Ocular Hypertension Treatment Study (OHTS)
This multicentric trial recruited 1,632 patients of ocular hypertension (OHT) to answer two questions. First, if early treatment in patients of OHT with topical medication would prevent the onset of primary open-angle glaucoma (POAG). Second, which patients of OHT are more likely to develop POAG, in other words, what are the risk factors for conversion from OHT to POAG? The patients who had IOP of at least 24 mmHg in one eye and 21 mmHg in other eye, were recruited in this study. They were randomized into two groups-those who received intraocular pressure (IOP) lowering drops (Medication arm) and those who did not receive any IOP lowering drops (Observation arm). The IOP reduction was targeted at 20% in the medication group. After enrollment, patients were examined every 6-months and follow-up included a white-on-white visual field at every visit and stereoscopic disc photograph annually. The endpoint was the development of new, reproducible defects on the visual field or optic nerve head.
The mean IOP reduction in the medication group achieved was 22.5% compared to 4% in the observation group. After 5-years, 4.4% of treated patients of OHT progressed to develop POAG, compared to 9.5% in the observation group. Thus, early treatment in OHT reduced the probability of getting progressed to POAG by over 50%. At 10-years also, the incidence of POAG was reduced by 50% with early treatment. The factors (risk) which were associated with progression included- older age, higher baseline IOP, thinner central corneal thickness (CCT), and increased cup-disc ratio (>0.5). Based on these, three stratifications were done-High risk, intermediate risk, and lower-risk. The absolute reduction of development of POAG was in the high-risk group.
Thus, OHTS has two important implications-First, early treatment in OHT provides relative protection against the development of POAG. Second, there are persons of OHT who are at higher risk of conversion to POAG. This group might be considered for initiating IOP lowering therapy.
Early Manifest Glaucoma Trial (EMGT)
EMGT was a controlled, randomized trial that recruited 255 newly diagnosed, untreated patients of the early stage of open-angle glaucoma. This included patients with POAG, normal-tension glaucoma (NTG), and also pseudoexfoliation glaucoma (10%). There were two objectives of this study-One if starting early treatment reduces the risk of progression in POAG, and secondly, to explore factors related to glaucoma progression and to study the natural history of POAG.
The mean age of participants was 68 years, with a median visual field mean deviation (MD) of -4 dB and a mean IOP of 20.6 mmHg. Nearly 66% of participants were women. The recruited patients were randomized into two groups. One group was treated immediately after diagnosis (Treatment group; had 129 patients), and another group were left untreated (Observation group; had 126 patients). The treatment group received laser trabeculoplasty followed by topical betaxolol twice daily in eligible eyes. Both groups were followed up on perimetry (every 3 months), fundus photograph (every 6 months), and IOP measurement at each visit. Any patient in the observation group if developed new, reproducible changes on disc photograph or visual field (i.e., progression) were offered treatment.
The mean IOP reduction achieved in the treatment group was 25% from baseline. The IOP remained stable in the observation group, except in patients of pseudoexfoliation, in which IOP increased annually on an average by 1 mmHg. The mean duration of progression in the observation group was 48 months and in the treatment group, it was 66 months. Hence, early treatment with laser trabeculoplasty followed by twice betaxolol deferred progression by a mean duration of 18 months. A 25% IOP reduction reduced the risk of progression in open-angle glaucoma by 50%. The risk of progression decreased by 10% with each 1 mmHg reduction of IOP from baseline. Additionally, it was revealed thinner central corneal thickness was associated with risk of progression in POAG, and lower blood pressure in NTG.
EMGT established the importance of IOP reduction in decreasing the risk of visual field progression and quantified the risk reduction with each mmHg of reduction. It also retreated the enhanced risk of progression in eyes with thinner CCT.
Collaborative Normal-Tension Glaucoma Study (CNTGS)
CNTGS was a multicentric, randomized control trial that recruited 140 patients with progressing normal-tension glaucoma (NTG). The study primarily aimed to know whether IOP has a role in the pathogenesis of NTG, and secondarily evaluated the role of IOP reduction in preventing progression in NTG.
Patients were randomized into two groups-one groups which received treatment (Treatment group; 61 patients) and the second group, which was not treated (Control group; 79 patients). All modes of treatment were offered-28 were treated either medically or with argon laser, and 33 were treated surgically. The endpoint was a new, reproducible change in the visual field or optic disc. The mean IOP in the treatment group was 10.6 mmHg compared to 16 mm Hg in the control group. There was about a 30% IOP reduction in the treatment group. The progression was evidenced in 35% of control group patients compared to 7% in the treatment group. The time to reach the endpoint (i.e., the earliest evidence of progression) was 1,695±143 days in the control group and 2,688±123 days in the treatment group. Untreated patients in the control group had a variable patterns of progression, some deteriorated rapidly, others moderately and nearly 50% did not have any evidence of progression during follow up of 5-7 years. Risk factors associated with progression included female gender, migraine headache, and optic disc hemorrhages. The incidence of cataracts was higher among the treatment group, mainly among those treated surgically.
Major implications of CNTGS are that IOP reduction in NTG is beneficial in cases with evidence of progression. The IOP reduction to the tune of 30% was archivable in about 75% of patients of NTG with laser and medical therapy, without the need for surgery. The mild cases of NTG may be observed over time. Although detecting progression may be challenging as in CNTGS visual fields were done more frequently than in real-world clinical practice.
European Glaucoma Prevention Study (EGPS)
EGPS was a multicentric, randomized, double-masked, controlled clinical trial, which recruited 1,081 patients (aged ≥ 30 years) of ocular hypertension (OHT) to study the efficacy of reduction of IOP by dorzolamide in preventing progression to POAG. Patients with IOP between 22-29 mmHg with two reliable normal fields and normal optic discs were recruited. The patients were randomized into two groups-group one patient were treated with topical 2% dorzolamide (Treatment group), and another group patient were treated with excipients of dorzolamide (Placebo group). The endpoints were reproducible progression visual field changes (at least on 3 consecutive fields) or optic disc or both.
The mean central corneal thickness (CCT) in these patients were above 570 µm. The mean IOP reduction in the treatment group was 22% and the placebo group was 19% at 5-years. The incidence of visual field endpoints was higher for the placebo group (7%) compared to the treatment group (4.9%). The optic disc endpoint probably suffered a high false-positive rate due to the study design. The EGPS also suffered a high dropout rate of 30%.
EGPS failed to detect a significant difference between medical therapy and placebo in reducing the incidence of POAG among patients of OHT at moderate risk of developing the POAG. The risk factors which predicted progression to POAG included older age, larger vertical cup-disc ratio, larger cup-disc ratio asymmetry, higher pattern standard deviation (PSD) on visual field, and thinner CCT.
Advanced Glaucoma Intervention Study (AGIS)
This randomized trial was designed to recruit patients of advanced, medically uncontrolled open-angle glaucoma. However, only one baseline visual field was used for enrollment as well patients with far advanced damage were excluded and those with early glaucoma were also included. It enrolled 789 eyes of 591 patients, aged between 35-80 years, in which adequate IOP reduction could not be achieved with maximum accepted and tolerated medical therapy. They were randomized into two group-group one patient were treated with initial argon laser trabeculoplasty (ALT), and group two patients with initial trabeculectomy. If needed, a second or third procedure were formed to control IOP. So, actually, in AGIS, long-term outcomes of two different interventional sequences were evaluated, which involved one application of ALT and twice trabeculectomy but in a different order. Hence, if needed sequence of intervention in group one patients were ALT-trabeculectomy-trabeculectomy (ATT), while in group two it was trabeculectomy-ALT-trabeculectomy (TAT). The endpoint was a sustained decrease of visual field and sustained decrease of visual acuity. The study used a score system (AGIS visual field defect score) to map changes in the visual field, which was based on the number and depths of clusters of adjacent depressed test sites in upper and lower hemifields and nasal area of total deviation printouts.
Nearly 65% of the patients remained stable. Eye with IOP under 18 mmHg at all visits over 6-years did not show any deterioration of visual field score. Though the lower mean IOP was achieved with TAT sequence than ALT, it was affected by ethnicity, and Afro-American patients had favorable outcomes with ATT sequence. The risk factors associated with failure included younger age and high preoperative IOP. Diabetes was an additional risk factor for failure of trabeculectomy. Trabeculectomy enhanced the cumulative probability of cataract formation, and at 5-years it was 78%.
AGIS showed that advanced glaucoma may need repeated interventions for control of IOP and stabilizing the visual field loss. It emphasized the need for a customized surgical approach in accordance with ethnicity. However, it retreated that lower IOP is associated with slower visual field progression. Increasing age and greater IOP fluctuations increased the odds of visual field progression.
Collaborative Initial Glaucoma Treatment Study (CITGS)
CITGS was a randomized trial to answer if initial medical therapy or trabeculectomy is better for newly diagnosed patient with open-angle glaucoma. Recruitment allowed patients of OHT who were at lower risk of progression. In total 607 patients, aged between 25-75 years, were randomized into two groups-medical treatment group, in which IOP was in which patients received topical medications and surgical treatment group patients were treated with initial trabeculectomy. In both the groups, if treatment failed, the patient received argon laser trabeculoplasty (ALT). The medical treatment group received topical medication in a stepped fashion, starting with a single agent and adding drugs if target IOP was not achieved or if visual fields are shown any progression. The primary outcome measure included deterioration (worsening of mean deviation by 3 dB) of visual field and quality of life. The secondary outcomes were visual acuity changes, IOP, and cataract formation.
The visual field progression was seen in 25% of the patients in the medical group and 21% of patients in the surgical group after 8 years. A subgroup analysis favored initial surgery in cases with moderate to advanced glaucoma (mean deviation of -10 dB or worse on the visual field) at diagnosis. The IOP reduction was greater with trabeculectomy than with medical therapy. The cataract formation was twice higher among patients who underwent trabeculectomy. The mean visual acuity in both groups was equal.
CIGTS showed that patients with mild to moderate glaucoma can be safely and effectively treated with both medication and surgery, and those with moderate to advanced glaucoma may benefit from early surgical intervention.
Tube versus Trabeculectomy (TVT)
This was a multicentric, randomized trial aimed to compare the efficacy and safety of trabeculectomy and tube shunt surgery in eyes with previous intraocular surgery and uncontrolled IOP on maximum tolerated medications. The study excluded patients with a higher risk of surgical failure like those with refractory glaucoma such as neovascular glaucoma. A total of 212 eyes from 212 patients were enrolled, with 107 in the tube group (Baerveldt-350 mm2 glaucoma drainage device) and 105 in the trabeculectomy group (Superior trabeculectomy with 0.4 mg/ml mitomycin-C for 4 minutes). The outcome measures included IOP, visual acuity, visual field, use of adjuvant medical therapy, surgical complications, and treatment failure. IOP >21 mmHg or ≤ 5mmHg or months or reduction <20% from baseline on two consecutive visits after 3- months or need of additional surgery to control of IOP or loss of perception of light was considered as treatment failure.
The average IOP reduction from baseline in the tube group was 43% compared to 51% in the trabeculectomy group but the difference was not significant. Similarly, the difference in adjuvant medical therapy between tube (average 1.4) and trabeculectomy (average 1.2) was not significant. Both tube and trabeculectomy produced a significant and sustained reduction in IOP at 5-years. The cumulative failure rate was significantly higher for the trabeculectomy group (47%) than the tube group (30%), but in both groups, it was most commonly due to inadequate IOP reduction. The rate of visual loss or serious complications were similar for the two groups.
The study expanded the scope of the use of tubes in the surgical management of glaucoma but did not establish the superiority of tube or trabeculectomy in patients with glaucoma having a lower risk of surgical failure.
Effectiveness in Angle-Closure Glaucoma of Lens Extraction (EAGLE)
EAGLE was a multicentric, randomized, controlled trial to assess the safety, efficacy, safety, and cost-effectiveness of clear-lens extraction compared with laser peripheral iridectomy (LPI) and topical medical treatment as first-line therapy in people with newly diagnosed primary angle closure (PAC) with elevated IOP (≥30 mm Hg) or primary-angle closure glaucoma (PACG) with mean deviation (MD) on visual field > -15dB. A total of 419 participants, aged 50-years and above were enrolled, of which 155 had PAC and 263 had PACG. They were randomized into two groups- The clear-lens extraction group, who underwent phacoemulsification with mono-focal intraocular lens implantation, and the LPI group, who were treated by standard LPI and topical medications. Laser Iridoplasty was allowed if angle closure persisted after initial treatment in either group. The outcome measures were IOP, Quality of Life (QoL), and the need for glaucoma surgery at 3 -years. Though the need for glaucoma surgery was considered a treatment failure, the patient remained on the trial.
The average QoL score was 0.052 higher and the average IOP 1.18 mmHg lower in the clear lens extraction group. The incidence of irreversible vision loss (>10 ETDRS letters) was 0.5% in the clear lens extraction group and 1.4% in the LPI group.
The study concluded that clear-lens extraction showed greater efficacy and more cost-effectiveness than LPI. More persons (1.4%) in the clear lens extraction group required intraocular surgery for complications than in the LPI group (0.5%). There was no difference in synechial angle closure and visual field deterioration between the two groups. Also, the cost was assessed only for a subset of patients treated.
Laser in Glaucoma and Ocular Hypertension Study (LiGHT)
The liGHT was a prospective, unmasked, multicentric, pragmatic, randomized controlled trial to compare topical medication versus selective laser trabeculoplasty (SLT) as initial treatment for ocular hypertension (OHT) and primary open-angle glaucoma (POAG). LiGHT recruited 718 patients with OHT (163 patients) or POAG (555 patients) who were randomized into two groups, either to receive topical medication (Medicine group;362 patients) or SLT (SLT group;365 patients). The first-line topical medication was prostaglandin analogue eye drops and beta-blockers as second-line drugs. Carbonic anhydrase inhibitors and alpha agonists were used respectively as third and fourth line drugs to control IOP. The primary outcome measures were health-related quality of life (HRQL) measured using EQ-5D-5L, and secondary outcomes were cost, cost-effectiveness, visual functions, and IOP.
There was no difference in HRQL, visual acuity, and IOP between the medication and SLT group. No patient in the SLT group required glaucoma surgery to achieve target pressure compared to 11 patients requiring in the medication group. At 3-years, 74% of patients of the SLT group required no eye drops to maintain IOP at target. The disease progression was seen in 36 eyes in the medicine group compared to 23 in the SLT group. The cost analysis showed that SLT was more cost-effective than eye drops as initial therapy at a willingness to spend £20,000 per quality-adjusted-life-year gained.
LiGHT supports that SLT is an alternative to medication therapy for newly diagnosed patients of OHT and POAG.
- Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study:Baseline Factors That Predict the Onset of Primary Open-Angle Glaucoma.Arch Ophthalmol.2002; 120:714–20.
- Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002; 120:701-13; discussion 829-30.
- Leske MC, Heijl A, Hyman L, et al. Early Manifest Glaucoma Trial: design and baseline data. Ophthalmology. 1999; 106:2144-53.
- Leske MC, Heijl A, Hussein M, et al. Factors for Glaucoma Progression and the Effect of Treatment:The Early Manifest Glaucoma Trial.Arch Ophthalmol.2003; 121:48–56.
- Heijl A, Leske MC, Bengtsson B, et al. Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002; 120:1268-79.
- The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol. 1998;126 :498-505.
- Anderson DR; Normal Tension Glaucoma Study. Collaborative normal tension glaucoma study. Curr Opin Ophthalmol. 2003; 14:86-90.
- Miglior S, Zeyen T, Pfeiffer N, et al. European Glaucoma Prevention Study Group. The European glaucoma prevention study design and baseline description of the participants. Ophthalmology. 2002; 109:1612-21.
- European Glaucoma Prevention Study (EGPS) Group, Miglior S, Pfeiffer N, Torri V, et al. Predictive factors for open-angle glaucoma among patients with ocular hypertension in the European Glaucoma Prevention Study. Ophthalmology. 2007; 114:3-9.
- Miglior S, Zeyen T, Pfeiffer N, et al. European Glaucoma Prevention Study (EGPS) Group. Results of the European Glaucoma Prevention Study. Ophthalmology. 2005; 112:366-75.
- The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 1. Study design and methods and baseline characteristics of study patients. Control Clin Trials. 1994; 15:299-325.
- The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol. 2000; 130:429-40.
- Musch DC, Lichter PR, Guire KE, et al. The Collaborative Initial Glaucoma Treatment Study: study design, methods, and baseline characteristics of enrolled patients. Ophthalmology. 1999; 106:653-62.
- Janz NK, Wren PA, Lichter PR, et al. CIGTS Study Group. The Collaborative Initial Glaucoma Treatment Study: interim quality of life findings after initial medical or surgical treatment of glaucoma. Ophthalmology. 2001; 108:1954-65.
- Gedde SJ, Schiffman JC, Feuer WJ, et al; Tube Versus Trabeculectomy Study Group. The tube versus trabeculectomy study: design and baseline characteristics of study patients. Am J Ophthalmol. 2005; 140:275-87.
- Gedde SJ, Schiffman JC, Feuer WJ, et al. Treatment outcomes in the Tube Versus Trabeculectomy (TVT) study after five years of follow-up.Am J Ophthalmol. 2012; 153:789-803.
- Azuara-Blanco A, Burr JM, Cochran C, et al; Effectiveness in Angle-closure Glaucoma of Lens Extraction (EAGLE) Study Group. The effectiveness of early lens extraction with intraocular lens implantation for the treatment of primary angle-closure glaucoma (EAGLE): study protocol for a randomized controlled trial. Trials. 2011; 12:133.
- Azuara-Blanco A, Burr J, Ramsay C, et al; EAGLE study group. Effectiveness of early lens extraction for the treatment of primary angle-closure glaucoma (EAGLE): a randomised controlled trial. Lancet. 2016;388:1389-97.
- Gazzard G, Konstantakopoulou E, Garway-Heath D, et al; LiGHT Trial Study Group. Laser in Glaucoma and Ocular Hypertension (LiGHT) trial. A multicentre, randomised controlled trial: design and methodology. Br J Ophthalmol. 2018; 102:593-8.
- Gazzard G, Konstantakopoulou E, Garway-Heath D, et al;LiGHT Trial Study Group. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. Lancet. 2019; 393:1505-16.