Wills Glaucoma Service Foundation Lighthouse

We need more randomized, long-term, controlled studies: AGIS, CIGTS, CNTGS, EMGT, FFSS, GLT, OHTS

Richard K. Parrish II, MD

Glaucoma Service 40 Anniversary Scientific Symposium

October 3-4, 2003

I. Rationale for clinical trials

A. Contemporaneous head to head testing of at least two treatments

B. Guarantees patient will receive one of two treatments, and will have a 50% of receiving whichever proves to be the best

C. Reduces selection bias, generates equal randomization

D. Provides uniform follow-up

E. Utilizes agreed upon criteria for success and failure before the trail starts

F. “Truth fears no Trial”

G. People believe the results

II. Glaucoma Laser Trial (GLT)

A. Purpose: To compare the safety and long-term efficacy of argon laser treatment of the trabecular meshwork with standard medical treatment for primary open-angle glaucoma (POAG).

B. Background: In the decade preceding the beginning of the trial, argon laser trabeculoplasty (ALT) was often used instead of surgery as the treatment of choice in patients with medically uncontrolled open-angle glaucoma. Although sometimes effective in controlling intraocular pressure (IOP), many eyes still required medical treatment.

C. Description:

1. GLT was conducted to determine whether ALT was effective treatment in patients with newly diagnosed, POAG.

2. Number of patients 271 (542 eyes)

3. Treatment randomization: one eye received ALT and the other standard topical stepped medical treatment

4. Length of follow-up: median duration 7 years (maximum 9 years)

5. Treatment parameters: Argon laser treatment in two sessions 1 month apart, 45-55 burns in each session.

D. Patient eligibility: 35 years or older, IOP of at least 22 mm Hg

E. Patient recruitment status: Jan 1984 and April 1987

F. Current status of study: Completed

G. Results

1. The eyes treated initially with ALT had lower IOP and better visual field and optic disk status than their fellow eyes treated initial with topical medications. As compared with eyes initially treated with medication, ALT eyes had a 1.2 mm Hg greater reduction in IOP and a 0.6 dB greater improvement in the visual field from entry into the GLT. The overall difference between eyes with regard to change in ratio of optic cup area to optic disk area from entry was –0.09 that indicated slightly more deterioration for eyes initially treated with medication.

H. Comment

1. Initial ALT was at least as effective as initial treatment with topical medication

2. First excellent clinical trial in glaucoma intervention.

3. Stepped regiment of pilocarpine, propine is probably irrelevant in view of newer medications: prostaglandin derivatives, topical carbonic anhydrase inhibitors, alpha 2 agonists

GLT Publication

1. Glaucoma Laser Trial Research Group: The Glaucoma Laser Trial: 1. Acute effects of argon laser trabeculoplasty on intraocular pressure. Arch Ophthalmol 107:1135-1142,1989

2. Glaucoma Laser Trial Research Group: The Glaucoma Laser Trial (GLT): 2. Results of argon laser trabeculoplasty versus topical medicines. Ophtahlmology 97:1403-1413, 1990

3. Glaucoma Laser Trial Research Group: The Glaucoma Laser Trial (GLT): 3. Design and methods. Controlled Clinical Trials 12:504-524, 1991.

4. Glaucoma Laser Trial Research Group: The Glaucoma Laser Trial: 4. Contra-lateral effects of timolol on the intraocular pressure of eyes treated with ALT. Ophthalmic Surg 22:324-329, 1991

5. Glaucoma Laser Trial Research Group: The Glaucoma Laser Trial (GLT): 5. Subgroup differences at enrollment. Ophthalmic Surg 24:232-241, 1993.

6. Glaucoma Laser Trial Research Group: The Glaucoma Laser Trial (GLT): Treatment group differences in visual field changes. Am J Ophthalmol 120:10-22, 1995.

7. Glaucoma Laser Trial Research Group: The Glaucoma Laser Trial (GLT) and Glaucoma Laser Trial Followup Study: 7. Results. Am J Ophthalmol 120:718-731, 1995.

III. Fluorouracil Filtering Surgery Study (FFSS)

A. Purpose: To determine whether subconjunctival injections of 5-fluourouracil (5-FU) increase the success of trabeculectomy in patients at high risk for failure after standard glaucoma filtering surgery.

B. Background: The use of 5-FU, an antimetabolite, had been shown to inhibit the proliferation of fibroblasts in tissue culture, and in preliminary studies it increased the success of filtering surgery in nonhuman primates prior to the FFSS.

C. Description:

1. Patients randomized to receive either 5-FU injections or standard postsurgical care without 5-FU.

2. Protocol: 5 mg injections given twice daily on postoperative days 1-7 and once daily on postoperative days 8-14.

D. Patient eligibility: men and women with IOP greater than 21 mmHg in one or both eyes despite maximal tolerated therapy and who were aphakic or had undergone previous filtering surgery.

E. Patient recruitment status: September 1985 through June 1988. 213 patients were followed for 5 years postoperatively

F. Current status of Study: completed.

G. Results:

1. Improved success rates at one, three and five years for 5-FU group versus standard treatment (80 vs 60, 56 vs 28, and 48 vs 21, respectively)

2. Risk factors for failure: number of previous ocular procedures with a conjunctival incision, and the time interval between the last ocular surgery and the filtering surgery

3. Bleb leaks were more likely to occur in the 5-FU group (9 percent) vs standard treatment (2 percent)

4. Risk of postoperative suprachoroidal hemorrhage was not associated with 5-FU, but was associated with the preoperative IOP. The higher the preoperative IOP, the greater the likelihood of this complication.

5. Complications of corneal and conjunctival epithelial defects are common side effects of postoperative 5-FU.

H. Comment: Although effective in reducing IOP compared to standard medical treatment after trabeculectomy, the results are frequently compared to non-clinical trial data regarding mitomycin. The findings of high preoperative IOP and acute postoperative hypotony were not anticipated as a risk factor for the development of suprachoroidal hemorrhage prior to this study. As a result of this finding, modifications to minimize postoperative hypotony, such as smaller and more tightly sutured flaps have been employed.

FFSS Publication

1. Fluorouracil Filtering Surgery Study Group: Fluorouracil Filtering Surgery Study one –year follow-up. Am J Ophthalmol 108:625-635, 1989.

2. Fluorouracil Filtering Surgery Study Group: Risk factors for suprachoroidal hemorrhage after filtering surgery. Am J Ophthalmol 113:501-5-7, 1992

3. Fluorouracil Filtering Surgery Study Group: Three-year follow-up of the Fluorouracil Filtering Surgery Study. Am J Ophthalmol 115:82-92, 1993

4. Fluorouracil Filtering Surgery Study Group: Five-year follow-up of the Fluorouracil Filtering Surgery Study. Am J Ophthalmol 121:348-366, 1996

5. Parrish RKII, Schiffman JC, Feuer WJ, Heuer DK, and the Fluorouracil Filtering Surgery Study Group: Prognosis and risk factors for early postoperative wound leaks after trabeculectomy with and without 5-fluouracil. Am J Ophthalmol 132:633-640, 2001

IV. Advanced Glaucoma Intervention Study (AGIS)

A. Purpose: To assess the long –range outcomes of sequences of interventions involving trabeculectomy and ALT in eyes that have filed initial medical treatment for glaucoma.

B. Background: Both ALT and trabeculectomy have been chosen as the first intervention in patients with advanced glaucoma. Because success is limited, some patients, over time, need to undergo a sequence of surgical interventions. Little is know about which sequence gives the best long-range outcome.

C. Description:

1. Eligible eyes are randomly assigned to one of two intervention sequences: (1)Trabeculectomy followed by ALT and second trabeculectomy (2) ALT followed by trabeculectomy followed by second trabeculectomy.

2. Primary outcome variable is average percent of eyes with decrease of vision, where decrease of vision is a substantial decline of either visual field or visual acuity attributable to glaucoma

D. Patient recruitment status: April 1988 through November 1992; 789 eyes of 591 patients

E. Patient eligibility: Men and women between 35 and 80 with POAG no successfully controlled by medication

F. Current status: Ongoing. Follow-up of patients continues.

G. Results

1. Vision in eyes of black patients with advanced glaucoma was better preserved in the group that started with ALT. Through 7 years, the average percent of eyes in black patients with decrease of vision was 28 percent in the ALT initial group compared with 37 percent in the trabeculectomy first group.

2. Vision in white patients tended to be better preserved in the program starting with laser surgery; however, after seven years the reverse was true, 31percent decreased in the trabeculectomy first group compared with 35 percent in the ALT first group

3. Lower targets IOPs are associated with preservation of IOP. The four groups achieved a target pressure of 18 mmHg or less in 100%, 75% to 99%, 50% to 74%, or less than 50% of visits. Average IOPs were 12.3, 14.7, 16.9, and 20.2 mm Hg, respectively

AGIS Publication

1. Advanced Glaucoma Intervention Study Investigators: The Advanced Glaucoma Intervention Study (AGIS): 1. Study design and methods, and baseline characteristics of study patients. Controlled Clinical Trials 15:299-325, 1994.

2. Advanced Glaucoma Intervention Study Investigators: The Advanced Glaucoma Intervention Study

3. AGIS Investigators: Advanced Glaucoma Intervention Study (AGIS): 3. Baseline characteristics of black and white patients. Ophthalmology 105:1137-1145, 1998.

4. AGIS Investigators: Advanced Glaucoma Intervention Study (AGIS): 4. Comparison of treatment outcomes with race: 7 yr results. Ophthalmology 105:1146-1164, 1998.

5. Schwartz AL, Van Veldhuisen PC, Gaasterland DE, Ederer F, Sullivan EK, Cyrlin MN, AGIS Investigators: The Advanced Glaucoma Intervention Study (AGIS): 5. Encapsulated bleb after initial trabeculectomy. Am J Ophthalmol 127:8-19, 1999.

6. AGIS Investigators: The Advanced Glaucoma Intervention Study, 6: Effect of cataract on visual field and visual acuity. Arch Ophthalmol 118:1639-1652, 2000.

7. AGIS Investigators: The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration Am J Ophthalmol 130:429-440, 2000.

8. AGIS Investigators: The Advanced Glaucoma Intervention Study 8: Risk of cataract formation after trabeculectomy. Arch Ophthalmol 2001; 1191171-1780

V. Collaborative Initial Glaucoma Treatment Study (CIGTS)

A. Purpose: To compare the long-term effect of treating newly diagnosed POAG with stand medical treatment versus filtration surgery.

B. Background: Recent studies challenged the conventional practice of treating all new POAAG patients with topical therapy. Some studies suggest that more effective control of glaucoma can be achieved with early filtration surgery. The impact of therapy on health-related quality of life may be different with medical and surgical therapy.

C. Description:

1. Randomization to either a stepped medical treatment regimen or filtration surgery to control POAG.

2. If initial medical treatment fails then ALT, and then trabeculectomy, if necessary.

3. If filtration surgery fails, then ALT and then medications.

4. Patients rather than eyes are the unit of randomization and the patient receives the same treatment in both eyes.

5. Before and at regular intervals after treatment patients were interviewed by telephone to assess their health-related quality of life. The Sickness Impact Profile, Visual Activities Questionnaire, and other components are used.

D. Patient Eligibility: Patients at least 25 years old with IOP of 20 mm Hg or greater and optic nerve damage and /or visual field loss in one or both eyes. All other causes of glaucoma other than POAG are excluded.

E. Patient recruitment status: Completed Fall 1993 through spring 1997 with 607 patients

F. Current status of study: ongoing

G. Results

1. Medical and surgical interventions are comparable through the first five years of the study.

H. Comments: After five years no clear-cut advantage to either medical or surgical intervention, both are successful in preserving visual function. The quality of life is not substantially different with either treatment

CIGTS Publication

1. Musch DC, Lichter PR, Guire KE, Standardi CL, CIGTS Investigators: The Collaborative Initial Glaucoma Treatment Study (CIGTS): Study design, methods, and baseline characteristics of enrolled patients. Ophthalmology 106:653-62, 1999.

2. Lichter PR, Musch DC, Gillespie BW, Guire KE, Janz NK, Wren PA, Mills RP, and the CIGTS Study Group. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology 108; 1943-1953, 2001

VI. Ocular Hypertension Treatment Study (OHTS)

A Purpose:

To determine whether medical reduction of IOP prevents or delays the onset of glaucomatous visual field loss and /or optic disc damage in ocular hypertensive subjects judged to be at moderate risk for developing POAG.

To produce natural history data to assist in identifying patients at most risk for developing POG and those most likely to benefit from early medical treatment.

To quantify risk factors for developing POAG among ocular hypertensive subjects.

B. Background: Despite the lack of convincing evidence for the efficacy of medical treatment in ocular hypertension, approximately 1.5 million glaucoma suspects in the United States are being treated with costly ocular hypotensive medications that carry the potential for serious and even life-threatening side effects. There is no consensus that medical reduction IOP prevents or delays the onset of visual field and/or optic nerve damage in ocular hypertensive subjects.

C. Description: Randomization to either observation or treatment with topical medications to lower IOP to predetermined level.

D. Patient eligibility: Men and women between the ages of 40 and 80 with IOP greater than or equal to 24 mm Hg, but less than or equal to 32 mm Hg in at least one eye and IOP greater than or equal to 21 but less than or equal to 32 in the fellow eye, normal visual fields and optic discs. Best corrected visual acuity of 20/40 or better. Exclusion: life threatening conditions, angle-closure glaucoma, diabetic retinopathy, other conditions than can cause visual field loss.

E. Patient recruitment status: Randomization completed.

F. Current status of study: ongoing

G. Results: none

H. Comments

Early publications suggest that more than one abnormal visual field is necessary to confirm early glaucomatous loss. Corneal thickness may affect the level of measured IOP. Thicker corneas may cause false high readings, and thinner than usual corneas may trigger lower than actual readings. Black patients have slightly thinner corneas than white patients. 555.7 +/- 40.0 micorns versus 579.0 +/- 37.0 microns.. Intraocular pressure lowering to a target of 20% below baseline resulted in a reduction of risk from 9.9% to 5.5% at five years. Risk factors for the development of glaucoma included increased intraocular pressure, pattern standard deviation, larger vertical and horizontal cup to disc ratio, thinner central corneas, and older age.

OHTS publication

1. Gordon MO, Kass MA for the Ocular Hypertension Treatment Study Group: The Ocular Hypertension treatment Study. Design and baseline description of the participants. Arch Ophthalmol 117:573-583, 1999

2. Piltz J, Gross R, Shin DH, Beiser JA, Dorr DA, Kass MA, Gordon MO, the Ocular Hypertension Study Group: Contralateral effect of topical beta –adrenergic antagonists in initial one-eyes trials in the Ocular Hypertension Treatment Study Am J Ophthalmol 130:441-453,2000.

3. Keltner JL, Hojnson CA, Quigg JM, Cello KE, Kass MA, Gordon MO for the Ocular Hypertension Treatment Study. Confirmation of visual field abnormalities in the Ocular Hypertension Treatment Study. Arch Ophthalmol 118:1187-1194, 2000.

4. Brandt JD, Beiser JA, Kass MA, Gordon MO, and the Ocular Hypertension Treatment Study (OHTS) Group. Central corneal thickness in the Ocular Hypertension Treatment Study (OHTS) 108:1779-1788, 2001.

5. Feuer WJ, Parrish RKII, Schiffman JC, Anderson DR, Budenz DL, Wells m-C, Hess DJ, Kass MA, Gordon AO, and the Ocular Hypertension Treatment Study Group. The ocular Hypertension Treatment Study: Reproducibility of cup/disk ration measurements over time at an Optic Disc Reading Center. Am J Ophthalmol 1333:19-28, 2002.

6. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;701-713.

7. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study. Baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002:120:714-720.

8. Palmberg PF. Answers from the Ocular Hypertension Treatment Study. (editorial) Arch Ophthalmol. 2002;120: 829-830.

VII. The Collaborative Normal-Tension Glaucoma Treatment Study (NTGS)

A Purpose: To determine if IOP reduction halts or slow the progression of visual field loss in patients with normal tension glaucoma.

B. Background: Considerable difference of opinion regarding the value of IOP lowering existed prior to the NTGS. Some ophthalmologists regarded IOP lower as useless in a condition of primary optic neuropathy and others believe that pressure lowering to very low levels could preserve visual field function

C. Description: One of the patients with NTG was randomized:

1. To be followed without treatment until there was evidence of slight deterioration. The other eye could be treated at the discretion of the treating physician, except that systemic carbonic anhydrase inhibitors could not be used.

2. To be placed on treatment with medication, ALT, and filtration surgery as required to lower the IOP by 30%.

3. In both arms, neither eye could receive beta-adrenergic blockers nor adrenergic agonists, because they might have systemic cardiovascular effects that could conceivably alter the course of the treated or untreated disease, confounding the data.

4. Some were randomized immediately: if the field defect threatened the point of fixation or there was previously documented progression of the disease.

5. Others were randomized later if there was visual field progression, progression of optic nerve head cupping, or a new disc hemorrhage.

D. Patient eligibility: unilateral or bilateral NTG evidenced by glaucomatous cupping of the disc and a defined type and severity of field loss with a median IOP of 20 mm Hg or less in 10 baseline measurements.

E. Patient recruitment status: 230 patients were enrolled from 24 collaborating centers. At the end of the study 145 eyes had been randomized: 66 to receive treatment and 79 eyes to serve as untreated controls.

F. Current status of study: completed

G. Results:

1. A 30% lowering of IOP can be achieved in patients with NTS with medical therapy and ALT about half the time, and perhaps this is even more feasible with medications not permitted in the NTG study protocol and with drugs that have more recently become available.

2. With repeated frequent visual field examinations in search of very subtle changes or a slow rate of progression, in NTG or likely in any other chronic glaucoma, there is a risk of judging falsely that progression has occurred. Progression must be evident on at least one subsequent file to be sure it is genuine.

3. Once pressure has been successfully lowered 30% from baseline, rate of progressive field loss is slower tan in a group that did not receive treatment.

4. Cataracts, which occur more frequently in treated patients who underwent filtration surgery, produce visual changes. In a clinical trail format with visual field as the sole outcome measure, correction for cataract effect must be made to uncover the benefit of lowering the IOP.

5. The rate of visual field progression in cases of untreated normal tension glaucoma is highly variable, some cases showing progression in a few months, but half not showing progression within five years.