Clinical Trials in Glaucoma
Treatment vs No Treatment Trials
1. OHTS: Ocular Hypertension Treatment Study (2002)
The OHTS had two major goals. The first one was to determine if early treatment of people who have increased intraocular pressure (IOP) with topical ocular hypotensive medication, would prevent them from developing Primary Open-Angle Glaucoma (POAG). The second goal of OHTS was to determine which people are more likely to develop glaucoma, and therefore perhaps benefit from treatment; and which people with increased IOP are unlikely to develop glaucoma and therefore could probably be followed without treatment.
The OHTS began recruiting participants in 1994. The investigators recruited 1,636 patients with ocular hypertension at 22 clinical centers around the United States. Twenty-five percent of the participants recruited were African-American. The participants recruited were then randomly assigned either to be followed carefully without treatment or to receive eyedrop medication with the goal of reducing their IOP by 20% or more and to reach an IOP of 24 mm Hg or less. The participants were seen twice a year and had visual field studies performed; they had photographs of their optic discs taken once yearly. 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. The patients entered into the study were between 40 and 80 years old, had normal visual fields, normal optic discs, and had IOP between 24 mm Hg and 32 mm Hg in one eye and between 21 mm Hg and 32 mm Hg in the other eye.
Main outcome measures
The primary outcome was the development of reproducible visual field abnormality or reproducible optic disc deterioration attributed to POAG. Abnormalities were determined by masked certified readers at the reading centers, and attribution to POAG was decided by the masked Endpoint Committee.
The results of OHTS proved that topical medication does reduce the incidence of glaucoma. After five years of following the patients recruited, this study determined that eyedrop treatment reduced the development of glaucoma by more than 50 percent. During the course of the study, the mean reduction in IOP in the medication group was 22.5%. The IOP declined by 4% in the observation group. At 60 months, the cumulative probability of developing POAG was 4.4% in the medication group and 9.5% in the observation group. A detailed analysis was then performed to determine which patients were at greater risk for developing glaucoma. The predictive factors found included increasing age, increasing IOP, decreased thickness of the cornea, and increased cup/disc ratio. Using these factors, this study was able to demonstrate that some ocular hypertensive patients are at very low risk of developing glaucoma, as low as one or two percent over five years, whereas other groups are at much higher a risk, as high as 25-35% over five years. Thus, some of these participants might benefit from receiving early treatment, whereas others appear to be at such low risk that it makes little sense to begin treatment.
Limitations of OHTS
- Study IOP goal was 20% reduction. May not be sufficient in some patients
- No measure of medication adherence.
- Not population- based epidemiologic study.
- Some risk factors under-represented
- High threshold for diagnosing POAG
- Criteria for conversion to POAG 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
Topical ocular hypotensive medication was effective in delaying or preventing the onset of POAG in individuals with elevated IOP. Although this does not imply that all patients with borderline or elevated IOP should receive medication, clinicians should consider initiating treatment for individuals with ocular hypertension who are at moderate or high risk for developing POAG. The OHTS supports offering eyedrop treatment to ocular hypertensive people who are at moderate to high risk for developing glaucoma, taking into consideration the person’s age, medical status, life expectancy, and personal preference. The risk can be determined by looking at the patient’s age, IOP, corneal thickness, cup/disc ratio, and higher pattern standard deviation. African Americans in this study appeared to fare worse than the other participants—more African Americans in the Observation Group developed glaucoma than did non-African Americans in the Observation Group, and more African-Americans in the Medication Group developed glaucoma than did non-African-Americans in the Medication Group. The poorer outcome in African Americans appears to be linked to the fact that African Americans have thinner central corneas and larger cup/disc ratios. The OHTS participants were studied very carefully to see if the medication was safe. There was little evidence of increased systemic or ocular risk associated with ocular hypotensive medication.
OHTS Pearls for clinical practice
- Early medical treatment reduces the cumulative incidence of POAG.
- The absolute effect is greatest in high risk individuals.
- There is little absolute benefit of early treatment in low risk individuals
- There are safe and effective treatment options for most ocular hypertensive patients.
- The risk of developing POAG continues over at least a 15 year follow-up.
- African Americans develop POAG at a higher rate despite similar treatment and similar levels of IOP. Higher incidence is related to baseline risk factors.
- Individualized assessment of risk is useful to patients and clinicians
2. EMGT: Early Manifest Glaucoma Trial (1999)
The EMGT evaluated the effectiveness of reducing IOP in early, previously untreated open-angle glaucoma. The primary purpose of the EMGT was to compare the effect of immediate therapy to lower the IOP versus late or no treatment on the progression of newly detected open-angle glaucoma, as measured by increasing visual field loss and/or optic disc changes. 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.
The EMGT was the first large, controlled, randomized clinical trial (phase 3) to evaluate the effects of treatment versus no treatment on early stage glaucoma. More specifically, the study compared glaucoma progression in treated (lowering IOP) versus control patients. The study also helped researchers chart the natural history of the disease. Patient screening began in October 1992 and ended in April 1997. Study participants came from the Swedish cities of Malmö and Helsingborg. Newly detected and untreated chronic open-angle glaucoma with repeatable visual field defects by Humphrey perimetry were eligible for inclusion from a population-based screening of more than 44,000 residents of Malmö and Helsingborg, Sweden. Exclusion criteria included the following: advanced visual field loss (MD less than or equal to 16 dB) or threat to fixation; mean IOP greater than 30 mm Hg or any IOP greater than 35 mm Hg in at least one eye; visual acuity less than 0.5 in either eye; or any conditions precluding reliable fields or photos, use of study treatment, or inability to complete 4-year follow-up protocols. The study followed 255 patients, of which 66 percent were women. All patients were between 50-80 years of age, inclusive (average age: 68), and all had early stage glaucoma (open angle glaucoma or normal tension glaucoma) in at least one eye. One group (129 patients) was treated immediately with medicines and laser to lower eye pressure. Treated patients had laser trabeculoplasty and started receiving topical betaxolol twice daily in eligible eyes. A second, control group had 126 patients who were left untreated. Follow-up visits include computerized perimetry and tonometry every 3 months and fundus photography every 6 months. Decisions to change or begin treatment were made jointly with the patient when EMGT progression occurs. Any patient in the control group whose glaucoma progressed was immediately offered treatment.
Main outcome measures
The EMGT progression was defined by sustained increases of visual field loss in three consecutive C30-2 Humphrey tests, as determined from computer-based analyses, or by optic disc changes, as determined from flicker chronoscopy and side-by-side comparisons of fundus photographs performed by masked, independent evaluators.
A total of 255 patients were randomized between 1993 and 1997 and were followed for at least 4 years. All had generally good health status; mean age was 68.1 years, and 66% were women. 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. After six years of follow up, scientists found that in the control group, it took an average of 48 months to detect early signs of advancing disease. However, in the treated group, it took an average of 66 months – 18 months longer – to detect these early changes. In the treated group, eye pressure was lowered by an average of 25 percent. All the study participants will continue to be followed and regularly monitored. In eyes reaching visual field progression, the mean change in mean deviation (MD) from baseline was -1.93 dB (SD +/- 0.20) and the mean change in number of significant points was +4.85 (SD +/- 0.35). These changes did not show linear dependency on baseline MD, IOP or time to progression. At baseline, the median IOP was higher for the 15 patients with exfoliation glaucoma (24.0 mm Hg vs 20.0 mm Hg for others). In patients without exfoliation glaucoma, IOP remained stable during follow-up. In comparison, patients with exfoliation glaucoma showed a significantly larger median change of 0.96 mm Hg/y. In the overall cohort, the only factor related to IOP change was exfoliation glaucoma. Among patients without exfoliation glaucoma, no factors were associated with IOP change.
Limitations of EMGT
- Quality of life measure was not part of the initial protocol
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. In patients with early glaucoma, IOP remained stable without treatment during a 6-year period, regardless of baseline IOP, except for patients with exfoliation glaucoma, in whom IOP increased by almost 1 mm Hg annually. No factors, aside from exfoliation glaucoma, were related to longitudinal changes in IOP. A 25% decrease of IOP from baseline (mean untreated IOP 20.6 mmHg) reduced the risk of progression by 50%. Treatment had positive effects in all groups of patients, higher and lower IOP, older and younger patients, early and later stage of disease. Risk of progression decreased 10% with each 1mmHg IOP reduction from baseline to the first follow up visit. In most cases, progression was found first by perimetry. Later analysis showed that thin central corneal thickness was a risk factor in POAG (IOP>21mmHg) and low blood pressure was a risk factor in normal tension glaucoma (IOP<21mmHg)
EMGT Pearls for clinical practice
- A 25% decrease of IOP from baseline reduced the risk of progression by 50%
- Risk of progression decreased 10% with each 1mmHg IOP reduction from baseline
- Visual field progression can be measured and expressed in more conventional units (a loss of about - 2dB in MD and an increase in about five highly significant points)
- Thin central corneal thickness was a risk factor in POAG (IOP>21mmHg)
- Low blood pressure was a risk factor in normal tension glaucoma (IOP<21mmHg)
3. CNTGS: Collaborative Normal Tension Glaucoma Study (1998)
The CNTGS evaluated the role of IOP control in preventing the progression in normal-tension glaucoma (NTG).
This randomized controlled multi-center clinical trial examined the influence of IOP in NTG. 140 patients with progressing NTG were included and randomized. Eligible patients had glaucomatous disc abnormalities and visual field defects according to standardized criteria. At least three reliable baseline visual fields and at least 20/30 visual acuity were required. Cases with advanced damage were excluded. One eye of each eligible subject was randomized either not to be treated (control group) or to have intraocular pressure 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 crossover effects. In patients undergoing surgery, a 20% reduction of IOP was allowed without requiring repeated surgery. Eyes were randomized if they met criteria for diagnosis of NTG and showed documented progression or high-risk field defects that threatened fixation or the appearance of a new disk hemorrhage. The clinical course (visual field and optic disk) of the group with lowered intraocular pressure was compared with the clinical course when intraocular pressure remained at its spontaneous untreated level.
Main outcome measures
The primary outcome measure was disease progression. Visual field progression had to be verified. Optic disc progression was confirmed by stereo disk photographs read by masked evaluators.
One hundred-forty eyes of 140 patients were included in this study. Sixty-one were in the treatment group (28 were treated medically or with argon laser trabeculoplasty, 33 surgically), and 79 were untreated controls. Mean IOP in the treatment group was 10.6mmHg and untreated group was 16.0mmHg. Survival analysis showed statistically significant difference in disease progression in the two groups when examining for specifically defined end-point criteria of optic disc appearances and field loss. Twenty-eight (35%) of the control eyes and 7 (12%) of the treated eyes reached end point. The mean survival time +/-SD of the treated group was 2,688 +/- 123 days and for the control group, 1,695 +/- 143 days. Of 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. Due to influence of cataract on visual field analysis, authors could only conclude that "therapy that is effective in lowering IOP and free of adverse side effects would be expected to be beneficial in patients who are at risk of disease progression." An intention-to-treat analysis in a subsequent paper from the Group failed to show any beneficial effect of treatment despite treatment group IOP 10mm versus 16mm for non-treatment.
Limitations of CNTGS
- Visual field criteria were changed during the course of study
- Central corneal thickness was not measured
- IOP values up to 24mmHg higher than usually defined NTG
- 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
The level of pressure influences the course of NTG, as evidenced by a slower rate of incident visual field loss in cases with 30% or more lowering of intraocular pressure. The rate of progression without treatment is highly variable, but often slow enough that half of the patients have no progression in 5 years. A faster rate occurs in women, in patients with migraine headaches, and in the presence of disc hemorrhages. The beneficial effect of IOP reduction on progression of visual change in NTG was only found when the impact of cataracts on visual field progression, produced largely by surgery, was removed. Lowering intraocular pressure without producing cataracts is beneficial. Because not all untreated patients progressed, the natural history of NTG must be considered before embarking on IOP reduction with therapy apt to exacerbate cataract formation unless normal-tension glaucoma threatens serious visual loss.
CNTGS Pearls for clinical practice
- A beneficial effect of IOP lowering was found only after data were corrected for the effect on visual field of cataract formation.
- There are factors independent from IOP leading to progression in NTG
- Risk factors for progression:
- Female sex
- History of migraine
- Optic disc hemorrhage
4. EGPS: European Glaucoma Preventing Study (2002)
The EGPS tried to evaluate the efficacy of reduction of IOP by dorzolamide in preventing or delaying POAG in patients affected by ocular hypertension (OHT).
The EGPS is a multicenter, randomized, double-masked, controlled clinical trial. 1081 patients (age, ≥30 years) were enrolled by 18 European centers. The patients fulfilled a series of inclusion criteria, including: IOP 22 to 29 mmHg; 2 normal and reliable visual fields (on the basis of mean deviation and corrected pattern standard deviation or corrected loss variance of standard 30/2 Humphrey or Octopus perimetry); normal optic disc as determined by the Optic Disc Reading Center. Patients were randomized to treatment with dorzolamide or placebo (excipients of dorzolamide).
Main outcome measures
Efficacy end points were visual field, optic disc changes, or both. A visual field change during follow-up had to be confirmed by 2 further positive tests. Optic disc change was defined on the basis of the agreement of 2 of 3 independent observers evaluating optic disc stereo slides. The safety end point was an IOP of more than 35 mmHg on 2 consecutive examinations.
The median duration of follow up for all enrolled patients was 55.3 months. During the course of the study, the mean reduction in IOP in the dorzolamide group was 15% after 6 months and 22% after 5 years. Mean IOP declined by 9% after 6 months and by 19% after 5 years in the placebo group.
Limitations of EGPS
- High drop-out rate
- Only one type of IOP-lowering medication was evaluated
- IOP difference reached between the two groups was small
Dorzolamide reduced IOP by 15% to 22% throughout the 5 years of the trial. However, the EGPS failed to detect a statistically significant difference between medical therapy and placebo in reducing the incidence of POAG among a large population of OHT patients at moderate risk for developing POAG, because placebo also significantly and consistently lowered IOP. However, the same predictors for the development of POAG in OHTS and EGPS: baseline older age, higher IOP, thinner central corneal thickness, larger vertical cup-to-disc ratio and higher Humphrey visual field patter standard deviation. The benefit of lowering intraocular pressure to reduce the rate of progression from OHT to POAG has been established in the OHTS. Failure to demonstrate a comparable benefit in the EGPS relates to the selective drop-out of treated and untreated patients with higher intraocular pressure levels and to the failure to achieve sufficient lowering of intraocular pressure. The evidence that the placebo effect was responsible for progressive intraocular pressure-lowering over the 5-year study is not convincing and is likely a result of the regression to the mean phenomenon.
EGPS Pearls for clinical practice
- Same predictors for the development of POAG in OHTS and EGPS: baseline older age, higher IOP, thinner central corneal thickness, larger vertical cup-to-disc ratio and higher Humphrey visual field pattern standard deviation
- EGPS failed to detect statistical difference between the chosen medical therapy and placebo, either in IOP lowering effect, or in the rate of progression to POAG.
Treatment vs Treatment Trials
1. CIGTS: Collaborative Initial Glaucoma Treatment Study (1999)
Determine if glaucoma is better treated by initial medical therapy or filtration surgery.
607 patients with newly diagnosed open angle glaucoma were randomised to either medication or trabeculectomy (with or without 5-fluorouracil). Primary outcome variables were visual field progression and Quality of Life. Secondary outcome variables were visual acuity, IOP and cataract formation.
After 8 years 21% or surgical patients and 25% of medical patients showed perimetric progression, defined as a worsening of MD by 3dBs. Patients randomized to surgery had initially worse quality of life and underwent cataract surgery more than twice as often as patients in the medically treated group. The average visual acuity in the two groups after 4 years was about equal. 1.1% of surgical patients had developed endophthalmitis after 5years. IOP reduction was greater with surgery than with medical therapy. (48% and mean final IOP 14-15mmHg vs 35% and mean final IOP 17-18mmHg).
Inclusion criteria may have allowed recruitment of ocular hypertensive patients together with glaucoma patients resulting in a mixed sample with little risk of showing progression.
2. AGIS: Advanced Glaucoma Intervention Study (1994)
Determine if advanced, medically uncontrolled open angle glaucoma is better treated by initial argon laser trabeculoplasty or trabeculectomy.
591 patients (789 eyes) with advanced open angle glaucoma who could not be managed by maximum tolerated medical therapy alone were randomized between two groups: first group underwent argon laser trabeculoplasty, followed by trabeculectomy if needed and then by a 2nd trabeculectomy (ATT) and second group underwent trabeculectomy , followed by argon laser trabeculoplasty if needed and then trabeculectomy (TAT). Follow-up time ranged between 4 and 10 years.
Eyes with IOP under 18mmHg at all visits over 6 years did not show an increase of their initial visual field defect. For a 7-year follow up, eyes assigned to initial trabeculectomy showed a greater mean decrease IOP and smaller cumulative probability of failure of the first intervention than eyes assigned to initial argon trabeculoplasty. In African-American patients average percent of eyes with decreased visual acuity and visual field were less for the ATT sequence than for TAT. Caucasians shared these results in the first 4 years, but then switched in favor of TAT. Younger age and higher preoperative IOP were associated with increased failure rates for both groups. Trabeculectomy failure was also associated with diabetes. The expected 5-year cumulative probability of cataract formation after trabeculectomy increased to 78%. In patients with advanced glaucoma a single confirmatory test performed 6 months after the visual field worsening indicates with 72% probability a persistent defect when the worsening is defined by at least 2 units of AGIS score or by at least 2 decibels of MD.
Only one visual field was used as baseline. Patients with far advanced damage were excluded while early cases of glaucoma were also included. No stratification for stage of disease was attempted in the associative analysis.
3. TVT: Tube vs Trabeculectomy Study (2005)
Compare the safety and efficacy of trabeculectomy to tube shunt surgery in eyes with previous intraocular surgery.
212 eyes of 212 patients with previous cataract and/or failed glaucoma surgery and uncontrolled glaucoma on maximum tolerated medical therapy were randomized to receive either nonvalved tube shunt surgery (Baerveldt implant) and/or trabeculectomy with application of mitomycin C for 4 minutes.
After three months, both procedures produced sustained pressure reduction to the low teens throughout the five-year duration of the study. Trabeculectomy had a higher long-term failure rate (47% vs 30% after five years) The tube shunt surgery group had a lower rate of early postoperative complications, although rates of visual loss and of late or serious complications were similar between the two groups. Trabeculectomy with mitomycin C achieved better early IOP control (first three months) and less use of adjunctive medical therapy (first two years only).
Patients with refractory types of glaucoma like neovascular glaucoma were excluded. Mitomycin C was used for 4 minutes, which is longer than most surgeons currently use and may account for the higher hypotony rate observed in the trabeculectomy group.
4. AVB: Ahmed Versus Baerveldt Study (2011)
Compare outcomes in patients undergoing placement of Ahmed verus Baerveldt glaucoma drainage implants.
A total of 238 patients were recruited by 10 surgeons from 7 international sites. Eligible patients were 18 years or older with glaucoma refractory to traditional medical, laser and surgical treatment with IOP persistently above goal. Patients undergoing multiple procedures or who were unable to adhere to compliance standards for the study were excluded. Patients were randomized to receive either an Ahmed valve glaucoma drainage implant (124 patients) or a Baerveldt (non-valved) glaucoma drainage implant (114 patients). Primary outcome was surgical success measured by five parameters: IOP, medications, adverse events, interventions and visual acuity. Complete success was defined as an IOP of 5-18mmHg with a 20% reduction of IOP, off all ocular antihypertensive drops, no adverse events, no need for further surgical or laser intervention and visual acuity within 2 lines of Snellen acuity from baseline. Failure was defined as any of the following: IOP less than 5 mmHg or greater than 18 mmHg or less than 20% reduction of IOP from baseline in 2 consecutive visits, vision threatening complication, additional glaucoma procedure required, visual acuity progression to no light perception. Outcomes were measured at one year and five years.
At one year, there was a significantly higher rate of failure in the Ahmed group compared to the Baerveldt group (43% versus 28%, respectively). The Baerveldt group also had a higher rate of complete success compared to the Ahmed group (17% versus 8%, respectively). The patients in the Ahmed valve group had lower IOP post-op day 1 and 1 month post-operatively but at 1 year of follow-up, IOP was lower in the Baerveldt group (mean IOP 16.5 mmHg in the Ahmed group and 13.8 mmHg in the Baerveldt group). The Ahmed group required fewer IOP lowering drops in the early post-operative period (up to 2 months), but at 1 year, patients in the Ahmed group were on significantly more drops (1.6 versus 1.2). Vision threatening complications occurred in 4 patients in the Baerveldt group and 2 patients in the Ahmed group.
Five year outcomes demonstrate a persistently higher rate of failure in the Ahmed group compared to the Baerveldt group (53.2% versus 40.05%, respectively). Few patients in either group met criteria for complete success (3 patients in the Ahmed group and 5 patients in the Baerveldt group). Mean IOP was significantly lower after glaucoma drainage implantation in both groups at 5 years (16 mmHg in the Ahmed group and 13.6 mmHg in the Baerveldt group). Medication burden was also decreased in both groups at 5 years but was lower in the Baerveldt group. There was a higher rate of hypotony in the Baerveldt group (6 patients) compared to the Ahmed group (1 patient).
IOP was the primary parameter determining success and was standardized at 5-18 mmHg which does not take into account individual patient goals. The pre-defined success parameters resulted in few patients meeting criteria for success. Furthermore, clinical progression of patients was not taken into account.
Both the Ahmed valve and Baerveldt drainage devices result in significantly lower IOP and reduce drop burden. Ahmed valves result in greater immediate IOP reduction while Baerveldt valves result in lower long term IOP. Eye drop burden was also lower in patients receiving Baerveldt valves. However, Baerveldt valves had a higher risk of vision threatening complications. Additionally, in patients with extremely elevated IOP, the superior early IOP reduction from the Ahmed valve may help reduce the risk of glaucomatous vision loss early.
5. LiGHT: Laser in Glaucoma and ocular HyperTension study (2019)
Compare eye drops versus selective laser trabeculoplasty (SLT) as the first line therapy for ocular hypertension and primary open angle glaucoma.
This was an observer-masked randomized control trial in which 718 patients were randomly assigned to receive either eye drops (362 patients) or SLT (356 patients). First line eye drops were prostaglandin analogues, second line were beta blockers, third and fourth line treatment were topical carbonic anhydrase inhibitors and alpha agonists. Primary outcome measure was patient quality of life, secondary outcomes were visual acuity, IOP, cost, disease progression and need for glaucoma surgery. Patient demographics and ocular characteristics were similar between the two groups.
There was no difference in quality of life scores between the eye drops and SLT groups. Visual acuity and IOP outcomes were similar between the two groups. At 36 months, 95% of patients undergoing SLT were at target IOP with 74.2% of patients off eye drops. 36 eyes in the eye drop group showed disease progression compared to 23 eyes in the SLT group. In the eye drop group 11 patients required incisional glaucoma surgery to lower IOP compared to zero patients in the SLT group. Cost analysis showed that the SLT was more cost effective than eye drops.
This study utilized a treat-to-target design that does not provide clear IOP reduction parameters. Drop adherence was not measured in the eye drop group.
SLT is both a clinically effective and cost effective option for first line treatment for primary open angle and ocular hypertensive patients. It may spare patients eye drops and reduce the risk of future glaucoma surgery.
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