Clinical Trials in Glaucoma

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Article initiated by:

Sara Sánchez Tabernero, MD

All contributors:

Monica Ertel, Lensa Moen, Nathaniel P. Skillin, MD, PhD, Ahmad A. Aref, MD, MBA, Dr John Davis Akkara (MBBS, MS, FAEH, FMRF, FAICO), Sara Sánchez Tabernero, MD, Manuel Ángel Marcos Fernández, MD, Francesc March de Ribot, MD, PhD, Leonard K. Seibold, MD, Brian Chou, MD

Assigned editor:

Leonard K. Seibold, MD

Review:

Assigned status Up to Date

 by Leonard K. Seibold, MD on June 26, 2026.

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Contributing Editors:	add

Open Angle Glaucoma Studies

Glaucoma Laser Trial (GLT)

Design: Control Clin Trials 1991;12:504–524 | Results: Ophthalmology 1990;97:1403–1413 | GLT Follow-up Study: Am J Ophthalmol1995;120:718–731

Objective

The goal of GLT was to determine the safety and efficacy of argon laser trabeculoplasty (ALT) in controlling intraocular pressure (IOP) and preventing disease progression compared with topical medication as initial treatment for primary open angle glaucoma (POAG).

Design

The GLT was a multicenter, randomized clinical trial that enrolled 271 treatment-naïve patients with an IOP in both eyes ≥22 mmHg on two consecutive visits and glaucomatous visual field loss or optic disc cupping. Each patient had one eye randomly assigned to ALT (laser first; LF) and the other eye assigned to a stepped medication regimen (medication first; MF) starting with twice daily timolol maleate 0.5%. ALT was applied in two sessions of 180˚ (45–50 burns, 600–1200 mW to blanch or barely form a bubble) separated by four weeks. Treatment escalation occurred if IOP was not adequately reduced over two consecutive measurements, visual field or optic disc deterioration occurred, or if there were adverse events. For the 203 patients who enrolled in the GLT Follow-up Study evaluating outcomes up to 9 years, treatment for both eyes of all patients was according to physician discretion.

Main Outcome Measures

The main outcome measures were prescription of >1 medication, change in visual field, change in optic disc, change in IOP, and change in visual acuity.

Results

LF eyes had significantly lower mean IOP than MF eyes by ~2 mmHg at 2 years and significantly fewer LF eyes required simultaneous prescription of two or more medications to control IOP. At the end of the study, 44% of LF eyes were controlled by ALT alone while 30% of MF eyes were controlled by timolol alone. 70% of LF eyes were controlled by ALT or ALT with timolol. 89% of LF eyes and 66% of MF eyes were controlled within the stepped medication regimen. There were no major differences between the two treatment approaches with respect to changes in visual acuity or visual field over the 2 years of follow-up. Peripheral anterior synechiae (PAS) extending to the trabecular meshwork had developed in 34% of LF eyes versus 3% of MF eyes by the 3-month follow-up visit, without significantly affecting IOP. Iris color was the major predictor for PAS formation. By the end of Glaucoma Laser Trial Follow-up Study, the number of medication-days for LF eyes was 62% of the number of medication-days for MF eyes, with persistently significant but small differences in IOP (1.2 mmHg), visual field (0.6 dB) and optic disc cupping favoring LF eyes.

Limitations

·       Eligibility criteria were designed to permit enrollment of phakic patients with minimal defect and to exclude patients with little visual field remaining, limiting generalizability

·       Concern over small (~0.5 mmHg) crossover effect of timolol affecting LF eyes

Conclusions

Initial treatment of POAG with ALT resulted in fewer medications and lower IOP at two years compared to initial treatment with timolol. There were no major differences between the two treatment approaches with respect to changes in visual acuity or visual field over the 2 years of follow-up. After 9 years, the benefit of initial treatment with ALT was small but persistent. ALT was associated with an increased risk for PAS formation, but this did not have any deleterious effects on IOP or glaucoma progression even after 9 years.

Clinical Pearls

·       Initial treatment of POAG with ALT is at least as efficacious as timolol

·       Formation of PAS after ALT does not have a deleterious effect on IOP control or glaucoma progression

Collaborative Normal Tension Glaucoma Study (CNTGS)

Results: Am J Ophthalmol. 1998;126:487–497 | Intent-to-Treat Analysis: Am J Ophthalmol 1998;126:498–505 | Summary: Curr Opin Ophthalmol 2003;14:86–90

Objective

The CNTGS evaluated the efficacy of lowering IOP in preventing the progression of normal-tension glaucoma (NTG).

Design

230 patients with NTG were enrolled in this multi-center, randomized controlled trial, with eligible patients having glaucomatous disc abnormalities and visual field defects according to standardized criteria, as well as a median IOP of 20 mmHg or less in 10 baseline measurements with no recorded IOP above 24 mmHg. Cases with advanced disease were excluded. Once entered into the study, participants were followed every 3 months and only randomized once the committee determined that progression had occurred. The less affected eye was randomized either as control (no treatment) or to have IOP lowered by 30% from baseline within 6 months and maintained for 4 years by surgical and/or medical means, excluding beta blockers and adrenergic agents because of their potential for crossover effects.

Main Outcome Measures

The primary outcome measure was disease progression, defined by visual field or optic disc changes meeting specific criteria.

Results

IOP at randomization was 16.1 mmHg for the control group (n=79) and 16.9 mmHg in the treatment group (n=61). In the treatment group, 28 were treated medically or with argon laser trabeculoplasty and 33 underwent surgery. Mean IOP after treatment was 10.6 mmHg compared to 16.0 mmHg in the control group. Survival analysis showed a statistically significant difference in disease progression in the two groups, with 28 (35%) of the control eyes and 7 (12%) of the treated eyes reaching the protocol-defined end point. The mean survival time (± SD) was 2,688 ± 123 days for the treated group and 1,695 ± 143 days for the control group. Of the 34 cataracts developed during the study, 11 (14%) occurred in the control group and 23 (38%) in the treated group, with the highest incidence in those whose treatment included filtration surgery. An intention-to-treat analysis in a subsequent paper from the group initially failed to show any beneficial effect of treatment, but this was attributed to the differences in rates of cataract development in the two groups. When the survival analysis was repeated with the data from cataract patients in both groups censored at the time of the cataract diagnosis, the favorable effect of IOP reduction was again identified.

Limitations

·       Visual field criteria were changed during the course of study

·       Central corneal thickness was not measured

·       Patients with IOP values up to 24 mmHg were enrolled as long as their median IOP was 20 mmHg across 10 measurements

·       Optic disc hemorrhage was used as a sign of progression for randomization into the study but not as an outcome measure of progression

·       Intent to treat analysis affected by coincident cataract formation

Conclusions

A 30% or greater reduction in IOP was effective in slowing the rate of progressive visual field loss in NTG, but the degree of IOP reduction was not directly tied to the rate of progression. A faster rate of progression occurred in women, in patients with migraine headaches, and in those with documented disc hemorrhages. The beneficial effect of IOP reduction on progression of visual change in NTG required correction for the impact of cataracts on visual field loss, which occurred at a much higher rate in those who underwent filtration surgery. Many enrolled patients showed no progression while not being treated and therefore were never randomized, and 65% of the untreated eyes in the control group did not progress after randomization during the 5-year study. Therefore, the risks of IOP-lowering treatment should be weighed against the clinician’s estimate of the expected course without treatment.

Clinical Pearls

·       A 30% reduction in IOP slowed visual field progression of NTG when corrected for accelerated cataract formation

·       The rate of visual field progression in untreated NTG is highly variable, and lowering of IOP may not be necessary for those who have a low risk of progression

·       Risk factors for progression include female sex, those with history of migraine, and those with documented history of optic disc hemorrhage

Advanced Glaucoma Intervention Study (AGIS)

Design: Cont Clin Trials 1994;15(4):299–325 | Results: Ophthalmology 1998;105:1146–1164 | Other publications from AGIS

Objective

AGIS aimed to determine whether ALT or trabeculectomy resulted in better visual field outcomes in patients with advanced, medically uncontrolled OAG.

Design

This multicenter, randomized controlled trial enrolled 789 eyes from 591 patients age 35–80 with advanced OAG that could not be managed by maximum tolerated medical therapy and met a combination of IOP, visual field, and optic disc criteria. Patients were randomized to two stepped treatment groups: ALT, followed by trabeculectomy if needed, and then by a second trabeculectomy (ATT), or trabeculectomy, followed by ALT if needed, and then trabeculectomy (TAT). The second and third steps of treatment were pursued if patients again met the same combination of criteria for enrollment (e.g., persistently elevated IOP with new visual field changes).

Main Outcome Measures

The primary outcome was worsening of visual function defined by visual field and visual acuity changes.

Results

TAT resulted in a greater mean decrease in IOP and lower cumulative probability of failure of the first intervention over 7 years in both white patients (40.6% for ATT, 13.1% for TAT) and black patients (34.5% for ATT, 21.3% for TAT). However, black patients assigned to ATT had less visual acuity and visual field loss than those assigned to TAT. A similar result was seen in white patients initially, but then switched in favor of TAT. Eyes with early average IOP <14 mmHg fared better than those with IOP > 17.5 mmHg, and eyes with IOP under 18 mmHg at all visits over 6 years did not show any worsening of their initial visual field defect score. Patients with IOP >17.5 mmHg were more likely to be younger and have diabetes. Diabetes was also associated with trabeculectomy failure. The 5-year cumulative probability of cataract surgery was 78% greater for eyes assigned to TAT than ATT. TAT initially resulted in a large difference in the requirement for additional IOP-lowering medications compared to ATT, but this effect narrowed to just 0.5 medications at 7 years. In a subset of patients with only one surgical intervention, long-term IOP fluctuation was associated with VF progression in patients with low mean IOP but not in patients with high mean IOP.

Limitations

·       Only one visual field was used as baseline

·       Patients with far advanced damage were excluded while patients with early OAG and very high IOP were included

·       No stratification for stage of disease was attempted in the associative analysis

·       Antifibrotics for trabeculectomies were introduced during the course of the study and were used in a small subset of patients

Conclusions

Initial trabeculectomy resulted in greater IOP reduction in both patient populations, which also decreased the need for adjunctive IOP-lowering medications. Patients with lower IOP after initial treatment fared better than those with IOP > 17.5 mmHg. Despite the greater IOP reduction with TAT, long-term visual function outcomes for black patients were better with ATT. Long-term visual function outcomes for white patients were better with TAT. Trabeculectomies were more likely to fail in patients with diabetes and resulted in a greater risk of cataract. Long-term IOP fluctuation was a predictive risk factor for visual field progression.

Clinical Pearls

·       AGIS supports the use of TAT for white patients and ATT for black patients with advanced glaucoma

·       Sustained IOP <18 mmHg after intervention prevented further visual field loss in both patient populations

·       Long-term IOP fluctuation is a risk factor for visual field progression in patients with low mean IOP

Ocular Hypertension Treatment Study (OHTS)

OHTS 1: Arch Ophthalmol. 2002;120:701–713, Arch Ophthalmol. 2002;120:714–720 | OHTS 2: Arch Ophthalmol. 2010;128(3):276–287 | OHTS 3: JAMA Ophthalmol. 2021;139(5):558–566

Objectives

The OHTS was completed in 3 phases (OHTS 1, OHTS 2, and OHTS 3). OHTS 1 had two major goals. The first was to determine if early treatment of ocular hypertension (OHT) with topical ocular hypotensive medication would reduce the incidence of POAG. The second goal was to determine whether baseline demographic and clinical factors of those with OHT could be used to predict the risk of developing PAOG. OHTS 2 and 3 followed the same patients who took part in OHTS 1 but treated all patients with medication to determine whether delaying treatment of those with OHT affected long-term outcomes.

Design

The investigators recruited 1,636 patients with OHT between 1994 and 1996 at 22 clinical centers around the United States. Patients were 40–80 years old, had normal visual fields, normal optic discs, and IOP between 24–32 mmHg in one eye and between 21–32 mmHg in the other eye. 25% were African American. Participants were randomly assigned either to be followed carefully without treatment (observation group, n=819) or to receive topical medication with the goal of reducing their IOP by ≥20% and to reach an IOP ≤24 mmHg (medication group, n=817). The diagnosis of glaucoma was made when the patient developed a reproducible visual field defect or a reproducible deterioration in the appearance of the optic disc. OHTS 2 began the day after OHTS 1 ended in June 2002, with all participants receiving medication. Treatment of all patients was no longer determined by study protocol once OHTS 2 ended in late 2008. OHTS 3 was a retrospective study of 20-year participant outcomes.

Main Outcome Measures

The primary outcome of OHTS 1 was the development of reproducible visual field abnormality or reproducible optic disc deterioration attributed to POAG. The primary outcome of OHTS 2 was the cumulative proportion of participants who developed POAG. The primary outcome of OHTS 3 was the 20-year cumulative incidence and severity of POAG in one or both eyes after adjustment for exposure time.

Results

After 5 years, the cumulative probability of developing POAG was 4.4% in the medication group and 9.5% in the observation group. The mean reduction in IOP was 22.5% ± 9.9% in the medication group compared to 4% ± 11.6% in the observation group. Baseline factors found to be predictive of developing POAG included older age, higher IOP, decreased corneal thickness, larger pattern standard deviation, and larger cup-to-disc ratio. African Americans had higher rates of POAG regardless of randomization, yet race was not identified as a significant risk factor. Instead, African Americans were found to be at higher baseline risk due to having thinner corneas and larger cup-disc ratios, with similar outcomes when compared to others in the same risk category. A history of diabetes mellitus was found to be protective against the development of POAG.

OHTS 2 found that the cumulative probability of developing POAG at 13 years was 22% in the original observation group compared to 16% in the original medication group. In the population of participants deemed high-risk based on predictive factors identified in OHTS 1, the cumulative probability of developing POAG at 13 years was 40% in the original observation group compared to 28% in the original medication group. The number needed to treat (NNT) to prevent 1 case of POAG over 13 years for the low-, medium-, and high-risk tertiles were 98, 16, and 7, respectively.

OHTS 3 reported the 20-year cumulative incidence of POAG in one or both eyes of participants, adjusted for exposure time, was 45.6% overall (49.3% in the original observation group and 41.9% in the original medication group). The incidence rates for the low-, medium-, and high-risk tertiles were 31.7%, 47.6%, and 59.8%, respectively. The 20-year cumulative incidence of visual field loss in one or both eyes after adjustment for exposure time was 25.2%.

Limitations

·       Limited baseline IOP range of 21–32 mmHg

·       Study IOP goal was 20% reduction and an IOP <24 mmHg, which may not be sufficient for some patients

·       No measure of medication adherence

·       Study was not powered adequately for some risk factors (e.g., race, sex, and heart disease)

·       High threshold for diagnosing POAG, and criteria for conversion to POAG was adjusted during study

·       Some of the patients with normal white-on-white perimetry were later reported (ARVO 2002) to have had SWAP defects at baseline, thereby casting doubt on the “normal” state of some of the participants

Conclusions

Treatment of individuals with OHT using topical ocular hypotensive medication was effective in reducing the incidence of POAG, an effect that was sustained after 20 years of follow-up. The OHTS supports offering topical ocular hypotensive medication to those with OHT who fall into the moderate- and high-risk categories for developing POAG, while taking into consideration the person’s age, medical status, life expectancy, and personal preference. Individual risk can be determined using a 5-factor baseline model including age, IOP, corneal thickness, cup-disc ratio, and pattern standard deviation. African Americans were found to be at higher baseline risk but had similar outcomes when compared to others in the same risk category. Finally, there was little evidence of increased systemic or ocular risk associated with ocular hypotensive medication.

Clinical Pearls

·       Early treatment of OHT reduces the incidence of POAG in moderate- and high-risk individuals, but there is little absolute benefit of early treatment in low-risk individuals

·       Baseline risk factors for progression include older age, higher IOP, decreased corneal thickness, larger pattern standard deviation, and larger cup-to-disc ratio

·       The risk of developing POAG continues over at least a 20-year follow-up period

·       African Americans develop POAG at a higher rate despite similar baseline IOP, which was attributed to higher baseline risk factors of corneal thickness and cup-disc ratio

Early Manifest Glaucoma Trial (EMGT)

Design: Ophthalmology 1999; 106(11):2144–2153 | Results: Arch Ophthalmol. 2002; 120(10):1268–1279, Arch Ophthalmol. 2003;121:48–56 | Long-term Follow-up: Am J Ophthalmol. 2023;252:286–294 | Other publications from EMGT

Objectives

The EMGT was the first large randomized controlled clinical trial to evaluate the effects of IOP-lowering treatment on the progression of early, previously untreated OAG. The secondary purposes were to determine the extent of IOP reduction attained by treatment, to explore factors that may influence glaucoma progression, and to describe the natural history of newly detected glaucoma.

Design

This study recruited 255 Swedish patients with treatment-naïve OAG and repeatable visual field defects by Humphrey perimetry between 1992 and 1997. Exclusion criteria included advanced visual field loss (MD ≤-16 dB) or threat to fixation, mean IOP greater than 30 mmHg, or any IOP greater than 35 mmHg in at least one eye. All patients were between 50–80 years of age and had early-stage OAG or NTG in at least one eye. 66% of participants were women. Patients were randomized to treatment with ALT plus topical betaxolol BID (n=129) or no treatment (n=126).

Main Outcome Measures

The primary outcome measure was disease progression, defined by visual field or optic disc changes meeting specific criteria.

Results

At baseline, mean IOP was 20.6 mmHg and 80% of eyes had IOP less than 25 mmHg. 10% of the patients had pseudoexfoliation glaucoma. IOP in the treatment group was reduced by an average of 5.1 mmHg (25%) at the first follow-up and remained relatively stable over the median follow-up period of 6 years. IOP also remained stable in the control group, regardless of baseline IOP, except for patients with exfoliation glaucoma, in whom IOP increased by almost 1 mmHg annually. Glaucoma progression occurred in 45% of participants in the treatment group compared to 62% in the control group at 6 years. Median time to progression was 66 months in the treatment group and 48 months in the control group. Progression risk decreased by 10% for each reduction of 1 mmHg from baseline to the first follow-up visit. Baseline factors associated with progression included IOP ≥21 mmHg, exfoliation, bilateral disease, MD ≤-4.0 dB, and age ≥68 years. Treatment was associated with a significant increase in clinical nuclear opacity gradings. A long-term follow-up study found no obvious impact of delaying treatment for those in the control group with no significant differences in visual impairment or visual field MD in patients followed up to 21 years.

Limitations

·       Quality of life measure was not part of the initial protocol

·       Almost all patients were white Europeans

·       Patients with advanced disease or very high IOP were not eligible

Conclusions

The EMGT was the first large randomized, clinical trial to evaluate the role of immediate pressure reduction compared to no initial reduction in patients with early glaucoma and normal or moderately elevated IOP. Treatment lowered the risk of progression in all groups of patients, and the magnitude of initial IOP reduction was a strong predictor of progression. In most cases, progression was found first by perimetry. Baseline risk factors associated with progression included higher IOP, exfoliation, bilateral disease, greater visual impairment, and older age.

Clinical Pearls

·       IOP-lowering treatment lowers the risk of progression in early OAG by 10% for each mmHg IOP reduction from baseline

·       Baseline factors associated with progression in all patients included IOP ≥21 mmHg, exfoliation, bilateral disease, MD ≤-4.0 dB, systolic perfusion pressure ≤125 mmHg, and age ≥68 years

·       Thin central corneal thickness and a history of cardiovascular disease were risk factors for OAG progression in patients with baseline IOP ≥21 mmHg

·       Systolic blood pressure ≤160 mmHg was a risk factor for OAG progression in patients with baseline IOP <21 mmHg

European Glaucoma Prevention Study (EGPS)

Design: Ophthalmology 2002;109:1612–1621 | Results: Ophthalmology 2005;112(3):366–375 | Other Reference

Objective

The EGPS evaluated the efficacy of reducing IOP with dorzolamide in preventing or delaying POAG in patients affected by OHT.

Design

1081 patients age ≥30 years were enrolled by 18 European centers in this randomized, double-masked, controlled clinical trial. The patients fulfilled a series of inclusion criteria, including: IOP 22–29 mmHg, two normal and reliable visual fields, and normal optic discs. Patients were randomized to treatment with dorzolamide or placebo (excipients of dorzolamide).

Main Outcome Measures

The primary outcome was the onset of POAG, defined as visual field changes, optic disc changes, or both (efficacy end points). The safety end point was an IOP of more than 35 mmHg on 2 consecutive examinations.

Results

Mean IOP in the treated group (baseline 23.4 mmHg) decreased by 15% after 6 months and 22% after 5 years. However, mean IOP also decreased in the placebo group (baseline 23.5 mmHg) by 9% after 6 months and by 19% after 5 years. At 60 months, the probability of reaching the efficacy or safety end point was 13.7% in the dorzolamide group and 16.4% in the placebo group (P = 0.1).

Limitations

·       30% of those enrolled didn’t complete the study

·       No patients of African ancestry participated, limiting generalizability

·       Study protocol did not include a target IOP reduction and was powered based on a greater expected difference in IOP reduction between the two groups

Conclusions

Dorzolamide reduced IOP by 15% to 22% throughout the 5 years of the trial. However, the EGPS failed to detect a statistically significant difference in the incidence of POAG, which was attributed to the clinically significant effect of the placebo on IOP. The authors had many theories on the observed progressive IOP-lowering effect of the placebo including a simple regression to the mean as well as those with higher IOP being more likely to withdraw from the trial. The EGPS also identified the same baseline predictors for the development of POAG as identified in the OHTS: older age, higher IOP, thinner central corneal thickness, larger vertical cup-to-disc ratio and higher visual field pattern standard deviation.

Clinical Pearl

·       Baseline risk factors for the progression of OHT to POAG match those from OHTS: older age, higher IOP, thinner central corneal thickness, larger vertical cup-to-disc ratio, and larger visual field pattern standard deviation

Collaborative Initial Glaucoma Treatment Study (CIGTS)

Design: Ophthalmology 1999;106(4):653–662 | Visual Field Results: Ophthalmology 2009;116(2):200–207 | Other References

Objective

CIGTS aimed to determine whether medication or trabeculectomy is more effective at delaying disease progression in newly diagnosed OAG.

Design

607 patients between the age of 25 and 75 with newly diagnosed OAG meeting a combination of IOP thresholds, visual field changes, and optic disc findings were enrolled in this multicenter, randomized controlled clinical trial. Exclusion criteria included prior IOP-lowering eye drop use and specific ocular comorbidities including prior ocular surgery and diabetic retinopathy. Participants were randomized to either a stepped medication regimen or trabeculectomy (with or without 5-fluorouracil), with the target IOP established individually based on the patient’s baseline IOP and visual field score. Additional treatments to reach the target IOP were specified in the study protocol.

Main Outcome Measures

The primary outcome was visual field progression, defined as a worsening of MD by ≥3 dB. Secondary outcomes included health-related quality of life (QOL), visual acuity, IOP, and cataract formation.

Results

After 8 years, 21.3% of surgical patients and 25.5% of medical patients met the visual field progression criteria. Patients with a baseline MD of ≤-10 dB showed less visual field loss by about 1 dB over 7 years when treated with surgery, while those with diabetes showed less visual field loss by about 0.8 dB between years 2 and 9 when treated with medication. IOP reduction from the baseline of ~27 mmHg in both groups was greater with surgery (14.4 mmHg at 6 years) than with medical therapy (17.7 mmHg at 6 years). Baseline IOP and mean IOP after surgery or during medical therapy were not associated with visual field loss, but those with greater IOP variability both at baseline and during the study were at greater risk of substantial visual field loss, along with those having greater maximum IOP. Older age at baseline was associated with more visual field loss over time. Patients randomized to surgery initially had worse QOL metrics related to local eye symptoms and underwent cataract surgery more than twice as often as patients in the medically treated group.

Limitations

·       Inclusion criteria may have been too broad, allowing recruitment of those with OHT and OAG and resulting in a mixed sample population with lower risk of progression

·       Medication compliance was not assessed

·       Additional treatment required to reach the target IOP resulted in crossovers from surgery to medication and vice-versa

·       Central corneal thickness was only collected on a subset of patients and was insufficient to address any association with progressive visual field loss

Conclusions

Despite the greater IOP reduction in the trabeculectomy group, visual field progression did not depend on initial treatment, most likely because of the aggressive IOP target <18 mmHg for both groups. However, those with advanced disease benefitted more from surgery while those with diabetes benefitted more from medication. Greater IOP variability and higher maximum IOP were associated with more visual field loss, as was older age. The impacts of initial treatment on QOL and visual acuity were largely similar between the two groups. Initial trabeculectomy resulted in the development of more cataracts requiring removal.

Clinical Pearls

·       Initial trabeculectomy may be beneficial for patients with more advanced disease, while initial medication may be beneficial for patients with diabetes

·       Increased IOP fluctuation and high maximum IOP are important predictors of progressive VF loss; more aggressive treatment should be considered for these patients

Ahmed Versus Baerveldt (AVB) Study

Design: Ophthalmology 2011;118(11):2172–2179 | 1-year Results: Ophthalmology 2011;118(11):2180–2189 | 5-year Results:Ophthalmology 2016;123(10):2093–2102

Objective

The AVB aimed to compare outcomes of Ahmed and Baerveldt glaucoma drainage implants in patients with uncontrolled glaucoma on maximum tolerated medical therapy, many of whom had failed or were at high risk of failing trabeculectomy

Design

This international multi-center randomized controlled trial enrolled a total of 238 patients age >18 with IOP persistently above goal on maximum tolerated medical therapy who had either failed trabeculectomy with antimetabolite or had disease at high risk of failing trabeculectomy (e.g., neovascular or uveitic glaucoma). Patients were randomized to receive either a valved Ahmed-FP7 implant (n=124) or a non-valved Baerveldt-350 implant (n=114).

Main Outcome Measures

The primary outcome was surgical failure defined as meeting one of the following: IOP outside the target range (5–18 mmHg) or reduced <20% from baseline for 2 consecutive visits after 3 months, severe vision loss related to the surgery, removal of the implant, or de novoglaucoma surgery required.

Results

At both one and five years, there was a significantly higher rate of failure in the Ahmed group compared to the Baerveldt group (53% vs. 40%, respectively at five years). Both devices resulted in a sustained decrease in mean IOP and number of drops from baseline (31.4 mmHg and 3.1 drops). Patients in the Ahmed valve group initially had lower IOP and required fewer IOP-lowering drops (up to 2 months), but at 1 year and 5 years, patients in the Ahmed group were on significantly more drops (1.8 vs. 1.2 at 5 years) with a significantly higher mean IOP (16.6 mmHg vs. 13.6 mmHg at 5 years) compared to the Baerveldt group. Both groups had a moderate but similar reduction in visual acuity over 5 years of follow-up. While complications rates were similar at 5 years (63% Ahmed vs. 69% Baerveldt), hypotony resulted in failure in 5 patients in the Baerveldt group and none in the Ahmed group.

Limitation

·       Visual function was not used as a marker for surgical failure, so those with clinical evidence of glaucoma progression or hypotony-related complications did not meet criteria for failure as long as they remained within the target IOP of 5–18 mmHg

Conclusions

Both implants were effective in reducing IOP and the need for glaucoma medications in this population. While the Ahmed group experienced greater immediate IOP reduction, the Baerveldt group had a lower failure rate and a lower IOP on fewer medications than the Ahmed group at 5 years. However, the Baerveldt implant carried a small risk of hypotony that was not seen with the Ahmed implant.

Clinical Pearls

·       Ahmed tubes result in greater immediate IOP reduction and safeguard against hypotony, which may reduce the risk of early glaucomatous vision loss in patients with extremely elevated IOP

·       Baerveldt tubes result in lower long-term IOP and drop burden, which may be a good choice for patients with a low long-term IOP target or in patients intolerant or poorly adherent to topical medications

Low-Tension Glaucoma Treatment Study (LoGTS)

Design: Ophthalmology 2005;112:376–385 | Results:Am J Ophthalmol 2011;151:671–681

Objective

The LoGTS aimed to evaluate whether brimonidine has a neuroprotective effect in NTG by comparing visual field stability in patients treated with brimonidine or timolol.

Design

LoGTS was a randomized, multicenter, double-masked clinical trial that enrolled 178 patients age ≥30 with untreated IOP ≤21 mmHg on a diurnal curve and glaucomatous visual field defects consistent with optic disc cupping. Exclusion criteria included an untreated pressure >21 mmHg, advanced visual field loss, and contraindications to study medications. Participants were randomized to monotherapy of both eyes with twice daily brimonidine tartrate 0.2% (n=99) or twice daily timolol maleate 0.5% (n=79). Follow-up visits included Humphrey 24-2 full threshold perimetry, tonometry every 4 months, and annual optic disc photography.

Main Outcome Measures

The primary outcome was visual field progression in either eye, defined by a specific set of study criteria.

Results

While IOP reduction was similar in both groups, fewer patients in the brimonidine group met the visual field progression criteria after a mean follow up period of 30 months (n=9 vs. n=31). 28 patients in the brimonidine group ultimately dropped out due to ocular allergy, compared to just 9 in the timolol group.

Limitations

·       Only 45% of patients in the brimonidine group and 71% of patients in the timolol group completed the study

·       Diurnal IOP was not measured after medications were started, with timolol known to have a minimal effect at night

Conclusions

Brimonidine and timolol have a similar IOP-lowering effect in NTG, yet brimonidine reduced visual field progression consistent with a non-IOP-related mechanism of action. Brimonidine has a higher risk of ocular allergy and systemic adverse events, resulting in greater non-compliance compared with timolol.

Clinical Pearls

·       Brimonidine may reduce visual field progression in NTG compared to timolol

·       Brimonidine has a high incidence of ocular allergy

Tube vs. Trabeculectomy (TVT) Study

Results: Am J Ophthalmol 2012;153(5):789–803 | Complications: Am J Ophthalmol 2012;153(5):804–814

Objective

The TVT study aimed to compare the safety and efficacy of trabeculectomy to tube shunt surgery in eyes with uncontrolled glaucoma despite previous trabeculectomy or cataract surgery and maximum tolerated medical therapy.

Design

This multicenter, randomized controlled trial enrolled 212 eyes of 212 patients with uncontrolled glaucoma on maximum tolerated medical therapy with a prior trabeculectomy and/or cataract surgery. Eligible patients with an IOP between 18–40 mmHg were randomized to either tube shunt surgery with the non-valved Baerveldt implant or trabeculectomy with application of mitomycin C (MMC) for 4 minutes.

Main Outcome Measures

Primary outcomes included IOP, visual acuity, use of supplemental medical therapy, and failure defined as IOP >21 mmHg or not reduced by 20%, IOP <5 mmHg, reoperation for glaucoma, or loss of light perception vision.

Results

After three months, both procedures had resulted in sustained IOP reduction to the low teens with the use of 1.2–1.4 additional IOP-lowering medications throughout the five-year duration of the study. Rates of visual field loss were similar between the two groups, but trabeculectomy had a higher long-term failure rate (47% vs 30% after five years). While the tube shunt surgery group had a lower rate of early postoperative complications, late or serious complications were similar between the two groups. Trabeculectomy with MMC achieved better early IOP control (first three months) and required less use of adjunctive medical therapy for the first two years, but had a significantly higher 5-year cumulative reoperation rate. No significant differences in 5-year visual acuity were seen between the two groups.

Limitations

·       Only those with prior history of ocular surgery were included, while patients with refractory types of glaucoma (e.g., neovascular glaucoma) were excluded

·       MMC was used for 4 minutes, which may be longer than many surgeons currently use and may account for the higher hypotony rate observed in the trabeculectomy group

Conclusions

Both Baerveldt tube shunts and trabeculectomy resulted in a significant and sustained decrease in IOP to the low teens in this population of patients with uncontrolled glaucoma while also decreasing supplemental medication use. Patients treated with tube shunts required fewer reoperations than trabeculectomies in this lower risk population and had a higher overall success rate based on the criteria in this study, whereas trabeculectomy provided better initial IOP control. Neither ultimately showed an advantage in 5-year visual acuity outcomes.

Clinical Pearl

·       Both tube shunt surgery and trabeculectomy with MMC are viable surgical options for treating medically uncontrolled glaucoma in patients with previous cataract extraction or failed filtering surgery

United Kingdom Glaucoma Treatment Study (UKGTS)

Design:Ophthalmology 2013;120:68–76 | Results: Lancet 2015;385:1295–1304 | Risk Factors: Ophthalmology 2020;127:1642–1651

Objective

The goal of the UKGTS was to determine whether reducing IOP with latanoprost eye drops, as compared to placebo, preserved the visual field of patients with newly diagnosed OAG.

Design

This randomized, multicenter, triple-masked, placebo-controlled trial conducted in the UK enrolled 516 patients with newly diagnosed, untreated OAG. Eligibility criteria were modelled after the EMGT to allow for comparison and meta-analysis, which included evidence of glaucomatous visual field defects in at least one eye with corresponding optic nerve damage. Patients with POAG and pseudoexfoliation glaucoma were included, while patients with pigment dispersion glaucoma, advanced glaucoma (MD ≤-10 dB in the better eye or ≤-16 dB in the worse eye), mean IOP ≥30 mmHg, or poor visual acuity were excluded. Patients were randomized to either latanoprost 0.05% eye drops (intervention group; n=258) or placebo eye drops containing the latanoprost vehicle (control group; n=258) administered once a day in both eyes. Visual field testing (24-2) was performed 16 times over 11 visits throughout a 24-month period, clustered at baseline, 18 months, and 24 months. This novel design was based on statistical modeling that demonstrated clustering increases the precision of estimates of the velocity of deterioration.

Main Outcome Measure

The primary outcome was time to visual field deterioration within 24 months, defined as a significant deterioration from baseline (p<0.05) in ≥3 identical test points in two consecutive tests (tentative deterioration) and confirmed by the same criteria applied to the next two consecutive tests.

Results

55 patients did not attend any post-baseline visits, leaving 231 in the intervention group and 230 in the control group. Treatment with latanoprost significantly prolonged the time to visual field deterioration (HR 0.44, 95% CI 0.28–0.69; p=0.0003) with treatment differences evident at 12 months. 25.6% of patients in the control group reached the deterioration endpoint at 24 months compared with 15.2% of patients in the intervention group (p=0.006). At 24 months, mean IOP reduction in the intervention group was 3.8 ± 4.0 mmHg compared to 0.9 ± 3.8 mmHg in the control group. No serious adverse events were attributed to the study drug. In a secondary analysis, bilateral disease, higher IOP, and disc hemorrhage were risk factors for visual field deterioration while smoking history seemed to be protective against deterioration.

Limitations

·       Relatively high number of patients lost to follow up or with incomplete follow up

·       Participants were all from the UK and predominately white (90%), limiting generalizability

·       Individuals with advanced OAG were excluded

Conclusions

UKGTS was the first placebo-controlled trial to demonstrate that IOP-lowering medication significantly prolonged the time to visual field deterioration in patients with newly diagnosed, mild to moderate OAG. Impressively, significant treatment effects were observed even at 12 months. The ability to detect progression within such a short observation period was due to the novel study design that combined frequent visual field tests, sensitive progression criteria, and a sufficiently large sample size.

Clinical Pearls

·       IOP-lowering treatment with latanoprost was effective in prolonging time to visual field progression for patients with newly diagnosed OAG

·       Visual field progression can be detected much faster with more frequent testing, reducing the typical observation period for clinical trials

Laser in Glaucoma and ocular HyperTension (LiGHT)

3-year Results: Lancet 2019;393:1505–1516 | 6-year Results: Ophthalmology 2023;130:139–151

Objective

The LiGHT trial aimed to compare health related quality of life (HRQoL), clinical effectiveness, and cost of eye drops to selective laser trabeculoplasty (SLT) as first-line therapy for OHT and POAG.

Design

This multicenter, observer-masked, randomized controlled trial enrolled 1235 eyes of 718 patients with newly diagnosed and untreated OHT and POAG and visual field loss not worse than -12 dB in the better eye and -15 dB in the worse eye. Eyes were randomly assigned to receive either a stepped eye drop regimen (n=362) or 360˚ SLT followed by repeat SLT and topical medications as required (n=356), with a target IOP based on the Canadian Target IOP Workshop for disease severity stratification. First-line eye drops were prostaglandin analogues, followed sequentially by beta blockers, topical carbonic anhydrase inhibitors, and alpha agonists. In the 6-year extension, a third SLT was permitted in the SLT group after 3 years and SLT was offered to the eye drop group to reduce medication load or as a treatment escalation.

Main Outcome Measures

The primary outcome measure was health-related quality of life (HRQoL) at 3 years.

Results

There was no meaningful difference in HRQoL scores between the eye drops and SLT groups at 3 or 6 years. Eyes in both groups had similar IOP at 36 months but those in the SLT arm had higher IOP at 72 months compared to the eye drop group (16.3 mmHg vs. 15.4 mmHg). Visual field MD and visual acuity were similar at 72 months, but significantly more eyes in the drops arm exhibited disease progression (26.8% vs. 19.6%), required trabeculectomy (n=32 vs. n=13), and required cataract surgery (n=95 vs. n=57) after 6 years. Drop-free IOP control at 72 months was achieved in 69.8% of eyes initially treated with SLT compared with 18.0% of eyes initially treated with IOP-lowering eye drops. Of the eyes initially treated with SLT and being drop and surgery free at 6 years, 90% of eyes (295 eyes) needed up to 2 SLT treatments in total. Of the eyes initially treated with eye drops and being drop free at 72 months, 79.5% (66 eyes) had switched to SLT. SLT was more cost effective than eye drops, with estimated savings of £451 per patient in the NHS system.

Limitation

·       Drop adherence was not measured in the eye drop group

Conclusions

Initial treatment of OHT and OAG with SLT is cost-effective with no significant difference in HRQoL. SLT safely offers IOP control without the need for additional medical or surgical treatment in more than 70% of eyes with OHT and OAG, while also reducing progression rates and the need for later glaucoma and cataract surgery.

Clinical Pearls

·       Initial SLT provides better long-term disease control than initial drop therapy for patients with newly diagnosed OHT and OAG

·       SLT should be offered as a first-line treatment for OAG and OHT.

Primary Tube vs. Trabeculectomy (PTVT) Study

5-year Results: Ophthalmology 2022;129:1344–1356

Objective

PTVT aimed to compare safety and efficacy of tube shunt surgery to trabeculectomy in eyes with uncontrolled glaucoma on maximum tolerated medical therapy and no previous incisional ocular surgery.

Design

This multicenter, randomized clinical trial enrolled 242 eyes of 242 patients between 18–85 years old with no previous incisional ocular surgery and medically uncontrolled glaucoma with an IOP between 18–40 mmHg. Participants were randomized to either tube shunt placement (Baerveldt 350 implant, n=125) or trabeculectomy with MMC (0.4 mg/mL for 2 minutes, n=117).

Main Outcome Measures

The primary outcome was the cumulative rate of surgical failure, defined as IOP >21 mmHg or less than a 20% reduction from baseline, IOP ≤5 mmHg, reoperation for glaucoma, or loss of light perception vision.

Results

After 5 years of follow up, the failure rate was similar between study groups at 42% in the tube group and 35% for trabeculectomy (P = 0.21). Mean IOP was significantly lower in the trabeculectomy group at 1 year (13.8 vs. 12.4 mmHg) and 3 years of follow up (13.9 vs. 12.1 mmHg), but was similar between groups at 5 years (13.4 mmHg vs. 13.0 mmHg). Adjunct medication use was significantly higher in the tube group at all timepoints of follow up and by 5 years was 2.2 medications in the tube group compared to only 1.3 medications in the trabeculectomy group. Rates of reoperation and vision loss were similar between the two groups.

Limitations

·       Patients with any prior ocular surgery were excluded

·       Only one type of tube shunt implant was utilized and a standardized dose of mitomycin C was used

Conclusions

Both tube shunt surgery and trabeculectomy resulted in a significant and sustained decrease in IOP to the low teens and similar failure rates and visual outcomes at 5 years. Patients with tube shunts required more medications, therefore trabeculectomy may be a better option for patients who are nonadherent or poorly tolerant of glaucoma medical therapy.

Clinical Pearl

·       PTVT did not demonstrate clear superiority of one treatment, but supports the use of trabeculectomy with MMC as the preferred initial surgical procedure in patients who are nonadherent or poorly tolerant of glaucoma medical therapy

Angle-Closure Glaucoma Studies

Effectiveness in Angle-closure Glaucoma of Lens Extraction (EAGLE)

Design: Trials 2011;12:133 | Results: Lancet 2016;388:1389 | Cost Analysis: BMJ Open 2017;7:e013254

Objective

The goal of the EAGLE study was to assess the efficacy, safety, and cost-effectiveness of early lens extraction (LE) compared to laser peripheral iridotomy (LPI) and topical medical treatment as first-line therapy in patients with newly diagnosed primary angle-closure glaucoma (PACG) or primary angle closure (PAC) with elevated IOP.

Design

This multicenter, international, randomized controlled trial enrolled 419 phakic patients age ≥50 with either (1) newly diagnosed PAC and IOP ≥30 mmHg or (2) PACG with ≥180˚ iridotrabecular contact, reproducible glaucomatous visual field defects, glaucomatous optic neuropathy, or both, and IOP >21 mmHg on at least one occasion. Patients with symptomatic cataract, advanced glaucoma with MD ≤-15 dB or cup-to-disc ratio >0.9, a previous episode of acute angle closure (AAC), or prior laser or ocular surgery were excluded. Patients were randomized to either phacoemulsification with a monofocal intraocular lens implant, with temporary medical treatment while awaiting surgery and laser iridoplasty if angle closure persisted (n=208), or to LPI with escalating topical medical therapy to achieve an IOP target of 15–20 mmHg (n=211). If maximum tolerated medical therapy did not control the IOP, glaucoma surgery was performed, and the treatment was classified as a failure. Patients assigned to standard care could undergo lens extraction during the study period only when indicated clinically for reduced vision, or if the treating ophthalmologist judged that LE could help control the IOP.

Main Outcome Measures

The main outcomes measures were patient-reported health status, IOP, and incremental cost-effectiveness ratio per quality-adjusted life-year (QALY) gained 36 months after treatment.

Results

155 (37%) participants had PAC and 263 (63%) had PACG. Initial treatment with LE resulted in a significantly higher mean health status score assessed with the European Quality of Life-5 Dimensions (EQ5D) questionnaire and significantly lower IOP by 1.18 mmHg compared to standard care. Only 21% of participants in the LE group received any further treatment to control IOP, compared with 61% of those in the standard care group who received at least one glaucoma drop. Only one patient in the LE group required additional glaucoma surgery compared to 24 operations in the standard care group. Visual field outcomes at 36 months were similar between the two treatment groups, although the study was not powered specifically to detect this difference. For the 179 of 285 UK participants for whom complete cost and QALY data were available, the incremental cost-effectiveness ratio was £14,284 per QALY gained for initial LE versus standard care at 36 months, but subsequent economic modeling suggested that LE may be cost saving by 10 years. 

Limitations

·       Patients with severe PACG and PAC with IOP <30 mmHg were excluded, limiting generalizability

·       Economic analysis was only performed for a subset of patients in the UK, limiting generalizability

·       It was not possible to mask interventions

·       Gonioscopy reporting was incomplete

Conclusions

Initial treatment of PAC and PACG with LE was superior to LPI plus topical medication across all study dimensions of quality of life, IOP control, and long-term cost-effectiveness. Perhaps more importantly, initial LE largely eliminated the need for further glaucoma surgery and significantly reduced the need for any further treatment to control IOP.

Clinical Pearl

·       Initial LE is more clinically- and cost-effective than LPI and topical medication therapy for patients with PACG or PAC with high IOP

Zhongshan Angle-Closure Prevention (ZAP) Study

6-year Results: Lancet 2019;393:1609–18 | 14-year Results: Ophthalmology 2023;130:786–794

Objectives

The ZAP study had 2 goals. The first was to evaluate the efficacy of LPI prophylaxis for patients with primary angle-closure suspect (PACS). The secondary goal was to identify risk factors for the conversion from PACS to primary angle closure.

Design

The ZAP study was a single center randomized controlled trial that enrolled 889 participants with bilateral PACS from Guangzhou, China. One eye was randomized to be treated with LPI, with the other eye untreated as a control. Exclusion criteria included peripheral anterior synechiae (PAS), IOP >21 mmHg, corneal opacity, visual acuity <20/40, and history of intraocular surgeries, penetrating ocular trauma, or AAC. Patients with IOP elevation >15 mmHg after the darkroom prone provocative test (DRPPT) were deemed to be at high risk of AAC and therefore excluded.

Main Outcome Measures

The primary outcome was the incidence of PAC at 6 years, consisting of the following 3 study end points: IOP of >24 mmHg confirmed by a recheck on another day within 1 week, PAS of 1 clock hour or more in either quadrant, or an episode of AAC. The study was extended to 14 years with the same outcome measure.

Results

A total of 33 LPI-treated eyes and 105 control eyes progressed to PAC after 14 years (P < 0.01). PAS ≥1 clock hour was found in 28 LPI-treated eyes and 98 control eyes. AAC and IOP ≥24 mmHg was uncommon in both groups. The hazard ratio for progression to PAC was 0.31 (95% confidence interval, 0.21-0.46) in LPI-treated eyes compared with control eyes. LPI-treated eyes experienced a mean IOP elevation of 0.34 mmHg and were more likely to require cataract surgery compared to control eyes (n=70 vs. n=54). Higher baseline IOP, shallower limbal anterior chamber depth (LACD), and shallower central anterior chamber depth (CACD) were associated with an increased risk for PACS progression in control eyes.

Limitations

·       Patients at high risk for AAC were excluded

·       45% of participants dropped out by the 14-year follow-up and many patients underwent cataract surgery during the study, which likely reduced their risk of conversion to PAC

·       All participants were Chinese and 83% were women, limiting generalizability

Conclusions

LPI reduced the relative risk of PACS progression to PAC by 69% over 14 years. Absolute risk remained low; the NNT to prevent 1 PAC occurrence over 14 years was 12.35. As the progression rate was relatively low and most PAC cases were asymptomatic, prophylactic LPI should be considered primarily for high-risk patients.

Clinical Pearls

·       Prophylactic LPI should be considered for high-risk individuals, but may accelerate cataract formation

·       Risk factors for PACS progression include increased baseline IOP, shallow LACD, and shallow CACD

·       Observation is a reasonable alternative management of PACS in low-risk individuals