s t u d y of clinical course a n d p r o g n o s i s of g l a u c o m a i n a d e q u a t e l y controlled b y m e d i c a t i o n s alone. The s t u d y i n c o r p o r a t e s a r a n d o m i z e d trial of t w o seThis report was prepared by Fred Ederer, MA, FACE, The EMMES Corporation, Potomac, MD, and Department of Ophthalmology, Georgetown University, Washington, DC; Douglas E. Gaasterland, MD, Department of Ophthalmology, Georgetown University, and University Ophthalmic Consultants Research and Educational Foundation of Washington, Washington, DC; and E. Kenneth Sullivan, PhD, The EMMES Corporation, Potomac, MD (writing team). The AGIS centers and investigators are listed at the end of this report. Address reprint requests to: Fred Ederer, The EMMES Corporation, 11325 Seven Locks Road, Suite 214, Potomac, MD 20854. Received July 23, 1993; revised January 11, 1994.

Controlled Clinical Trials 15:299-325(1994) © ElsevierSciencePublishing Co., Inc. 1994 655 Avenueof the Americas, New York, New York 10010

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quences of surgical treatments. AGIS investigators at 11 clinical centers in the United States enrolled 789 eyes of 591 patients between April 1988 and November 1992. Follow-up is projected to continue until November 1996. This paper presents the study’s rationale, objectives, design and methods, and the baseline characteristics of study patients and eyes. Further details on design and methods are given in the AGIS Manual of Operations 111.

STUDY RATIONALE

AND OBJECTIVES

Rationale Open-angle glaucoma, a major cause of blindness, involves elevated intraocular pressure, damage and loss of optic nerve axons, progressive loss of visual field (side vision), and ultimately, in some cases, loss of central vision. Treatment is intended to reduce elevated intraocular pressure, which is believed to cause damage to the optic nerve. Standard treatment begins with one type of medication. If needed, this may be followed by a stepwise increase in dosage and by the stepwise addition of as many as three other types of medications 121. Step increases are continued only if they are effective in reducing pressure, accepted and tolerated by the patient, and not otherwise contraindicated. When maximum effective, accepted, and tolerated medications fail to reduce intraocular pressure adequately and there has been some visual field loss, the patient is said to have advanced glaucoma. The current standard method of managing advanced glaucoma is with an initial surgical treatment, either argon laser trabeculoplasty (ALT) or trabeculectomy, a type of filtering surgery, and with adjunctive medical therapy, as needed. Should the first operation, with added medical therapy, fail to control the disease, a second operation is offered; should the second operation, with added medical therapy, fail, a third operation is offered; and so on. Before 1980 filtering surgery was the first-line surgical treatment for advanced glaucoma. It was thereafter displaced by ALT, which is now the initial operation used for most patients in the United States. In 1985 several reports appeared that indicated substantial loss of effectiveness of ALT to control pressure within 2-5 years, despite continued use of medications [3-51. Filtering surgery, which has been used for nearly a century, is more complex, more invasive, and is often followed by more severe complications than ALT. It is performed under anesthesia (general or local), which entails greater risks than the anesthetic eyedrops used for ALT. Major complications of filtering surgery are bleeding, infection, early shallow anterior chamber, accelerated formation of cataract, and problems with the filtration bleb [6]. Filtering surgery appears to have several advantages over ALT: it is reported to be more effective in controlling pressure for at least 5 years, and eyes receiving this surgery are reported to require fewer postintervention glaucoma medications 17-101 and less additional glaucoma surgery [7,11,12] to accomplish this control. Whether ALT is in fact the better first-line surgical treatment is not known. Indeed, this is a major question AGIS is attempting to answer. There have not been any large, systematic, long-term studies that provide

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information about visual outcome in advanced glaucoma. In the absence of appropriate studies, little is known about the clinical course of advanced glaucoma, about factors that determine outcome, and about how well the two methods of surgery protect against long-term vision loss.

Objectives AGIS was designed to provide answers to a number of questions about advanced glaucoma, the most important of which are the following: (1) What is the clinical course and what are the outcomes after current therapies? (2) How effective in preserving vision are two sequences of surgical treatments, one starting with ALT and the other with trabeculectomy, a type of filtering surgery? (3) What are the early and late complication rates? (4) Can factors be identified that predict outcome with sufficient accuracy to help the ophthalmologist in planning treatment for a patient?

STUDY

DESIGN

AND METHODS

Study Organization Investigators at 11 clinical centers have had the responsibility for recruiting, enrolling, examining, treating, and following study patients in accordance with specifications set forth in a detailed manual of operations. Each clinical center is staffed by one or more ophthalmologists, one of whom is clinic director, and by one or more technical staff, one of whom is clinic coordinator. Four of the clinical centers are assisted by a satellite facility, each staffed at minimum by a clinic director and clinic coordinator, who may also be the clinic director and clinic coordinator of the parent facility. A coordinating center is responsible for coordinating study activities and communications, maintaining a quality assurance program, randomizing eyes to treatment, and receiving, editing, processing, and analyzing study data. The coordinating center is staffed by an epidemiologist, who is the center director, a biostatistician, who is deputy director, a data coordinator, a protocol monitor, an administrative coordinator, and additional technical staff. Committees include the Steering Committee, responsible for approving changes in policy and procedure, generating scientific publications, and reviewing abstracts and manuscripts submitted for presentation or publication; the Policy and Treatment Effects Monitoring Board, responsible for reviewing and advising on study design and methods, protocol changes, and problems that arise in study conduct, and for reviewing the accumulated data every 6 months for efficacy and safety; and the Operations Committee, responsible for managing the day-to-day conduct of the study. The Steering Committee consists of five permanent and four rotating members. The permanent members are the two study cochairmen, one of whom is a clinic director and the other is the director of the coordinating center, another clinic director, a consultant ophthalmologist, and a representative of the National Eye Institute (the funding agency). The rotating members are three clinic directors, each serving 3-year terms, and a clinic coordinator, who serves a l-year term. The voting members of the Policy and Treatment Effects Monitoring Board are an

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Table 1

IOP, G l a u c o m a V i s u a l F i e l d Score, a n d D i s k R i m D e t e r i o r a t i o n C r i t e r i a for E l i g i b i l i t y a n d F a i l u r e IOP Consistently Elevated (mm Hg) b

Glaucoma Visual Field Score

Documented Disk Rim Deterioration"

A

->18~

Not required

B C

>-18~ ->21

D E F G H I

->21 ->22 ->23 ->24 ->26 ->30

Increase of ->3 ("visual field deterioration') c ->2 >6, with at least one of four paracentral points depresssed 20 dB or more from normal ->11 ->7 ->4 ->3 >~2 ->1

Criterion"

Required Not required

Not Not Not Not Not Not

required required required required required required

"When an eye meets more than one of the eligibility or failure criteria, it is classified according to the criterion whose letter designation appears last in the alphabet (eg, an eye meeting criteria G and H is classified H). blOP is consistently elevated at or above a specified pressure when two lOP determinations made on separate days not more than 30 days apart while the eye is on maximum tolerated and effective medical therapy are both at or above that pressure. cVisual field deterioration and disk rim deterioration must be ascertained while the eye has been on maximum tolerated and effective medications. '~For eligibility, the eye must have had at least one previous measurement, with or without medicines, of lOP >21mm Hg by applanation or indentation tonometry. e p i d e m i o l o g i s t ( c h a i r m a n ) , t h r e e o p h t h a l m o l o g i s t s , t h r e e statisticians, a n d a b i o e t h i c i s t ; n o n v o t i n g m e m b e r s a r e the t w o s t u d y c o c h a i r m e n a n d the N a t i o n a l E y e I n s t i t u t e r e p r e s e n t a t i v e . T h e O p e r a t i o n s C o m m i t t e e c o n s i s t s of t h e t w o s t u d y c o c h a i r m e n a n d t h e d e p u t y d i r e c t o r of t h e c o o r d i n a t i n g center.

Eligibility and Exclusion Criteria To b e e l i g i b l e for A G I S , t h e p a t i e n t s a n d e y e s s e l e c t e d for s t u d y h a d to m e e t s p e c i f i e d criteria. O n e o r b o t h of a p a t i e n t ' s e y e s c o u l d b e e n r o l l e d . F o r b o t h to b e e n r o l l e d , e a c h e y e h a d to m e e t t h e e l i g i b i l i t y criteria a n d the t w o e y e s h a d to b e e n r o l l e d s i m u l t a n e o u s l y . T h e c o m b i n e d e l i g i b i l i t y criteria for i n t r a o c u l a r p r e s s u r e , v i s u a l field score, a n d d i s k r i m d e t e r i o r a t i o n (see eligib i l i t y c r i t e r i o n 5, b e l o w ) a l s o s e r v e as f a i l u r e criteria d u r i n g f o l l o w - u p : w h e n a t r e a t e d e y e d e t e r i o r a t e s so m u c h t h a t it a g a i n m e e t s t h e s e criteria for e n r o l l m e n t , t h e p r e c e d i n g g l a u c o m a o p e r a t i o n is s a i d to h a v e failed, a n d the p a t i e n t is o f f e r e d t h e n e x t o p e r a t i o n in t h e s e q u e n c e (Table 2).

Eligibility Criteria. 1. A g e 3 5 - 8 0 y e a r s . 2. O n e of t h e f o l l o w i n g t y p e s of o p e n - a n g l e g l a u c o m a in t h e s t u d y eye: a) p r i m a r y o p e n - a n g l e g l a u c o m a in a p h a k i c eye, o r b) o p e n - a n g l e g l a u c o m a in a p h a k i c e y e 4 w e e k s o r m o r e after l a s e r i r i d o t o m y , p r o v i d e d t h e e y e is n o t i n f l a m e d , s t e r o i d m e d i c a t i o n h a s n o t b e e n u s e d for a w e e k , a n d less t h a n o n e - t w e l f t h of t h e t r a b e c u l a r m e s h w o r k

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Sequences of Three Assigned Glaucoma Operations Operation

Sequence 1

Sequence 2

1. First 2. Second (after failure of first) 3. Third (after failure of second)

Trabeculectomy ALT Trabeculectomy

ALT Trabeculectomv Trabeculectomy

ALT,argon laser trabeculoplasty. circumference is blocked by peripheral anterior synechiae. 3. Study eye is on maximum medical therapy (i.e., maximum effective, accepted, and tolerated glaucoma medical treatment); for an eye to be on maximum medical therapy, at least one medication from each of three groups, a) miotic, b) ~ blocker, epinephrine derivative, or both, and c) systemic carbonic anhydrase inhibitors, if not contraindicated, must have been tested and continued unless found not to be effective, or not accepted or not tolerated by the patient. 4. Patient has had at least one threshold, quantitative, automated visual field test in either eye at any time before the eligibility visual field test. 5. Study eye, while on maximum medical therapy, meets at least one of the nine combinations of criteria for consistently elevated intraocular pressure (IOP), glaucoma visual field defect, and optic disk rim deterioration specified in Table 1.6. Visual acuity score of 56 or better (approximate Snellen equivalent -~6/24 = 20/80) in the study eye. 7. Visual field score of at least 1 and not more than 16. 8. Study eye is treatable with either ALT or trabeculectomy. 9. Patient is able to cooperate with study procedures and able to perform tests reliably. 10. Patient signs consent form.

Exclusion Criteria. 1. Discernable congenital anomaly of the anterior chamber angle. 2. Eyes with secondary glaucoma, eyes with pigment dispersion, and patients with syndrome of exfoliation of the lens capsule in either eye. 3. Concurrent active disease in the study eye that may affect intraocular pressure or its measurement. 4. Patients on kidney dialysis. 5. History of laser or incisional surgery in the eye considered for study, except laser iridotomy; laser retinal treatment anterior to the vortex vein ampullae; or local retinal cryotherapy, involving less than two quadrants, for retinal holes anterior to the vortex vein ampullae. 6. Eyes that have undergone gonioplasty in more than 180 ° of the anterior chamber angle circumference. 7. Eyes with proliferative or severe nonproliferative retinopathy. 8. Eyes with (dilated) pupil diameter of less than 2 ram. 9. Eyes with field loss attributed to a nonglaucoma condition. 10. Fellow eye previously enrolled in AGIS. 11. Likelihood that the patient would not be able to meet the study's long-term visit schedules.

Enrollment and Randomization

Eyes were enrolled into the study following telephone agreement between the clinic coordinator and the data coordinator at the study's coordinating center that the patient and eye(s) met all the eligibility criteria. Then the data coordinator, from a stratified list generated by a formal randomization procedure, assigned the eye to one of the two sequences of surgical procedures

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AGIS Investigators shown in Table 2. The stratification variables were clinical center (11 strata) and visual field score (2 strata). When both of the patient's eyes were enrolled, the ophthalmologist specified, before the treatment assignment was issued, which eye was to be treated first. The eye to be treated first was r a n d o m l y assigned to one of the two sequences in Table 2 and the fellow eye assigned to the other sequence. W h e n only one eye was enrolled, the fellow eye became ineligible for subsequent enrollment in the study.

Sequences of Surgical Treatments: Treatment Failure As shown in Table 2, patients are offered the second glaucoma operation w h e n the first one fails and the third w h e n the second fails. After failure of the third operation, eyes are managed with additional surgery at the discretion of the patient and the treating ophthalmologist. Two kinds of failure of surgical glaucoma treatment, early and late, are defined. Early failure occurs within 6 weeks after the first or second half of argon laser trabeculoplasty (ALT) or within 6 weeks after trabeculectomy. The occurrence of early failure is determined by the ophthalmologist m e m b e r of, or an ophthalmologist consultant to, the Operations Committee according to guidelines specified in the manual of operations. The guidelines involve m a g n i t u d e of IOP elevation, duration of elevation, a m o u n t of visual field loss, a m o u n t and type of deterioration of disk rim, and evidence that the elevation has caused, or is likely to cause, additional ocular damage. Late failure, occurring 6 weeks or more after the most recent glaucoma operation, is essentially defined by the same criteria as study eligibility (Table 1): maxim u m tolerated and effective medications, IOP, visual field loss, and disk rim deterioration. When an eye, at any time after enrollment, again meets the ocular eligibility criteria of Table 1, the last glaucoma operation the eye received is declared a failure and the patient is offered the next glaucoma operation in the assigned sequence (Table 2).

Masking An attempt has been m a d e to mask information on treatment of study eyes from the examiners w h o perform the visual acuity, visual field, and IOP tests. The attempt has not always been successful because in some cases the examiners gain k n o w l e d g e of the treatment assignment. The examiners record on the examination form whether or not they are aware, at the time of the examination, what treatment sequence the eye had been assigned to or what operations the eye had undergone.

Study Measurements: Examination and Scoring Procedures Visual Acuity. The AGIS visual acuity examination protocol is essentially that of the Early Treatment Diabetic Retinopathy Study (ETDRS) [13]. The main difference is that the AGIS box is rear-lighted, though it has about the same illumination characteristics as the ETDRS front-lighted box [14]. Two 20-watt "cool daylight" fluorescent tubes illuminate the chart. Study personnel use

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three visual acuity charts, each with a different letter s e q u e n c e - - o n e for refraction, one for testing the right eye, and one for testing the left eye [15]. Each chart has five high-contrast Sloan letters in each of 14 lines, with lines of equal difficulty, and with letter height reduced by a factor of 0.7943 from line to line (letter height is halved after every three lines). The charts and the box are distributed by Lighthouse Low Vision Products. Visual acuity examiners, w h o are trained and certified, follow standard procedures for encouraging patients to make m a x i m u m efforts to read as m a n y letters as possible. Patients are tested at a distance of 4 m and, if fewer than 20 letters are read correctly (i.e., visual acuity is less than about 20/100), also at 1 m. When 20 or more letters are read correctly at 4 m, the visual acuity score is the n u m b e r read correctly plus 30. When fewer than 20 letters are read correctly at 4 m, the visual acuity score is the 4-m total plus the n u m b e r of letters read correctly, at 1 m, of the 30 letters on the six top lines. The m a x i m u m visual acuity score is 100, corresponding to a Snellen visual acuity of 20/10. A visual acuity score of 5 corresponds to a Snellen visual acuity of about 5/200. If no letters are read correctly at 1 m, the ability to count fingers at 30 cm, detection of hand motion, and presence or absence of light perception are recorded. Visual Field. Visual field tests are conducted with a H u m p h r e y Visual Field Analyzer equipped with Statpac 2 software. Contact lenses m a y be used for phakic and aphakic eyes w h e n such use is believed to improve testing. When visual acuity is insufficient to count fingers at 30 cm, the visual field score is recorded as 20, the m a x i m u m (worst) visual field score. The H u m p h r e y perimeter is set for the central 24-2 threshold test, size III white stimulus, and full-threshold strategy, with the foveal threshold test turned on. The pupil diameter has to be 2 m m or more before testing begins. If necessary, the pupil is dilated before the test. For each test an appropriate age-related plus-power lens is a d d e d to the distance refraction for best-corrected vision. The room lights are d i m m e d without direct light fall!ng on the patient. Examiners are trained to give to the patient occasional e n c o u r a g e m e n t and reminders to blink and to maintain fixation. Test results are checked for reliability [16]. If the test is unreliable, as evidenced by a rating of 3 or more, it is repeated. If both tests are unreliable, the more reliable of the two is selected for the study, unless the test was for study eligibility, in which case the eye was found ineligible. Visual field defects are scored 0, 1, 2 . . . . . . 20 [16,17]. The visual field is considered to be abnormal if three or more contiguous test locations in the total deviation plot are depressed to decibel levels equal to or greater than any of the values shown in Fig. 1. In addition, the field is abnormal if any two contiguous test locations, excluding those six in the nasal area, are depressed to values equal to or greater than the decibel amounts s h o w n in Fig. 1, and at least one of these sites is depressed by 12 decibels or more. Any two test sites are contiguous if they are diagonally, horizontally, or vertically adjacent. The visual field score becomes larger with increases in the n u m b e r of depressed test sites and with increased depth of the depressions [16]. Field defect scores are classified into five groups: 0 (no defect), 1-5 (mild), 6-11 (moderate), 12-17 (severe), 18-20 (end-stage).

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UPPER HEMI FIELD NASAL~~7

TEMPORAL .OWER HEMI FIELD

Figure 1 Threshold decibel values in the three sectors of the C-24-2 field Statpac total deviation plot. Depressions equal to or greater than threshold values in contiguous locations indicate abnormality.

Intraocular Pressure. At the time of IOP m e a s u r e m e n t , (1) the eye m u s t not h a v e received pupil dilating medications at the current visit to the clinic and (2) the last g l a u c o m a medications m u s t h a v e been taken recently e n o u g h to satisfy the criteria of Table 3. IOP is m e a s u r e d with a G o l d m a n n applanation t o n o m e t e r on a slit-lamp biomicroscope. Calibration is checked at least every 6 m o n t h s with the weight s y s t e m at 0, 2, and 6 g. The variation m u s t be within + 2 m m H g for the t o n o m e t e r to be used. The IOP m e a s u r e m e n t , after topical anesthesia and fluorescein, is usually p e r f o r m e d b y two persons, an operator and a reader. The reading in m m H g is r o u n d e d to the next higher integer. Each m e a s u r e m e n t is repeated, and if the two m e a s u r e m e n t s differ b y 3 m m H g or more, a third m e a s u r e m e n t is taken. The m e d i a n of the two or three m e a s u r e m e n t s b e c o m e s the determination.

Table 3

Time Intervals During Which Intraocular Pressure Must Be Measured

Type of Prescribed Glaucoma Treatment

Prescribed Daily Frequency

Time Interval from Last Treatment to Pressure Measurement

Massage Pilocarpine Ocusert Pilopine 4% ointment Other medication Other medication Other medication Other medication

---4 times daily 3 times daily 2 times daily Once daily

At least 1 hr 10 hr to 7 days 4-24 hr 1-6 hr 1-8 hr 1-12 hr 1-24 hr

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Gonioscopy. Gonioscopy is performed at a slit-lamp biomicroscope after the eye is topically anesthesized and a mirrored gonioscopy lens is applied to the cornea. The number of clock-hours of the circumference of the trabecular meshwork containing peripheral anterior synechiae and the height (or extension) of the highest synechiae in each involved quadrant is determined. Funduscopy. The

clinical morphology of the optic disk is assessed at a slitlamp biomicroscope after dilating the pupil with mydriatics and applying a lens for stereoscopic viewing. Recorded are the nasal, superior, temporal, and inferior neural rim widths in disk diameters, the meridional location of the thinnest rim, the presence of notching, and the presence of hemorrhage(s) on the rim tissue or adjacent peripapillary retina.

Reference Baseline Values Intraocular pressure and visual field measurements tend to fluctuate considerably from time to time. Because of this variability, and because measurements made for determination of eligibility were restricted in range but follow-up measurements were not, follow-up changes, if measured from the baseline eligibility value, would be subject to regression to the mean or "from the mean" [18]. To obviate the regression problem, the study protocol required that additional "reference" measurements of IOP and visual field be taken at least one day after the eligibility measurement but before the initial glaucoma surgery was performed. Changes from baseline in IOP and visual field score are measured from the reference values rather than from the eligibility values. The reference values, which did not affect eligibility, were not constrained, as were the eligibility values, by imposed lower or upper limits.

Frequency of Measurements At baseline visual acuity, gonioscopy, and funduscopy were each assessed once, visual field twice, and IOP three times. Except for the second visual field and the third IOP, which served as reference values, these measurements were used to determine eligibility. IOP is also determined at 1 and 4 weeks after each glaucoma operation. During follow-up, visual acuity, visual field, and IOP are assessed at 3 and 6 months after enrollment, and every 6 months thereafter. Gonioscopy is performed at 3 and 18 months after enrollment, and every 12 months thereafter. Funduscopy is performed at 6 and 12 months after enrollment, and every 12 months thereafter.

Surgical Treatments for Glaucoma

Trabeculectomy. In trabeculectomy a small segment of the trabecular meshwork is surgically removed. The goal of this filtering operation is to improve fluid drainage out of the anterior chamber of the eye to the space beneath the conjunctiva, the thin membrane that covers the sclera (the white of the eye).

308

AGIS Investigators In AGIS, a standard trabeculectomy [19] is performed in an operating room with the use of an operating microscope after local or general anesthesia. The u p p e r nasal quadrant is the preferred surgical site, with the u p p e r temporal quadrant as the next choice. Postoperative laser suture lysis is permitted.

Argon Laser Trabeculoplasty (ALT). In trabeculoplasty, an outpatient procedure, the laser is used to make small burns in the trabecular meshwork. A mirrored contact lens with an antireflective coating is placed against the cornea after topical anesthesia. In AGIS, half of the trabecular m e s h w o r k is treated in each of two sessions 1-6 weeks apart. In each session the surgeon evenly distributes about 50 laser applications over 180 ° on the trabecular meshwork, always turning the mirrored lens clockwise, starting with the mirror of the lens at the 12 o'clock meridian in the first half and at the 6 o'clock meridian in the second half. The spots of the laser application are 50 ~,m in air and 0.1 sec in duration, with the energy setting sufficient to cause blanching at the threshold of bubble formation in the target tissue. The p o w e r setting is in the range of 0.4-1.2 watts. When ALT is the second operation in the sequence, the treatment m a y be limited by the presence of peripheral anterior synechiae (PAS): if the treatable part of the circumference is reduced to less than 240 ° by PAS, ALT is completed in one session; if the treatable circumference is reduced to less than 90 °, or if ALT is otherwise contraindicated, the p r o c e d u r e is not performed; rather, the eye is treated by the third operation in the sequence, which in both sequences is trabeculectomy.

Cataract Surgery. An ophthalmologist participating in AGIS is authorized to perform cataract surgery on AGIS eyes with visual acuity defects only if (1) the ophthalmologist believes that the defect is due to cataract, (2) the patient states that the defect is adversely affecting his or her lifestyle, and (3) either the visual acuity score is less than 65 (the approximate Snellen equivalent is 20/50) or the Operations Committee approves, in recognition of the patient's special needs, an exception to the visual acuity requirement. Cataract operations in AGIS are not authorized (1) in the interval between the occurrrences of a treatment failure and the next assigned glaucoma operation, (2) in the interval between the occurrences of an assigned glaucoma operation and the next scheduled 3- or 6-month visit, or (3) less than 3 months after the occurrence of an assigned glaucoma operation. An eye requiring cataract removal receives conventional cataract surgery if, since the most recent glaucoma operation, (1) the IOP has been consistently ~17 m m Hg, (2) no glaucoma medications are currently prescribed, and (3) the most recent visual field score is less than 10. Otherwise the eye may receive, at the ophthalmologist's discretion, either conventional cataract surgery or a combined cataract-trabeculectomy procedure. The combined procedure is considered cataract surgery, not glaucoma surgery, and therefore cannot be one of the operations in the assigned sequence. Antimetabolite Treatment. Before 1990, in the absence of their demonstrated effectiveness as adjuncts to glaucoma surgery, antimetabolites were not used in AGIS. AGIS surgeons have used postoperative 5-fluorouracil since 1990

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and intraoperative mitomycin C since 1991. Indications for antimetabolite treatment in AGIS are based on evidence of effectiveness [20-23], and treatment is limited to defined situations. Adjunctive use of antimetabolites in AGIS is mandatory for all second trabeculectomies and for first trabeculectomies when the eye has had previous cataract surgery; use is optional, at the discretion of the ophthalmologist, for all combined cataract-trabeculectomy operations and for any surgery on eyes that have failed two or more previous filtering operations. No other uses of antimetabolites are authorized in AGIS. The method, dosage, and schedule of administration follow specifications detailed in the study protocol [1, section 9.3].

Encapsulated Bleb. Encapsulated bleb, a postoperative complication of trabeculectomy, is managed according to a three-step strategy, with the next step taken only if the preceding step fails: (1) medical therapy, (2) needling, and (3) revision [1, chapter 15]. Adherence to Medical Therapy Throughout the enrollment period, from April 1, 1988 to November 30, 1992, an interviewer at the coordinating center interviewed study patients by telephone regarding their adherence to medical therapy. All patients were interviewed at baseline regarding preenrollment adherence, and those who completed the 12-month visit before August 31, 1992 were also interviewed at about the time of that visit regarding postenrollment adherence. The conduct of the interviews from a central rather than local site was an attempt to avoid response bias due to the possible tendency of patients to want to please the doctor or the coordinator. For similar reasons, the purpose of the interview was blurred by including questions about the quality of the patient's life. The patients were told and reminded that the information from the interview would not be made available to the staff at their clinical center.

Quality Enhancement The AGIS protocol to enhance data quality comprises training and certification of personnel, internal clinic monitoring, and external clinic monitoring.

Training and Certification of Clinic Personnel. Clinical center personnel must be trained and certified to conduct the following AGIS activities: refraction, visual acuity measurement, visual field testing and scoring, IOP determination, IOP reading, data forms completion, patient enrollment, trabeculectomy, and ALT. For each activity there are three progressive levels of certification: preliminary, provisional, and full. Examiners must be provisionally certified and ophthalmic surgeons fully certified to perform these activities on AGIS patients. Provisional certification expires after one year. Full certification is renewed annually based on evidence that the activity has been performed a specified minimum number of times during the year. The training and certification faculty established standards of certification and designated AGIS certifiers.

AGIS Investigators

310

Internal Clinic Monitoring. Each clinic director designates a clinic staff member to be the clinic monitor, who is responsible for maintaining adherence to study procedures within that clinic by monitoring the functioning and calibration of equipment, the training and certification of personnel, the carrying out of procedures, the completion of data forms, and prevention of patient's dropping out and missing visits. The clinic monitor reports problems that potentially affect data quality to the clinic director and the protocol monitor (see below). External Clinic Monitoring. External clinic monitoring is carried out by editing the centrally collected data for completeness, internal consistency, and outliers, and by three activities of the protocol monitor, who is a coordinating center staff member: structured, regularly scheduled telephone calls (protocol review calls) to each clinical center, periodic protocol review visits to each clinical center, and monthly reports of findings to the Operations Committee. The protocol review calls were held weekly at the outset and then gradually decreased in frequency to four times a year. The calls follow a structured agenda that includes questions about staff changes, functioning and calibration of equipment, patient recruitment, satisfaction of patients with clinic visits, satisfaction of staff with working conditions, problems in meeting study requirements, and problems in completing data forms. During the protocol review visits the protocol monitor reviews the clinical center's operations, checks examining equipment for proper functioning and calibration, observes patient examinations, audits samples of data forms that had been submitted to the coordinating center to assure accurate transcription from clinic records, audits, completeness of follow-up of potential failures and reporting of failures, and discusses operational problems with staff.

Primary and Secondary Response Variables Sustained decrease of vision and decrease of vision are, respectively, the AGIS primary and secondary response variables. In defining these variables, we introduce the following terms. DVF, decrease of visual field, is the occurrence in an eye at any scheduled 6-month follow-up examination of an increase (worsening) from reference value of four or more points in visual field score. DVA, decrease of visual acuity, is the occurrence in an eye at any scheduled 6-month follow-up examination of a decrease (worsening) from eligibility value of 15 or more points (letters) in visual acuity score. VF, visual field score, is the occurrence in an eye at any scheduled 6-month follow-up examination of a visual field score of 19 or more. Decrease of vision is the occurrence in an eye of DVF, DVA, or VF. Sustained decrease of vision is the occurrence in an eye of decrease of vision at each of 3 consecutive 6-month follow-up examinations. Should an eye have multiple occurrences of sustained decrease of vision, only the first occurrence is counted. The event sustained decrease of vision occurs at its consummation, i.e., at the third consecutive 6-month follow-up examination at which decrease of vision occurred.

311

AGIS Design and Methods Table 4

95% Confidence Intervals for Various Percentages of Event Rates Based on Sample Sizes of 400 and 200 Percentage

N = 400

N = 200

1 5 10 20 30 40 50 60

0.3-2.5 3.1-7.6 7.2-13.4 16.2-24.3 25.6-34.8 35.2-45.0 45.0-55.0 55.0-64.8

0.1-3.6 2.4-9.0 6.2-15.0 14.7-26.2 23.8-36.9 33.2-47.2 42.9-57.1 52.8-66.8

Sample Size The m i n i m u m sample size requirement of 790 eyes is based on an average follow-up of 5 years. To provide protection against dropouts, including deaths, losses to follow-up, and missed visits, the calculated sample size was increased to 790 by 15%, 10% for deaths and 5% for other losses. The major contrast to be m a d e in the comparative study is P(A) - P(T), where P(A) and P(T), respectively, designate the 5-year incidence rates of sustained decrease of vision in the groups assigned to sequences beginning with ALT and trabeculectomy. Based on the data of Rollins and Drance [11], we estimate the larger of the two 5-year event rates to be 40%. We would like to be able to show that the lower of the two rates is smaller by a factor of one-third. At two-tailed ot = 0.01 and ~ = 0.20, Idl = P(A) - P(T) -> 0.133 From the approximate formula given by Kahn [24], the m i n i m u m sample size n e e d e d for each group, uncorrected for dropouts, is 336 eyes. Corrected for an estimated 15% dropouts, the m i n i m u m sample size becomes 395 eyes per g r o u p or 790 eyes in all. The s t u d y of clinical course and prognosis has n u m e r o u s outcome variables, most of which are expressable as percentages, such as rates of sustained decrease of vision, decrease of vision, failure of surgery, and complications of surgery, and percentage of time patient was prescribed medical therapy. Table 4 shows 95% confidence intervals for various percentages in each assigned treatment sequence, assuming a sample size of 400 eyes in each sequence and, alternatively, 200 eyes in each sequence. The n u m b e r 400 represents an approximation of the initial n u m b e r of eyes in each sequence, while 200 approximates the n u m b e r that might start the second assigned surgical treatment in each sequence. The confidence intervals for the 400 eyes are narrow; for the 200 eyes they are wider but still sufficiently n a r r o w to yield useful information. BASELINE CHARACTERISTICS OF STUDY PATIENTS A N D EYES Of the 789 s t u d y eyes, 12 were enrolled with inadequate documentation or incorrect determination of eligibility (Table 5). An additional 3 eyes were misstratified at randomization because of incorrectly reported visual field scores.

312

AGIS Investigators Table 5

N u m b e r of Eyes Enrolled with I n a d e q u a t e D o c u m e n t a t i o n or Incorrect Determination of Eligibility Number

First of two eligibility IOP determinations made more than 30 days before enrollment Visual field test before the eligibility visual field test to document visual field deterioration of ~3 --not done --done while eve was not on maximum tolerated and effective medications Eye not on maximum tolerated and effective medications for first eligibility IOP determination Visual field score incorrectly determined TOTAL

4 2 12

The information on patient a n d eye characteristics presented in Tables 6-10 describes the patient p o p u l a t i o n and s h o w s that r a n d o m i z a t i o n generally succeeded in creating two g r o u p s with similar characteristics.

Patient and Eye Characteristics Baseline patient a n d eye characteristics are classified in Tables 6 (demographic characteristics), 8 (medical characteristics), and 9 (ocular characteristics) according to w h e t h e r both eyes or one eye w a s enrolled, and, if one eye, according to assigned treatment sequence. Table 7 cross-classifies the patients according to age at enrollment, sex, and race. Of the 591 enrolled patients, 46% are m e n and 54% w o m e n ; 42% are white, 56% black, and 2% other races; at baseline, 53% w e r e married, 62% had at least a high school education, a n d 61% w e r e 65 or m o r e years old (Table 6). White patients tended to be older than black patients, with 65% of white patients and 58% of black patients aged 65 or m o r e (Table 7). W o m e n , particularly white w o m e n , tended to be older than men: 72% of white w o m e n and 59% of black w o m e n were aged 65 or more. The c o r r e s p o n d i n g percentages for white and black m e n w e r e 58 and 56, respectively (Table 7). Only 10 patients w e r e of race other than white or black, too few for a m e a n i n g f u l analysis of age a n d sex. At baseline, 38% of patients reported h a v i n g at least one first-degree relative with o p e n - a n g l e glaucoma, a n d an additional 7% reported h a v i n g a m o r e distant blood relative with the disease. Fifty percent said they had systemic hypertension, 20% that they h a d other vascular or coronary disease, 11% that they h a d been prescribed systemic ~ blockers, and 20% that they had diabetes (Table 8). Of the 789 s t u d y eyes, 52% w e r e right eyes and 48% left eyes; 12% had h a d laser iridotomy. The distribution of eyes according to eligibility visual field defect w a s 25% mild, 45% m o d e r a t e , a n d 30% severe; the distribution according to reference visual field defect w a s 3% none, 29% mild, 40% moderate, 27% severe, a n d 1.5% end-stage. Thus, b e t w e e n the eligibility a n d reference visual fields, there w a s an increase in the percentage of scores at both ends of the

42.1 56.2 1.7

8.0 53.1 14.9 24.0

8.1 29.9 33.3 21.8 6.8

3.6 10.2 25.5 44.2 16.6

249 332 10

47 314 88 142

48 177 197 129 40

21 60 151 261 98

a

ALT-trabeculectomy-trabeculectomy. bTrabeculectomy-ALT-trabeculectomy.

45.7 54.3

270 321

67.0

100.0

591

All patients Sex Male Female Race White Black Other Marital status Never married Married Divorced or separated Widowed Education Grade 6 or less Grades 7-11 High school graduate Some college Some graduate school Age 35-44 45-54 55-64 65-74 75-80 Median age

%

No.

All Patients

6 21 45 87 39

20 64 68 36 10

16 94 30 58

76 119 3

73 125

198

No.

68.0

3.0 10.6 22.7 43.9 19.7

10.1 32.3 34.3 18.2 5.1

8.1 47.5 15.2 29.3

38.4 60.1 1.5

36.9 63.1

100.0

%

Both Eyes Entered

2 22 51 94 37

13 57 73 48 15

13 109 28 56

82 121 3

99 107

206

No.

68.0

%

1.0 10.7 24.8 45.6 18.0

6.3 27.7 35.4 23.3 7.3

6.3 52.9 13.6 27.2

39.8 58.7 1.5

48.1 51.9

100.0

A-T-Ta

13 17 55 80 22

15 56 56 45 15

18 111 30 28

91 92 4

98 89

187

No.

65.0

%

7.0 9.1 29.4 42.8 11.8

8.0 29.9 29.9 24.1 8.0

9.6 59.4 16.0 15.0

48.7 49.2 2.1

52.4 47.6

100.0

T-A-Tb

One Eye Entered

Patients

8 43 96 181 76

33 121 141 84 25

29 203 58 114

158 240 6

172 232

404

No.

68.0

%

2.0 10.6 23.8 44.8 18.8

8.2 30.0 34.9 20.8 6.2

7.2 50.2 14.4 28.2

39.1 59.4 1.5

42.6 57.4

100.0

A-T-T

Eyes

19 38 100 167 61

35 120 124 81 25

34 205 60 86

167 211 7

171 214

385

No.

67.0

%

4.9 9.9 26.0 43.4 15.8

9.1 31.2 32.2 21.0 6.5

8.8 53.3 15.6 22.3

43.4 54.8 1.8

44.4 55.6

100.0

T-A-T

D i s t r i b u t i o n of P a t i e n t s A c c o r d i n g to Baseline D e m o g r a p h i c Characteristics a n d A s s i g n e d T r e a t m e n t S e q u e n c e

Characteristic

Table 6

314 Table 7

AGIS Investigators Distribution of Patients According to Age at Enrollment, by Race and Sex Age at Enrollment 35-44

45-54

Patients

No.

%

No.

All White Black Other Male White Black Other Female White Black Other

21 8 12 1 10 5 5 0 11 3 7 1

3.6 3.2 3.6 10.0 3.7 3.8 3.7 0.0 3.4 2.5 3.6 16.7

60 13 46 1 21 6 14 1 39 7 32 0

%

55-64 No.

10.2 151 5.2 66 13.9 82 10.0 3 7.8 84 4.6 43 10.3 41 25.0 0 12.1 67 5.9 23 16.3 41 0.0 3

65-74

75-80

All ages

%

No.

%

No.

%

No.

%

Median age

25.5 26.5 24.7 30.0 31.1 33.1 30.1 0.0 20.9 19.3 20.9 50.0

261 124 135 2 119 60 58 1 142 64 77 1

44.2 49.8 40.7 20.0 44.1 46.2 42.6 25.0 44.2 53.8 39.3 16.7

98 38 57 3 36 16 18 2 62 22 39 1

16.6 15.3 17.2 30.0 13.3 12.3 13.2 50.0 19.3 18.5 19.9 16.7

591 249 332 10 270 130 136 4 321 119 196 6

100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0

67.0 68.0 67.0 63.5 66.0 66.0 65.5 70.0 68.0 69.0 67.0 62.0

severity scale: the percentage that had no defect or a mild defect increased from 25% to 32%, and the percent end-stage increased from 0 to 1.5. These changes m a y have occurred because of regression to or from the mean [18], i.e., the constraints on visual field scores at eligibility ( m i n i m u m of 1 and m a x i m u m of 16) were lifted for the reference test. Five percent of second eligibility IOP determinations were 18 to 20 m m Hg, 57% 21-25 m m Hg, and 38% 26 m m H g or more. Reference IOPs were generally lower, likely a consequence of regression to the mean; in particular, the percentage u n d e r 20 m m H g increased from 5 to 25. With respect to all characteristics in Tables 6, 8, and 9, the percent distributions in patients with both eyes entered were similar to those with one eye entered. The m e d i a n duration of glaucoma at the time of enrollment was substantially shorter for blacks (4 years) than for whites (6 years), indicating that the disease progressed to the a d v a n c e d stage more rapidly in blacks, or that g l a u c o m a diagnosis was delayed longer in blacks (Table 10). At the time of enrollment, all patients were on m a x i m u m tolerated and effective medications for glaucoma. The average n u m b e r of prescribed medications per patient was 2.7 (Table 11). Less than 3% of patients were not prescribed any medications, either because the medications were not effective or because the patients did not accept or tolerate them. A b o u t 88% of patients were prescribed ~ blockers, 80% miotics, 52% carbonic anhydrase inhibitors, and 47% epinephrine (Table 12). Nine eyes of six patients w h o entered the s t u d y failed to receive an initial assigned surgical treatment because the patients refused. Three additional eyes received initial glaucoma treatments that were opposite to the assigned operations: in one patient, because of a clinic error, the eye assigned to initial ALT received trabeculectomy, and the eye assigned to initial trabeculectomy received ALT. A n eye in another patient received initial ALT when the assigned trabeculectomy became contraindicated because of unstable angina.

19.8

11.0 20.3 6.3 8.3 5.8

225 42 297

117

65 120 37 49 34

aALT-trabeculectomy-trabeculectomy. ~Trabeculectomy-ALT-trabeculectomy. cParents, siblings, or children.

38.1 7.1 50.3

591

%

100.0

No.

Characteristic

All Patients

15 42 14 13 15

43

80 10 106

198

No."

7.6 21.2 7.1 6.6 7.6

21.7

40.4 5.1 53.5

100.0

%

Both Eyes Entered

30 53 17 23 13

43

70 20 113

206

No.

%

14.6 25.7 8.3 11.2 6.3

20.9

34.0 9.7 54.9

100.0

A-T-T~

20 25 6 13 6

31

75 12 78

187

No.

%

10.7 13.4 3.2 7.0 3.2

16.6

40.1 6.4 41.7

100.0

T-A-Tb

One Eye Entered

Patients

45 95 31 36 28

86

150 30 219

404

No.

%

11.1 23.5 7.7 8.9 6.9

21.3

37.1 7.4 54.2

35 67 20 26 21

74

155 22 184

385

No.

All eyes

100.0

A-T-T

D i s t r i b u t i o n of P a t i e n t s A c c o r d i n g to Baseline M e d i c a l H i s t o r y a n d A s s i g n e d T r e a t m e n t S e q u e n c e

All patients Blood relatives with open-angle glaucoma First degree ~ More distant With hypertension With vascular or coronary disease With prescribed systemic blockers With diabetes, total Diet only Oral medications Insulin

Table 8

%

9.1 17.4 5.2 6.8 5.5

19.2

40.3 5.7 47.8

100.0

T-A-T

316 Table 9

AGIS Investigators D i s t r i b u t i o n of E y e s A c c o r d i n g to B a s e l i n e O c u l a r C h a r a c t e r i s t i c s and Assigned Treatment Sequence ALT-trabeculectomytrabeculectomy

Total

TrabeculectomyALT-trabeculectomy

Characteristic

No.

%

No.

%

No.

%

N u m b e r of eyes Laterality of eye Right Left Had previous laser iridotomy Eligibility visual field defect 1-5 (mild) 6-11 (moderate) 12-16 (severe) 17 (severe) Mean Median Reference visual field defect 0 (none) 1-5 (mild) 6-11 (moderate) 12-17 (severe) 18-20 (end-stage) Mean Median Second a eligibility intraocular pressure 18-20 m m Hg 21-22 m m Hg 23-25 m m Hg ->26 m m Hg Mean Median Reference intraocular pressure 0-20 m m Hg 21-22 m m Hg 23-25 m m Hg ->26 m m Hg Mean Median Eligibility criterion b A B C D E F G H I Not available

789

100.0

404

100.0

385

100.0

408 381 91

51.7 48.3 11.5

212 192 46

52.5 47.5 11.4

196 189 45

50.9 49.1 11.7

197 356 235 1

25.0 45.1 29.8 0.1

92 199 112 1

22.8 49.3 27.7 0.2

105 157 123 0

27.3 40.8 31.9 0.0

8.9 9.0 22 226 313 216 12

8.9 9.0 2.8 28.6 39.7 27.4 1.5

11 108 165 114 6

8.5 8.0

8.8 9.0 2.7 26.7 40.8 28.2 1.5

11 118 148 102 6

8.6 8.5

40 164 284 301 25.5 24.5

5.1 20.8 36.0 38.1

196 167 191 235 24.0 23.0

24.8 21.2 24.2 29.8

19 55 20 73 119 120 159 139 73 12

2.4 7.0 2.5 9.3 15.1 15.2 20.2 17.6 9.3 1.5

18 79 157 150

8.3 8.0

4.5 19.6 38.9 37.1

25.5 24.5 25.0 21.0 26.0 28.0

24.7 21.3 22.3 31.7

95 82 86 122 24.2 23.0

23.9 23.0 8 28 11 35 61 70 81 71 34 5

5.7 22.1 33.0 39.2

22 85 127 151

25.5 24.5 101 85 105 113

2.9 30.6 38.4 26.5 1.6

2.0 6.9 2.7 8.7 15.1 17.3 20.0 17.6 8.4 1.2

11 27 9 38 58 50 78 68 39 7

2.9 7.0 2.3 9.9 15.1 13.0 20.3 17.7 10.1 1.8

317

AGIS Design and Methods Table 9

Continued ALT-trabeculectomytrabeculectomy

Total Characteristic Characteristics of eyes meeting eligibility criterion Bc Hemorrhage ->50% decrease in rim width Notch to edge ->0.2 increase in cup/disk ratio Eligibility visual acuity score 56~4 65-74 75-85 >-86 Mean Median

TrabeculectomyALT-trabeculectomy

No.

%

No.

%

No.

%

7 36 21

12.7 65.5 38.2

5 18 11

17.9 64.3 39.3

2 18 10

7.4 66.7 37.0

18

32.7

10

35.7

8

29.6

47 6.0 164 20.8 374 47.4 204 25.9 79.4 81.0

17 91 192 104

4.2 22.5 47.5 25.7

30 73 182 100

7.8 19.0 47.3 26.0

79.5 81.0

79.3 80.0

aSecond of two eligibility intraocular pressures; eight of the first eligibility intraocular pressure values lacked adequate documentation of satisfying the eligibility criteria, bSee Table 1 for definitions of eligibility criteria. cCriterion B is a combination of (1) disk deterioration while patient was on maximum medical therapy and (2) visual field score ->2. Some eyes had more than one disk deterioration characteristic.

Comparison of Characteristics of the Two Randomized Groups The c o m p a r i s o n s of eyes assigned to the two r a n d o m i z e d sequences s h o w that m o s t characteristics of the two g r o u p s are similar, with the following exceptions: eyes assigned to A-T-T, s o m e w h a t m o r e often than eyes assigned to T-A-T, w e r e in patients w h o w e r e old, female, or black, or w h o had h y p e r t e n s i o n or diabetes.

DISCUSSION AGIS, with 789 eyes of 591 patients enrolled, is the largest r a n d o m i z e d trial of g l a u c o m a to date. The G l a u c o m a Laser Trial (GLT), a s t u d y of n e w l y d i a g n o s e d open-angle glaucoma, enrolled 542 eyes of 271 patients, r a n d o m l y assigning one eye to ALT and the other to medical treatment [25,26]. Visual function o u t c o m e s are being d e t e r m i n e d in the ongoing G l a u c o m a Laser Trial Followup Study. Other studies h a v e c o m p a r e d medical m a n a g e m e n t with trabeculoplasty or filtering surgery in patients n e w l y diagnosed with glauc o m a [27-30]. T w o small studies of a d v a n c e d open-angle g l a u c o m a (i.e., after medical t r e a t m e n t failed) h a v e c o m p a r e d effects of two initial surgical treatments, trabeculectomy and thermal sclerostomy [31,32]. W h e n both of a patient's eyes w e r e simultaneously eligible for enrollment in AGIS, both w e r e usually enrolled. The investigators agreed that w h e n both eyes w e r e enrolled, then, to m i n i m i z e risk of vision loss in both eyes, the two eyes w o u l d need to be assigned to opposite surgical treatment sequences (i.e., if one eye was assigned to A-T-T, the other eye w o u l d be assigned to T-A-T, and vice versa). A s t u d y design issue that arose in the p l a n n i n g stage was w h e t h e r the fellow eye of an AGIS patient that was not eligible at the time of

110 36 73 1 46 19 27 0 64 17 46 1

White Black Other Male White Black Other Female White Black Other

No.

Patients

<2

%

18.6 14.5 22.0 10.0 17.0 14.6 19.9 0.0 19.9 14.3 23.5 16.7

169 57 109 3 75 28 45 2 94 29 64 1

No.

2-4 % 28.6 22.9 32.8 30.0 27.8 21.5 33.1 50.0 29.4 24.4 32.7 16.7

139 64 70 5 69 38 29 2 70 26 41 3

No.

5- 9 % 23.5 25.7 21.1 50.0 25.6 29.2 21.3 50.0 21.8 21.8 20.9 50.0

101 52 48 1 51 28 23 0 50 24 25 1

No.

% 17.1 20.9 14.5 10.0 18.9 21.5 16.9 0.0 15.6 20,2 12.8 16.7

10 -14

72 40 32 0 29 17 12 0 43 23 20 0

No.

~ 15

12.2 16.1 9.6 0.0 10.7 13.1 8.8 0.0 13.2 19.3 10.2 0.0

%

591 249 332 10 270 130 136 4 321 119 196 6

100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0

%

Any duration No.

Years of Duration of Glaucoma Since Reported Diagnosis

6.9 8.0 6.0 5.3 6.8 7.6 6.2 4.5 6.9 8.5 5.9 5.8

5.0 6.0 4.0 5.5 5.5 6.0 4.0 4.5 5.0 6.0 4.0 6.0

Median

Average duration Mean

D i s t r i b u t i o n of P a t i e n t s A c c o r d i n g to Years of D u r a t i o n of G l a u c o m a Since R e p o r t e d Year of D i a g n o s i s , b y Sex a n d Race

All

333

T a b l e 10

319

AGIS Design and Methods Table 11

Distribution of Eyes According to N u m b e r of Prescribed Glaucoma Medications at Baseline, by Assigned Treatment Sequence ALT-trabeculectomytrabeculectomy

Total No of Prescribed Medications Any or none 0 1

2 3 4 Mean no. of medications

Trabeculectomy-ALTtrabeculectomy

No. of eyes

%

No. of eyes

%

No. of eyes

~

789 20 70 226 312 161

100.0 2.5 8.9 28.6 39.5 20.4

404 11 37 111 163 82

100.0 2.7 9.2 27.5 40.3 20.3

385 9 33 115 149 79

100.0 2.3 8.6 29.9 38.7 20.5

2.7

2.7

2.7

enrollment of the first eye (e.g., because the IOP was not high enough) could be enrolled at a later time during patient follow-up if the eye then met the eligibility criteria. Since all fellow eyes, whether enrolled or not, were being followed anyway, it would take little additional effort to include them in the study if they became eligible. Ultimately it was decided not to enroll these eyes for the following reasons. Whereas at the time the patient was enrolled neither the patient nor the physician k n e w the u p c o m i n g treatment sequence, if the fellow eye was going to be enrolled during follow-up, both the patient and the doctor w o u l d k n o w in advance that the assignment would be opposite that of the first eye. AGIS investigators and the Policy and Treatment Effects Monitoring Board were concerned about possible enrollment bias derived from this foreknowledge. For example, having achieved a good result with the initial surgical intervention in the first eye, a patient might refuse the opposite intervention for the second eye; or, an AGIS ophthalmologist w h o thought that the assigned intervention was not optimal might find a way, on the basis of borderline eligibility characteristics, to render the second eye ineligible. Whether such biases would in fact occur, the study design could be criticized on the basis of their possible occurrence. AGIS was not designed to be a study of patients w h o are representative of advanced glaucoma patients in the United States, or even of patients in the catchment areas of the 11 AGIS clinical centers. AGIS patients, at the time of enrollment, either had been u n d e r care for glaucoma at one of the 11 clinical centers participating in AGIS or had been referred to an AGIS clinical center for care by another ophthalmologist. Figure 2 compares, in a cumulative percent distribution, the ages at baseline of the 271 patients enrolled in the GLT with those of the 591 patients enrolled in AGIS. GLT patients, all of w h o m were newly diagnosed with glaucoma at the time of enrollment, were recruited in a m a n n e r similar to that used by AGIS. Because differences in sex and race distributions between the two studies, though small, could affect the age comparisons, in Fig. 2 we adjusted the age distributions for race and sex by the direct m e t h o d of standardization [33] using the GLT race-sex distribution as a standard. The estimated m e d i a n ages are 67 for AGIS and 61 for GLT. The 6-year difference

320 Table

AGIS

12

Frequency of Glaucoma Treatment Sequence

Medication

Use at Baseline, by Assigned

ALT-trabeculectomytrabeculectomy

Total

Investigators

TrabeculectomyALT-trabeculectomy

Treatment sequence

No.

%

No.

%

No.

%

Numberofeyes A. Miotic Prescribed Contraindicated or patient intolerant Not effective Not prescribed B. B blocker Prescribed Contraindicated or patient intolerant Not effective Not prescribed C. Epinephrine Prescribed Contraindicated or patient intolerant Not effective Not prescribed D. Carbonic anhydrase inhibitor Prescribed Contraindicated or patient intolerant Not effective Not prescribed Summary of medications prescribed” A and (B or C) and D [Aor(BorC)]andD, A and (B or C) but not D A or (B or Cl but not D D only None

789

100.0

404

100.0

385

100.0

634

80.4

328

81.2

306

79.5

127 28 0

16.1 3.5 0.0

61 15 0

15.1 3.7 0.0

66 13 0

17.1 3.4 0.0

690

87.5

350

86.6

340

88.3

80 0 19

10.1 0.0 2.4

42 0 12

10.4 0.0 3.0

38 0 7

9.9 0.0 1.8

370

46.9

185

45.8

185

48.1

119 194 106

15.1 24.6 13.4

58 102 59

14.4 25.2 14.6

61 92 47

15.8 23.9 12.2

408

51.7

213

52.7

195

50.6

349 32 0

44.2 4.1 0.0

173 18 0

42.8 4.5 0.0

176 14 0

45.7 3.6 0.0

341 63 265 96 4 20

43.2 8.0 33.6 12.2 0.5 2.5

179 32 132 48 2 11

44.3 7.9 32.7 11.9 0.5 2.7

162 31 133 48 2 9

42.1 8.1 34.5 12.5 0.5 2.3

aThe letters refer to the above types of medications.

in median age between the two populations is similar to the 5-year median duration of glaucoma since diagnosis in the AGIS patients. Thus, an interval from diagnosis of glaucoma to the onset of advanced glaucoma of about 5 or 6 years appears characteristic of the AGIS patients. As noted earlier, this duration is shorter for blacks than whites by an average of about 2 years (Table 10). Randomization ap$ears to have succeeded in creating two assignment groups that are well balanced with respect to most baseline demographic, medical, and ocular characteristics. The exceptions to this balance in demographic and medical history characteristics will warrant attention at the time of ‘data analysis of the outcomes of the two surgical treatment sequences.

AGIS Design and Methods

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60 -

E

$ 60b a al

40

50

60

70

60

Age at enrollment (years)

Figure 2

Cumulative percent distributions of ages at enrollment of AGIS and GLT patients. The AGIS distribution has been adjusted to the GLT sex and race distribution by the direct method.

The Advanced Glaucoma Intervention Study is supported by grants from the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services (grant nos. 2 UlO EY06824-06 through 2 UlO EY06827-06,2 UlO EY06830-06 through 2 UlO EY06835-06, 2 UlO EY07057-06, and 7 UlO EY09640-02). We are grateful to the Glaucoma Laser Trial (GLT) Research Group for providing us with data on the age-sex-race distribution of GLT patients.

REFERENCES 1. Advanced Glaucoma Intervention Study (AGIS) Manual of Operations: National Technical Information Service, Accession No. PB93-220192. Springfield, VA 2. American Academy of Ophthalmology Quality of Care Committee, Glaucoma Panel: Preferred practice pattern: primary open-angle glaucoma. American Academy of Ophthalmology, San Francisco, 1992 3. Grinich NP, VanBuskirk EM, Samples JR The long-term efficacy of argon laser trabeculoplasty. Abstract. Ophthalmology 92, Program Supplement: 100, 1985 4. Schwartz AL, Love DC, Schwartz MA: Long-term follow-up of argon laser trabeculoplasty for uncontrolled open-angle glaucoma. Arch Ophthalmol 103:14821484, 1985 5. Gilbert CM, Brown RH: The effect of argon laser trabeculoplasty on the management of primary open angle glaucoma in a resident clinic. Invest Ophthalmol Vis Sci (Suppl) 26:226, March 1985 (Abstract) 6. Gaasterland DE, Ederer F: A general approach to the management of difficult glaucoma; advanced glaucoma. In: The Clinician’s Guide to the Management of

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7. 8. 9. 10.

11.

12. 13.

14. 15. 16. 17.

18. 19. 20. 21. 22. 23.

24. 25. 26. 27. 28.

Difficult Glaucoma. Higginbotham and Lee, eds. Blackwell Scientific, Oxford, 1994, pp 215-228 Jerndal T, Lundstrom M: 330 trabeculectomies: a long time study (3-5 1/2 years). Acta Ophthalmologica 58:947, 1980 Shields MB: Surgery of the anterior chamber angle. Laser trabeculoplasty. In: Textbook of Glaucoma. 3rd ed. Williams and Wilkins, Baltimore, 1992, pp 538-547 Shields MB: Filtering surgery. In: Textbook of Glaucoma. 2nd ed. Williams and Wilkins, Baltimore, 1992, pp 577-611 Watson PG, Allen ED, Graham CM, Porter GP, Pickering MS: Argon laser trabeculoplasty or trabeculectomy. A prospective randomized block study. Trans Ophthalmol Soc UK 104:55-61, 1984 Rollins DR, Drance SM: Five-year follow-up of trabeculectomy in the management of chronic open-angle glaucoma. Symposium on Glaucoma, New Orleans Academy of Ophthalmology, 1981 Watson PG, Grierson I: The place of trabeculectomy in the treatment of glaucoma. Ophthalmology 88:175-196, 1981 Early Treatment Diabetic Retinopathy Study Research Group: Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics: ETDRS Report Number 7. Ophthalmology 98:741-756, 1991 Ferris FL, Sperduto RD: Standardized illumination for visual acuity testing in clinical research. Am J Ophthalmol 94:97-98, 1982 Ferris FL, Kassoff A, Bresnick GH, Bailey I: New visual acuity charts for clinical research. Am J Ophthalmol 94:91-96, 1982 The AGIS Investigators: Advanced Glaucoma Intervention Study (AGIS): 2. Visual field scoring and reliability. Ophthalmology (in press) Katz J, Sommer A, Gaasterland DE, Anderson DR: Comparison of analytic algorithms for detecting glaucomatous visual field loss. Arch Ophthalmol 109:16841689, 1991 Ederer F: Serum cholesterol changes: effects of diet and regression toward the mean. J Chron Dis 25:277-289, 1972 Spaeth, GL: Glaucoma surgery. In: Ophthalmic Surgery. Principles and Practice. Spaeth GL, ed. WB Saunders, Philadelphia, 1982 The Fluorouracil Filtering Surgery Study Group: Fluorouracil Filtering Study One-Year Follow-Up. Am J Ophthalmol 108:625-635, 1989 Kitazawa Y, Kawase K, Matsushita H, Minobe M: Trabeculectomy with mitomycin. A comparative study with fluorouracil. Arch Ophthalmol 109:1693-1698, 1991 Palmer SS: Mitomycin as adjunct chemotherapy with trabeculectomy. Ophthalmology 98:317-321, 1991 Skuta GL, Beeson CC, Higginbotham EJ, Lichter PR, Musch DC, Bergstrom TJ, Klein TB, Falck FY Jr: Intraoperative mitomycin versus postoperative 5-fluorouracil in high-risk glaucoma filtering surgery. Ophthalmology 99:438-444, 1992 Kahn HA: An Introduction to Epidemiologic Methods. Oxford University Press, New York, 1983 GLT Research Group: The Glaucoma Laser Trial (GLT): 2. Results of argon laser trabeculoplasty vs topical medicines. Ophthalmology 97:1403-1413, 1990 GLT Research Group: The Glaucoma Laser Trial (GLT): 3. Design and methods. Controlled Clin Trials 12:504-524, 1991 Smith RJH: Medical vs. surgical therapy in glaucoma simplex. Br J Ophthalmol 56:277-283, 1972 Smith RJH: The enigma of primary open-angle glaucoma. Trans Ophthalmol Soc UK 105:618-627, 1986

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29. Migdal C, Hitchings R: Control of chronic simple glaucoma with primary medical, surgical and laser treatment. Trans Ophthalmol Soc UK 105:653-656, 1986 30. Jay JL, Allan D: The benefit of early trabeculectomy versus conventional management in primary open-angle glaucoma relative to severity of disease. Eye 3:528535, 1989 31. Spaeth GL, Poryzees E: A comparison between peripheral iridectomy with thermal sclerostomy and trabeculectomy: a controlled study. Br J Ophthalmol 65:783789, 1981 32. Lewis RA, Phelps CD: Trabeculectomy vs. thermosclerostomy. A five-year followup. Arch Ophthalmol 102:533-536, 1984 33. Armitage P, Berry G: Statistical Methods in Medical Research. Blackwell Scientific Oxford, 1987, pp 400-403 APPENDIX Participating Institutions, Current Investigators, and Former Investigators Who Participated for Two or More Years CLINICAL CENTERS ABBREVIATIONS: CD, clinic director; CI, Coinvestigator; CC, clinic coordinator; SC, satellite coordinator; T, technician Emory University, Atlanta, Georgia: Reay H. Brown, MD (CD); Mary Lynch, MD (CI); Donna Leef, CO, COMT (CC)(T); Johnny Gunsby, COT (T); Kathy Lober, COA (T); Kathy Moore (T); Candace Stepka (T). Past participating personnel: Angela Vela-Thomas, MD (CD). Georgetown University, Washington, DC: Douglas E. Gaasterland, MD (CD); Ellen Coyle, COMT (CC)(T); Mary Hundley, COT (T). Satellite facility: Frank Ashburn, MD (CD); Lynn Vayer, COT (SC)(T). Past participating personnel: Karl Michelitsch, COMT (CC) (deceased); Susan Lauber, MA (CC); Elizabeth Burt, COT (T), Anne Rae (T). Ohio State University, Columbus, OH: Paul A. Weber, MD (CD); Robert Derick, MD (CI); Kathryne McKinney, COMT (CC)(T); Diane Moore (T). Satellite facility: N. Douglas Baker, MD (CD); Fred Kapetansky, MD (CI); Dave Lehman, MD (CI); Becky Gloeckner (SC)(T); Lisa J. Sharf, COA (T); Billi Romans (T). Past participating personnel: Yvonne Satterwhite (T); Lori Simmons (T).

Piedmont Hospital, Atlanta, GA: Angela Vela-Thomas, MD (CD); Thomas S. Harbin, Jr., MD (CI); Randall R. Ozment, MD (CI); Julie Wright, COT (CC)(T); Linda Butler, COT (T); June LaSalle, COA (T); Marianne Perry, COT (T); Dana Nummerdor (T); Lisa Wille (T). Past participating personnel: Anne Eckel, COA (T); Celeste Session, COA (T); Anja Martin, COA (T).

Sinai Hospital~Detroit, Southfield, Mh Marshall N. Cyrlin, MD (CD); Roselyn Fazio, BS, COT (CC)(T).

University of Illinois, Chicago, IL: Jacob T. Wilensky, MD (CD); Kim Lindenmuth, MD (CI); Catherine A. Nail, COMT (CC)(T); Donna Rathbone, COT (T); Valeria Gates, OT (T); Marlem Tadelman, COT (T). Satellite facility: Sriram Sonty, MD (CD); Gloria Hopkins, LPN (T). Past

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participating personnel: Eve J. Higginbotham, MD (CD); Gary Scholes, MD (CI); Rosanna Uva, COT (CC); Loreen Pappas, COT (T); Diane Frohlichstein, COT (T); Julie Fiene, COT (T). University of Michigan, Ann Arbor, Mh Eve J. Higginbotham, MD (CD); Terry J. Bergstrom, MD (CI); Paul R. Lichter, MD (CI); Carol Standardi, RN, CRNO (CC)(T); Jennifer Ziehm-Scott, COA (T); Renee PapierniakDubiel (T); Carol Pollack-Rundle, COT (T). Past participating personnel: Gregory L. Skuta, MD (CD); Charles Beeson, MD (CI); Ralph P. Crew, DO (CI); Linda Kruseke, COA (T); Barbara Michael, COT (T); Joyce Dederian, COA (T); Donna Wicker, OD (T); Desiree Aaron, COA (T); Judith Birk, COA (T); Therese Van Heck, COT (T). University of Virginia, Charlottesville, VA: Robert C. Allen, MD (CD); Steven A. Newman, MD (CI); John R. Nordlund, MD, PhD (CI); C. Kay Fendley, COA (CC)(T); Cindi Berghuis, COT (T); James Chisholm, COA (T); Christine Evans, COT (T); Ellen Murphy, COA (T). Past participating personnel: Louis J. Schott, MD (CI); Robert Fornili, OD (CC). Washington Hospital Center, Chevy Chase, MD: Arthur L. Schwartz, MD (CD); Howard Weiss, MD (CI); Scott Wehrly, MD (CI); Stephen Pappas, MD (CI); Maureen O'Dea, MD (CI); Anne Boeckl, MD (CC)(T); Patrick Lopez, COT (T); Karen Carmody, COT (T); Richard Mercer (T); Victoria Monks, COA (T); Kathy Vawter, COA (T). Satellite facility: Cindy V. Witol, CO (T). Past participating personnel: Mark Morris, MD (CI); Maria Cirone, MD (CI); John Gurley, MD (CI); Cathy Reed, COMT (CC); Janet Browning, COT (T); Elaine Harris (T). Wills Eye Hospital, Philadelphia, PA: L. Jay Katz, MD (CD); George L. Spaeth, MD (CI); Richard P. Wilson, MD (CI); Fillis Samuel, COT (CC)(T); Alaine Block (T). Past participating personnel: Sue Kao, MD (CI); Coleen C. Beckershoff (T). Yale University, New Haven, CT: Joseph Caprioli, MD (CD); Eydie Miller, MD (CI); Maureen Roche, COMT (CC)(T); Gail Grottole (T); Anne Leone (T). Past participating personnel: Charles Tressler, MD (CI). COORDINATING CENTER

The EMMES Corporation, Potomac, MD: Fred Ederer, MA, FACE (Director); E. Kenneth Sullivan, Ph.D. (Deputy Director); Elizabeth L. Wagner, BS (Data Coordinator); Gary Entler, COT (Protocol Monitor); Marline Bradford (Interviewer); Katherine L. Tomlin, MA (Administrative Coordinator); Elaine Stine (Alternate Interviewer). Past participating personnel: Anne S. Lindblad, PhD (Deputy Director); James D. Knoke, PhD (Deputy Director), Marsha Denekas, MLT (Data Coordinator); Carol Smith, MT (Protocol Monitor), Tamara Voss, BA (Administrative Coordinator). PROJECT OFFICE

National Eye Institute, Washington, D.C.: Richard L. Mowery, PhD (NEI Representative); Gaye Lynch (Grants Management Specialist); Past participating personnel: Frances Goff (Grants Management Specialist).

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STUDY GROUPS

Study Cochairmen: Douglas E. Gaasterland, MD, Fred Ederer, MA, FACE. Policy and Treatment Effects Monitoring Board (PATEMB): Curt D. Furberg, MD (Chairman); John E. Connett, PhD; Matthew D. Davis, MD; David K. Dueker, MD; Sylvan B. Green, MD; The Rev. Canon Michael P. Hamilton; Paul F. Palmberg, MD, PhD; Marvin A. Schneiderman, PhD; Ex officio members: Fred Ederer, MA, FACE; Douglas E. Gaasterland, MD; Richard L. Mowery, PhD. Operations Committee: Fred Ederer, MA, FACE, Douglas E. Gaasterland, MD; E. Kenneth Sullivan, PhD; 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; Richard L. Mowery, PhD. Elected investigator members: Marshall N. Cyrlin, MD (1988); Angela Vela-Thomas, 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 (1993-1995). Elected Clinic Coordinator members: Donna Leef, CO, COMT (1988); Kathryne McKinney, COMT (1989); Cathy Reed, COMT (1990); Rosanna Uva, COT (1991); Fillis Samuel, COT (1992); Maureen Roche, COMT (1993). Training and Certification Faculty: Fred Ederer, MA, FACE, Gary Entler, COT; Douglas E. Gaasterland, MD; Aaron Kassoff, MD (Consultant); L. Jay Katz, MD; Donna Leef, CO, COMT; Gregory L. Skuta, MD; Carol Standardi, RN, Elizabeth L. Wagner, BS. Past participating personnel: Anne S. Lindblad, PhD; Cathy Reed, COMT, Coleen C. Beckershoff.