Glaucoma Landmark Studies

---

The Baltimore eye study determined the need for more screening methods to detect glaucoma.  In the 1991 Baltimore eye study, researchers found that tonometry, optic nerve assessments, and medical history did not provide a reasonable balance of sensitivity and specificity to adequately screen a person for glaucoma.  

Key Points:  

• IOP is one of the strongest known risk factors for open-angle glaucoma, but the use of IOP as a referral criterion for glaucoma had little sensitivity 
• Measuring cup-to-disc ratios and neuroretinal rim width was also limited in its usefulness for screening glaucoma, showing a poor balance of sensitivity and specificity 

Overall, the Baltimore eye study is a landmark study because it showed that population-based glaucoma screening programs could not rely on tonometry alone to determine a person’s disease status. The effectiveness of past techniques was limited and new approaches to glaucoma screenings were encouraged. 

A study for the AGES! In the AGIS study, 789 eyes with medically recalcitrant open-angle glaucoma (OAG) were randomized to two different treatment sequences: argon laser trabeculoplasty --> trabeculectomy --> trabeculectomy (ATT; n=404) and trabeculectomy --> argon laser trabeculoplasty --> trabeculectomy (TAT; n=385). The primary outcomes include visual field (VF) & visual acuity (VA), and other outcomes included intraocular pressure (IOP), surgical complications, time to treatment failure, additional medical therapy needed.

Key Points:

• Compared to TAT, ATT provided less overall loss of visual acuity (VA) and visual field (VF) in black patients, whereas white patients with TAT had less overall VA & VF loss
• Less visual field loss was associated with an average IOP of 14mmHg or less during the first 18 months after the first surgical intervention, as well as for eyes with IOP of 18mm Hg or less for all study visits
• Younger age and higher IOP were related to decreased ALT efficacy

Overall, the AGIS study is a landmark study because it studied varying sequences of surgical and procedural interventions in glaucoma patients. The key conclusion at the time surrounded the different optimal treatment algorithm for white and black patients. However, given the development of treatment options such as SLT and MIGS since the study, the outcomes of the study should be considered in the context of the times of the study.

Nowadays we can’t imagine a world without lasers in glaucoma!Published in 1990, the Glaucoma Laser Trial (GLT) sought to determine the safety and efficacy of Argon Laser Trabeculoplasty (ALT) compared to topical medications (timolol drops) as first-line treatment of primary open-angle glaucoma (POAG). In this multicenter RCT from the early 1990s, 271 patients were included, and the two eyes of each patient were randomized into two groups: ALT first (LF, n = 271) or timolol maleate 5% first (MF, n = 271). 

Key Points:

• Compared to MF eyes, LF eyes resulted in lower IOP and less reliance on ocular antihypertensive medications at 2-year follow-up
• Visual acuity and visual fields were stable at 2-year follow-up in both groups
• A 3.5-year follow-up study found slightly less deterioration in visual fields of LF eyes than in MF eyes

GLT is a landmark study that challenged the traditional paradigm of maximizing medical therapy before utilizing laser treatment. This study found ALT to be effective and safe in patients with POAG and comparable to medical therapy overall. However, despite these findings, ALT was rarely used as a first-line therapy due to the adoption of more effective glaucoma medications (prostaglandin analogues) and due its risk of trabecular meshwork scarring over multiple treatments. ALT paved the way for the introduction of newer forms of laser trabeculoplasty, such as selective laser trabeculoplasty (SLT).

 No pressure… but we may need to lower the pressure. Prior to the CNTGS, there was no consensus regarding the treatment of normal tension glaucoma – glaucomatous optic nerve damage in the setting of normal range intraocular pressures (IOP). In this 1998 study, patients with normal tension glaucoma were randomized into a treatment cohort (pressure lowered by >30%) and an untreated, control cohort to determine if lowering IOP played a protective role in patients with normal tension glaucoma. 

Key Points

• At follow-up, mean IOP was significantly lower in the treatment group compared to the control (10.6 mm Hg vs 16.0 mm Hg, P < 0.0001)
• When using the defined endpoints of optic disc changes or visual field loss, survival analysis showed significantly greater progression of glaucomatous disease in the untreated control (P < 0.0001)
• Cataracts developed more often in the treatment group, likely due to surgical intervention (38% vs 14%, P = 0.0011)
• A follow-up, intention-to-treat analysis initially found no difference in visual field survival analysis outcomes between cohorts, but after excluding patients with cataracts (i.e., a treatable problem), they found favorable outcomes for the treatment group (P = 0.0018)

Overall, the CNTGS is a landmark study because it highlights the role of pressure-lowering therapy in preventing disease progression of normal tension glaucoma. Importantly, the visual field benefits were only identified once excluding patients for visual changes secondary to cataract formation. Still, the clinical relevance of the CNTGS showed that treating IOP, even in patients with normal IOP, reduces glaucomatous visual field damage in patients with NTG.

Medication or Surgery: Which path to tread in open-angle glaucoma? In the Collaborative Initial Glaucoma Treatment Study (CIGTS), a total of 607 patients with newly diagnosed open-angle glaucoma were randomized into either medication or surgery (trabeculectomy with and without 5-fluorouracil). Over a period of up to five years, visual field loss (primary outcome), in addition to visual acuity (VA), intraocular pressure, and the development of cataracts were monitored.

Key Points:  

• Visual field outcomes did not significantly differ based on initial treatment
• Surgical patients experienced a heightened risk of VA loss in the early phases, though by the 4-year mark, VA was almost on par between the two groups
• The initial surgical intervention group maintained a lower IOP (14-15 mmHg) compared to the initial medical group (17-18 mmHg)
• There was a higher rate of patients who underwent cataract removal in the surgery group

Overall, the CIGTS stands as a landmark study because it offered valuable insight into the long-term outcomes of both medical and surgical initial treatment for open-angle glaucoma. Prior to this study, there were uncertainties regarding the comparative effects of these treatments. The CIGTS elucidated that visual field loss can be minimized for both treatment methods, while also highlighting potential risks associated with each treatment, such as the higher rate of cataract removal in surgically treated patients.

An ounce of eye drops might be worth a pound of prevention. In the 2002 OHTS trial, subjects with ocular hypertension (but not glaucoma) were randomized to observation or to topical treatment to reduce IOP by 20% and to <24 mmHg. Subjects were monitored for the development of glaucoma.

Key Points:

• At 60 months, 4.4% of subjects in the treatment group and 9.5% in the observation group developed POAG (P < 0.0001).
• Treatment reduced IOP in ocular hypertensive subjects from a mean of 25 mmHg to a mean of 19 mmHg while maintaining a favorable safety profile.  

Overall, the landmark OHTS trial showed that treating ocular hypertension reduced the risk of developing POAG by more than half. Clinicians should consider treatment in ocular hypertensive patients with moderate to high risk of developing glaucoma. 

In the 2003 Early Manifest Glaucoma Trial (EMGT) study, 255 patients with open-angle glaucoma (OAG) were randomized to argon laser trabeculoplasty (ALT) with topical betaxolol (n=129) or no immediate treatment (n=126) and had follow up appointments every three months for four years.

Key Points:

• Treated patients had half the risk of disease progression than control patients
• Patients randomized to treatment had substantial immediate lowering of intraocular pressure (IOP), lowering the risk of early OAG progression
• Higher baseline IOP, exfoliation, bilateral OAG and age were factors significantly associated with disease progression

Overall, the EMGT study is a landmark study because it quantitatively concluded that initial IOP reduction is crucial in lowering the risk of progression in early OAG and that the magnitude of immediate IOP reduction postoperatively predicted disease progression.

Go, Baerveldt, I choose you!...Er, I choose you, Ahmed! In the ABC trial, 276 patients with refractory glaucoma were randomized to receive either the Ahmed FP7 Glaucoma Valve or the Baerveldt 101-350 Glaucoma Implant and were followed for five years to assess intraocular pressure, number of glaucoma medications, and surgical failure rates.

Key Points:  

• Both implants provided similar rates of surgical failure (39.4% Baerveldt, 44.7% Ahmed), but fewer failures in the Baerveldt group were from reoperation 
• The Ahmed group had significantly lower IOP at POD1 and POW1, but then the Baerveldt group had lower IOP measurements afterwards
• The Baerveldt group had a greater IOP reduction and lower IOP at five years than the Ahmed group at 5 years, but a greater percentage had persistent hypotony (13% vs. 2%) and loss of light perception (26% vs. 12%)
• The Baerveldt group generally had lower numbers of residual glaucoma medications, but this difference was not statistically significant at 5 years

Overall, the ABC study is a landmark study, because it showed that the Ahmed and Baerveldt had similar rates of surgical success in patients with refractory glaucoma. Although the Baerveldt might provide more IOP reduction and require fewer surgical interventions for glaucoma in the long-term, it’s safety must be weighed against the larger percentage of safety end points (hypotony, loss of light perception, etc.), compared with the Ahmed group.

In the famous words of DJ Khaled…”Another One”. Similar to the ABC study (published in 2015), the AVB study (published in 2016) directly compared the Ahmed valve to the Baerveldt implant. The goals of this study were to determine which had a higher rate of treatment failure, defined as 1) IOP out of target range, 2) additional surgery required, 3) Removal of the implant, and 4) Severe vision loss related to surgery. To do so, 238 patients were randomized to the two implants and followed over five years.

Key Points:  

• Cumulative probability of failure was higher in the Ahmed group (53.2%) than in the Baerveldt group (40.0%) (P = 0.037)
• Both groups led to significant IOP reduction: Ahmed group decreased from 31.1 to 16.6 mmHg; Baerveldt group decreased from 31.9 to 13.6 mmHg
• Complication rates were similar between groups (P = 0.30), but refractory hypotony and post-operative IOP spikes were higher in the Baerveldt group

Overall, the AVB study is a landmark study, because it confirms what the ABC study showed, highlighting the greater IOP reduction of Baerveldt, but also noting that potential downsides compared to Ahmed valves.

Is there a plumber in the house? The TVT study sought to compare the safety and efficacy of tube shunt surgery to trabeculectomy with mitomycin C (MMC) in eyes with prior intraocular surgery. Patients aged 18-85 years old with intraocular pressure (IOP) ≥ 18 mm Hg and ≤ 40 mm Hg on maximum tolerated medical therapy, and who had previously undergone cataract surgery and/or failed filtering glaucoma surgery were randomized into 2 groups: the 350 mm Baerveldt implant group (n = 107) and the trabeculectomy with MMC group (n = 105). 

Key Points:

• Both procedures resulted in similarly sustained IOP reduction through 5 years of follow-up
• Trabeculectomy group experienced significantly higher failure rate (46.9%) when using more stringent IOP criteria compared to the tube group (29.8%) at 5 years (P = 0.002)
• Trabeculectomy group underwent higher reoperation for glaucoma (29%) compared to tube group (9%) 

TVT is a landmark study in changing practice patterns to expand tube implantation in cases beyond refractory glaucoma. This study demonstrated that tube implantation is more efficacious in lowering IOP in patients who failed previously filtration surgery, rather than undergoing a repeat trabeculectomy.

Proving Prostaglandins’ Power to Preserve Vision. Latanoprost, a prostaglandin analog, has been used in the management of open-angle glaucoma since the 1990’s. Despite its known ability to lower intraocular pressure (IOP), there were never placebo-controlled trials to assess its impact on visual field preservation until the UKGTS Trial. The primary outcome was time to visual field deterioration within 24 months. 

Key Points:  

• At 24 months, mean reduction in IOP was 3.8 mmHg in the latanoprost group (n=231) and 0.9 mmHg in the placebo group (n=230).
• Visual field preservation was significantly longer in the latanoprost group than the placebo group, with an adjusted hazard ratio of 0.44 (95% CI 0.28 – 0.69; p = 0.0003).

Overall, this study showed that latanoprost preserves the visual function of patients with open-angle glaucoma. This study enabled statistically significant differences in vision to be assessed in the shortest recorded observation period, thereby demonstrating the benefit of prostaglandin therapy on vision preservation in patients with open angle glaucoma.

  The horizon may be out of sight, but thanks to the HORIZON trial, a brighter future for glaucoma patients is now in sight. Combined glaucoma and cataract surgery has become increasingly common in North America with the introduction of minimally invasive glaucoma surgery devices and techniques. The HORIZON trial compared clinical outcomes of patients following cataract surgery with (n=369) and without a Hydrus Microstent (n=187)

Key Points:

• At 5 years, the Hydrus Microstent and Cataract Surgery group (HMS) included a higher proportion of eyes with IOP of 18 mmHg or less without medications than the Cataract Surgery Only (CS) group (49.5% vs. 33.8%; P = 0.003)
• The HMS group had a greater likelihood of IOP reduction of 20% or more without medications than the CS group (54.2% vs. 32.8%; P < 0.001). 
• The number of glaucoma medications was 0.5 ± 0.9 in the HMS group and 0.9 ± 0.9 in the CS group (P < 0.001), and 66% of eyes in the HMS group were medication free compared with 46% in the CS group (P < 0.001). 
• No clinical or statistically significant differences were found in the rate of endothelial cell loss from 3 to 60 months between the HMS and CS alone groups (P = 0.261).

Overall, the HORIZON landmark study demonstrated that use of a Schlemm's canal microstent in addition to traditional cataract surgery was found to be safe and resulted in lowered intraocular pressure and a reduction in medication use. The study also found that the long-term presence of the microstent did not have a negative impact on the corneal endothelium

An eye drop a day keeps glaucoma at bay, but a laser one time can save a whole lotta dime. Prior to the LiGHT study, the standard first step of therapy for open-angle glaucoma (OAG) started was topical medications. Selective Laser Trabeculoplasty, an alternative, relatively non-invasive treatment, was frequently offered after patients were started on drops. In the LiGHT study, 718 patients with treatment-naïve OAG or ocular hypertension were randomized to SLT or eye drops to assess for quality-of-life outcomes, clinical efficacy (measured by intraocular pressure and required additional treatments), and cost.

Key Points:

• SLT was effective at lowering eye pressure – at 6 years, 69.8% of patients with SLT were at goal IOP without any drops or incisional surgery, though 90% of those patients required SLT twice
• There were no significant differences in quality-of-life measures at either 3 or 6 years between the two groups
• Initiation with SLT was found to be significantly more cost effective than initiation with eye drops

The LiGHT study proposed a new paradigm in the treatment of glaucoma and ocular hypertension, aiming to offer SLT to any newly diagnosed patient. It showed rather good clinical efficacy and reduced societal costs for SLT, though quality of life measures were not different. All in all, SLT is an effective measure to treat many types of glaucoma, and could have the added benefit of being less costly.