CLINICAL TRIAL 7-1

Collaborative Initial Glaucoma Treatment Study (CIGTS) Essentials

Purpose: To determine whether patients with newly diagnosed open-angle glaucoma (OAG) are better treated by initial treatment with medications or by immediate filtering surgery.

Participants: A total of 607 patients with OAG (primary, pigmentary, or pseudoexfoliation) recruited between 1993 and 1997.

Study design: Multicenter randomized controlled clinical trial comparing initial medical therapy with initial surgical therapy for OAG.

Results: Although intraocular pressure (IOP) was lower in the surgery group, initial medical and initial surgical therapy resulted in similar visual field outcomes after up to 9 years of follow-up. Early visual acuity loss was greater in the surgery group, but the differences between groups converged over time. Also, cataracts were more common in the surgery group. At the 8-year follow-up examination, substantial worsening (≥3 dB) of visual field mean deviation from baseline was found in 21.3% of the initial surgery group and 25.5% of the initial medical group. Patients with worse baseline visual fields were less likely to progress if treated with trabeculectomy first. Patients with diabetes mellitus were more likely to progress if treated initially with surgery.

The quality of life (QOL) reported by the 2 treatment groups was similar. The most per sis tent QOL finding was a greater number of symptoms reported at a higher frequency by the surgery group.

The overall rate of progression of OAG was lower in CIGTS than in many clinical trials, possibly because of more aggressive IOP-lowering goals and the stage of the disease. Individualized target IOPs were determined according to a formula that accounted for baseline IOP and visual field loss. Over the course of follow-up, IOP in the medical therapy group averaged 17–18 mm Hg (IOP reduction of approximately 38%), whereas IOP in the surgery group averaged 14–15 mm Hg (IOP reduction of approximately 46%). IOP fluctuation was a risk factor for progression in the medically treated group but not the surgically treated group. The rate of cataract removal was greater in the surgically treated group.

CLINICAL TRIAL 7-2

Ocular Hypertension Treatment Study (OHTS) Essentials

Purpose: To evaluate the safety and efficacy of topical ocular hypotensive medications in preventing or delaying the onset of visual field loss and/or optic nerve damage in participants with ocular hypertension.

Participants: A total of 1637 patients with ocular hypertension recruited between 1994 and 1996.

Study design: Multicenter randomized controlled clinical trial comparing observation and medical therapy for ocular hypertension.

Results 2002: Topical ocular hypotensive medication was effective in delaying or preventing the onset of primary open-angle glaucoma (POAG). The incidence of glaucoma was lower in the medication group than in the observation group (4.4% vs 9.5%, respectively) at 60 months’ followup. No increase in adverse events was detected in the medication group.

The 5-year risk of developing POAG was associated with the following baseline factors: older age (22% increase in relative risk per de cade), larger vertical and horizontal cup–disc ratios (32% and 27% increases in relative risk per 0.1 increase, respectively), higher pattern standard deviation (22% increase in relative risk per 0.2 dB increase), and higher baseline IOP (10% increase in relative risk per 1 mm Hg increase). Central corneal thickness (CCT) was found to be a powerful predictor for the development of POAG (81% increase in relative risk for every 40 μm thinner). The corneas in OHTS participants were thicker than those in the general population, and African American participants had thinner corneas than others in the study.

Results 2007: The OHTS prediction model for the development of POAG was independently validated in the European Glaucoma Prevention Study.

Results 2010: Topical ocular hypotensive medication was initiated in the original observation group after 7.5 years (median) without medication, and medication was continued for 5.5 years thereafter. Participants in the original medication group continued topical ocular hypotensive medications for a median of 13 years. The proportion of participants who developed POAG was 0.22 in the original observation group and 0.16 in the original medication group. The primary purpose of the follow-up study was to determine whether delaying treatment resulted in a persistently increased risk of conversion to glaucoma, even after the initiation of therapy. It was found that delayed initiation of treatment still resulted in a decrease in the rate of developing glaucoma, just as it did earlier in the course.

CLINICAL TRIAL 7-3

Collaborative Normal Tension Glaucoma Study (CNTGS) Essentials

Purpose: To determine whether the optic nerve damage seen in eyes without statistically elevated IOP was IOP dependent or IOP independent.

Participants: From 24 centers, a total of 230 eyes of 230 participants were enrolled. Inclusion criteria were as follows:

• the presence of glaucoma in 1 or both eyes (as judged by the investigators)

• age between 20 and 90 years

• had never had a recorded IOP above 24 mm Hg

To determine baseline IOP, each participant was required to undergo 10 IOP readings after medication washout, 6 of which were distributed on a single day. The median of the IOP measurements had to be 20 mm Hg or less, and none could be above 24 mm Hg. Finally, each participant was also required to complete 3 reliable baseline visual fields within 1 month. Exclusion criteria were: systemic β-blockers or clonidine, the presence of other ocular disease that might affect the visual field, previous intraocular surgery, narrow angles, visual acuity worse than 20/30, and severe visual field loss.

Study design: Multicenter randomized controlled clinical trial comparing observation and treatment for normal tension glaucoma (NTG). Randomization to treatment (30% reduction in IOP after treatment with medications, laser trabeculoplasty, or incisional surgery) or observation occurred at enrollment only if there was clear evidence of glaucoma worsening in the time before enrollment. Otherwise, eyes were observed and then randomized after they demonstrated worsening of glaucoma, which was primarily determined using a study-specific analysis of visual fields. Determination of worsening could also be made by observation of optic disc changes.

Results: At the end of the study, 79 eyes had been randomized to observation, 66 to treatment (of which 5 dropped out), and the remaining 85 never showed evidence of worsening. In the intent-to-treat analysis, visual field worsening occurred in 31 eyes (39%) in the observation group and 22 (33%) in the treated group; this difference was not statistically significant. When the data were reevaluated by censoring results obtained after the development of visually significant cataract in a given eye, visual field worsening was determined to be more likely in the observation group (27%) than in the treatment group (12%). The difference in the 2 analyses was attributed to the higher rate of cataract in the sub-group that underwent filtration surgery.

In a secondary analysis of those who met the treatment target, 28 (35%) of the observation eyes and 7 (12%) of the treated eyes worsened after randomization. Visually significant cataract developed in 11 eyes (14%) in the observation group and 23 (38%) in the treated group. Another secondary analysis of the 160 participants in the untreated group showed that after 7 years, only half demonstrated a detectable change in visual field.

CLINICAL TRIAL 7-4

Early Manifest Glaucoma Trial (EMGT) Essentials

Purpose: To evaluate the effectiveness of lowering IOP in patients with early, newly detected OAG.

Participants: Patients 50 to 80 years of age with newly diagnosed OAG and early glaucomatous visual field loss were identified mainly through a population-based screening of more than 44,000 residents of Malmö and Helsingborg, Sweden. Exclusion criteria were thus: advanced visual field loss; mean IOP greater than 30 mm Hg or any IOP greater than 35 mm Hg; and visual acuity less than 0.5 (20/40). Between 1993 and 1997, 255 patients were randomized.

Study design: Multicenter randomized controlled clinical trial comparing observation and treatment with betaxolol and argon laser trabeculoplasty for OAG.

Results: At 6 years, 62% of untreated patients showed progression, whereas 45% of treated patients progressed. On average, treatment reduced IOP by 25%. In a univariate analysis, risk factors for progression included no IOP-lowering treatment, older age, higher IOP, pseudoexfoliation syndrome, more advanced visual field loss, and bilateral glaucoma. In multivariate analyses, the risk of progression with IOP-lowering treatment was reduced by half (HR = 0.50; 95% confidence interval, 0.35–0.71). Each mm Hg of IOP lowering decreased the risk of glaucomatous progression by 10%. Risk factors for progression included higher baseline IOP, older age, pseudoexfoliation syndrome, bilateral disease, worse mean deviation, and frequent disc hemorrhages. IOP fluctuation was not found to be a significant risk factor.

In the observation group, the rate of visual field progression was most rapid in the subgroup of patients with pseudoexfoliation syndrome and slowest in those with baseline IOPs within the normal range.

CLINICAL TRIAL 7-5

Advanced Glaucoma Intervention Study (AGIS) Essentials

Purpose: To compare the clinical outcomes of 2 treatment sequences: argon laser trabeculoplasty–trabeculectomy–trabeculectomy (ATT) and trabeculectomy–argon laser trabeculoplasty–trabeculectomy (TAT).

Participants: A total of 789 eyes of 591 patients with medically uncontrolled OAG recruited from 1988 to 1992.

Study design: Multicenter randomized controlled clinical trial comparing 2 treatment sequences (ATT and TAT) for patients with OAG uncontrolled with medical therapy.

Results:

AGIS 4 and AGIS 13: Black patients treated with the ATT sequence had a lower combined visual acuity and visual field loss than those treated with the TAT sequence. White patients had a lower combined visual acuity and visual field loss at 7 years if initially treated with the TAT sequence. In the initial follow-up period, white patients in the TAT group had greater visual acuity loss than those in the ATT group; by 7 years, this loss was similar.

AGIS 5: The mean IOP at the 4-week postoperative visit was higher in eyes with encapsulated blebs than in those without; with resumption of medical therapy, eyes with and without encapsulated blebs had similar IOPs after 1 year.

AGIS 6: Visual function scores improved after cataract surgery. Adjustment for cataract did not alter the findings of previous AGIS studies.

AGIS 7: Lower IOP was associated with less visual field progression. Less visual field progression was noted for eyes with an average IOP of 14 mm Hg or less during the first 18 months after the first surgical intervention, and for eyes with IOP of 18 mm Hg or less for all study visits.

AGIS 8: Approximately half of the study patients developed cataract in the first 5 years of follow-up. Trabeculectomy increased the relative risk of cataract formation by 78%.

AGIS 9: The treatment protocol with initial trabeculectomy slows the progression of glaucoma more effectively in white patients than in black patients. The treatment protocol with initial ALT was slightly more effective in black participants than in white participants.

AGIS 10: Assessment of optic nerve findings showed good intraobserver but poor interobserver agreement.

AGIS 11: Reduced effectiveness of ALT was associated with younger age and higher IOP. The ineffectiveness of trabeculectomy was associated with younger age, higher IOP, diabetes mellitus, and postoperative complications (markedly elevated IOP and inflammation).

AGIS 12: Risk factors for sustained decrease of the visual field included better baseline visual fields, male sex, worse baseline visual acuity, and diabetes mellitus. Risk factors for sustained decrease in visual acuity included better baseline visual acuity, older age, and less formal education.

AGIS 14: In patients with visual field progression, a single 6-month confirmatory visual field test had a 72% probability of verifying a per sis tent defect. When the number of confirmatory visual field tests was increased from 1 to 2, the percentage of eyes that showed a per sis tent defect increased to 84%.

2009 AGIS Report: IOP fluctuation was an in de pen dent predictor of progression of OAG in eyes with lower baseline IOPs but not in those with higher baseline IOPs.

Most of the relevant findings from AGIS that reflect clinical practice are from post hoc analysis; thus, they may not fully take into account unmeasurable confounding factors and enrollment bias.

CLINICAL TRIAL 7-6

The United Kingdom Glaucoma Treatment Study (UKGTS)

Purpose: To determine the change in the frequency of visual field deterioration in treatment-naïve patients treated with latanoprost compared to those treated with placebo.

Participants: From 10 centers, 516 patients with newly diagnosed mild-to-moderate open-angle glaucoma were enrolled. Potential study participants were excluded for the following reasons:

• mean deviation worse than −10 dB in the better eye or −16 dB in the worse eye

• IOP above 35 mm Hg on 2 visits or IOP that averaged more than 30 mm Hg on 2 visits

• unreliable performance on visual field tests

• poor-quality optic nerve imaging with scanning laser ophthalmoscopy

• the presence of significant cataract

• previous intraocular surgery other than cataract extraction

• diabetic retinopathy

Study design: Enrolled patients were randomized 1:1 to either treatment with latanoprost 0.005% or to placebo and then monitored with frequent visual field tests and optic nerve imaging during 11 visits within 2 years. Visual field worsening was determined with the guided progression analysis (GPA) available on the Humphrey Field Analyzer. The optic nerve was imaged with confocal scanning laser ophthalmoscopy, scanning laser polarimetry, time-domain optical coherence tomography, and monoscopic disc photography. IOP was measured with Goldmann tonometry, dynamic contour tonometry, and the ocular response analyzer. Study endpoints were visual field worsening determined by GPA, IOP greater than 35 mm Hg on 2 visits, and decline of best-corrected visual acuity to worse than 20/60. The UKGTS was designed with the shortest observation period of any of the major therapeutic trials of open-angle glaucoma. This shortened period was achieved by a novel arrangement of the visual field tests in which they were clustered at the beginning and end of the periods of interest, rather than being spaced evenly.

Results: The UKGTS is important because it is the first randomized, placebo-controlled study of the effect of topical glaucoma medications and because of its novel design of testing intervals and clustering, which allowed the investigators to identify differences in visual field worsening in a relatively short time. Over 24 months, 59 participants in the placebo group had worsening of their visual field compared to 35 in the latanoprost group. The mean change in visual field mean deviation in those who worsened was −1.6 dB.