Dr Panayiota Founti

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Not all randomised controlled trials (RCTs) are equal: depending on the scientific question asked and the robustness of methodology, some can substantially affect clinical practice and are therefore considered landmark studies. Although it is now well established that IOP reduction is the cornerstone in the management of 

 it was not until the late 1990s that the evidence to support this notion became available.

A number of landmark RCTs published in the late 1990s and early 2000s provided solid evidence that the lowering of IOP reduces the risk of progression of open-angle glaucoma (OAG)

 and the risk of conversion of ocular hypertension to OAG.

 Two additional landmark RCTs independently identified the same risk factors for the conversion of ocular hypertension to OAG.

 These data enabled the development of a risk prediction equation with predictive utility (risk calculator).

Although these early landmark studies were hugely important for the management of ocular hypertension and OAG, questions remained unanswered regarding the medical and surgical management of glaucoma. Some of these questions have been answered by more recent landmark RCTs, which I will discuss here.

Whereas aqueous shunts were already commonly used for the management of complex/refractory glaucoma and were starting to become popular as an alternative to trabeculectomy in those at high risk of filtration failure, it remained unknown which was the best approach for patients with prior ocular surgery. The Tube Versus Trabeculectomy(TVT)

 study was designed to investigate the safety and efficacy of tube shunt surgery versus trabeculectomy with mitomycin C (MMC) in eyes with prior cataract and/or filtration surgery.

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The study enrolled 212 patients who had had prior cataract and/or failed filtration surgery and uncontrolled glaucoma on the maximum number of medications. Outcome measures were: IOP; visual acuity; visual field; surgical complications; glaucoma medications; and treatment failure. The follow-up period was 5 years.

The cumulative probability of failure was higher for trabeculectomy versus tube shunt surgery. No difference in mean IOP was observed, but IOP control in the first 2 years was better with trabeculectomy. Early complications were more frequent with trabeculectomy but there was no difference in late postoperative complications.

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There was no significant difference between groups in the number of medications needed, although the trabeculectomy group required fewer in the first 2 years. Thus, theTVT study provided evidence that both tube surgery and trabeculectomy with MMC are appropriate in those with previous cataract and/or failed filtration surgery.

However, the study’s results need to be interpreted with caution because the subgroup of patients with previous failed trabeculectomy may have introduced bias in favour of the tube group. For the same reason, tube surgery may be more appropriate in those with failed filtration surgery. The TVT study challenged the traditional paradigm that tube shunts should be reserved for patients with refractory glaucoma.

The purpose of the Primary Tube Versus Trabeculectomy (PTVT)

 study, which followed on from the TVT study, was to investigate the safety and efficacy of tube shunt surgery versus trabeculectomy with MMC in eyes without prior filtration surgery. The population size was 242; patients had not had prior filtration surgery and had uncontrolled glaucoma on maximum medications.

The outcome measures were rate of surgical failure, mean IOP, complications and reoperation for glaucoma. The follow-up period was 3 years.

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The PTVT showed that both tube shunt surgery and trabeculectomy with MMC are effective in lowering IOP as a primary glaucoma procedure. However, trabeculectomy may be more appropriate if the target IOP is quite low, such as in normal pressure glaucoma.

Given the higher rate of success and the need for fewer medications in the trabeculectomy group, the latter may be more appropriate if a goal of surgery is to minimise the use of glaucoma eyedrops. In vi

ew of the similar rates of reoperation for glaucoma found between the groups, trabeculectomy should probably be the primary procedure of choice in younger patients.

Despite the wealth of data on the efficacy of IOP-lowering treatment in the management of OAG, before 2014 there were no data from placebo-controlled trials to demonstrate efficacy in the preservation of visual function. In addition, although prostaglandins were in common use as first-choice treatment for the management of OAG, there was no published evidence for a protective effect on vision.

The UK Glaucoma Treatment Study (UKGTS) was the first placebo-controlled trial to investigate whether treatment with a topical prostaglandin reduces the frequency of visual field progression in patients with OAG compared with placebo.

A secondary analysis was conducted to explore risk factors for visual field progression.

 In this study, which enrolled 516 newly diagnosed OAG patients, the outcome measure was time to visual field progression and patients were followed up at 2 years.

The UKGTS demonstrated that topical prostaglandins are effective at preserving visual function in OAG, even in those with relatively low baseline IOP. However, two-thirds of patients in the placebo group had no detectable progression within 24 months, so one could consider an observation period before starting treatment in certain patients with OAG. This approach may help identify those who might be suitable for monitoring alone, thus avoiding the unnecessary burden of treatment.

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The study identified bilateral disease, higher IOP and disc haemorrhage as risk factors for visual field progression, and treatment with latanoprost and possibly smoking history as protective factors against visual field progression. The likelihood of lifetime visual impairment is an important factor to consider. With the average life expectancy from the diagnosis of OAG having been estimated at 9–13 years,

 the benefits of treatment need to be balanced against the risk of overdiagnosis

In addition, the UKGTS has shown that, with appropriate study design, it is possible for future RCTs to detect differences in visual function in a much shorter period than the typical 4–5 years used in previous trials. This knowledge is hugely important for novel drug development with consequent cost reduction.

The aforementioned landmark RCTs focused on OAG, which remains the most common type of glaucoma across the world.

 Comparatively little attention was paid to primary angle closure glaucoma (PACG), which accounts for 25% of glaucoma cases worldwide. Though not as common as OAG, PACG tends to progress faster and, therefore, is more likely to lead to blindness.

Since the mid-1970s, laser peripheral iridotomy (LPI) was the treatment of choice in primary angle closure and PACG.

 In more recent years, surgical lens extraction has been advocated as an alternative treatment for the disease; however, its effectiveness had not been investigated in high-quality randomised or non-randomised studies.

Considering the best surgical approach in angle closure patients

The purpose of the Early Lens Extraction for the Treatment of Primary Angle-Closure Glaucoma (EAGLE)18 study was to investigate the efficacy, safety and cost-effectiveness of clear-lens extraction versus LPI combined with medical treatment in patients with newly diagnosed advanced angle-closure disease (primary angle closure and PACG).

In EAGLE, 419 patients aged over 50 who had primary angle closure and IOP ≥30 mmHg or PACG were enrolled; outcome measures were patient-reported health status, IOP and cost-effectiveness and the follow-up period was 3 years. 

This study provided evidence that clear-lens extraction has greater efficacy and is more cost-effective than LPI and should therefore be considered as first-line treatment in patients with advanced angle closure disease.

However, one needs to remember that all study participants in the EAGLE study had IOP ≥30 mmHg. Therefore, these data may not apply to all patients with primary angle closure and PACG.

Although the EAGLE study provided clear direction on the best management option for advanced angle closure disease,

 until recently little was known about whether primary angle closure suspects (PACS; defined as those with ≥6 clock hours of no visible trabecular meshwork on gonioscopy, normal IOP, no peripheral anterior synechiae and no glaucoma)

The purpose of the Zhongshan Angle Closure Prevention(ZAP) trial was to assess the efficacy and safety of prophylactic LPI against PACG in Chinese people who are PACS.

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In 889 individuals (identified through community-based screening) who had bilateral PACS, the outcome measures were incident primary angle closure disease (composite endpoint of high IOP, peripheral anterior synechiae or acute angle-closure). Patient follow-up was 7 years.

The ZAP trial showed that prophylactic LPI is of modest benefit in PACS. The risk of these asymptomatic individuals developing primary angle closure over a 6-year period was low, (<1%). Based on the data from the study, one would have to treat 44 PACS to prevent one case of new primary angle closure disease over a 6-year period. Therefore, the ZAP trial data do not support the widespread practice of LPI in PACS.

Prior to a study known as ‘selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma’(LiGHT),

 very few randomised trials had compared the outcomes of medical treatment versus laser trabeculoplasty in OAG and ocular hypertension.

Among these, only the Glaucoma Laser Trial had enrolled previously untreated patients,

 comparing the efficacy and safety of argon laser trabeculoplasty versus timolol maleate 0.5%: all patients received both treatments (randomisation per eye).

Eliminating the potential land mines in glaucoma surgery

Therefore, until recently, there were no high-quality data comparing selective laser trabeculoplasty (SLT) with newer IOP-lowering medications in treatment-naive patients, and no data comparing the effects of these treatment options on quality of life (QoL). The LiGHT trial was designed to compare QoL outcomes, clinical effectiveness and cost-effectiveness of SLT versus medical treatment in treatment-naive patients with ocular hypertension and OAG.

The study enrolled 718 treatment-naive patients with OAG or ocular hypertension. Outcome measures were health-related quality of life (HRQoL) at 3 years, cost and cost-effectiveness, disease-specific HRQoL, and clinical effectiveness and safety. The follow-up period was 3 years.

The LiGHT trial was unable to detect a difference in HRQoL between the treatment groups. However, it provided evidence that SLT is more likely to be cost-effective than medical treatment and provides drop-free IOP control in the majority of patients for at least 3 years.

Using pivotal study data to guide glaucoma patient management decisions

One of the strengths of the LiGHT trial was that the treatment escalation protocol was robust but, at the same time, pragmatic. Therefore, SLT should be considered as first-line treatment in newly diagnosed patients with ocular hypertension and early-to-moderate OAG. However, this also means that one may have to address patients’ perceptions of the necessity of monitoring visits, in the absence of daily treatment.

Another important clinical implication from the LiGHT trial is that few patients are likely to experience a severe IOP spike post-SLT. This is important for patient reassurance, but also for avoiding unnecessary hospital visits post-treatment.

Dr Founti is a glaucoma specialist and a consultant ophthalmic surgeon at Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom. She is also an honorary senior research associate at the University College London Institute of Ophthalmology. She has no conflict of interest related to the subject matter to report.

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Landmark randomised controlled trials have advanced the understanding and treatment of glaucoma.

Author | Dr Panayiota Founti

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The impact of landmark studies on clinical practice in glaucoma