Using pivotal study data to guide glaucoma patient management decisions

In order to improve patient care, guidelines for clinical and therapeutic management should be based on high quality scientific evidence, such as the fifth edition of the European Glaucoma Society guidelines,¹ which contains only references from high quality systematic reviews, landmark glaucoma trials and population-based studies. Randomised controlled trials (RCTs) are one the most reliable sources of this type of evidence because, if well conducted, they can produce unbiased and generalisable data on diagnosis and therapy, giving fundamental insights into patient management.

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The Early Manifest Glaucoma Trial (EMGT) and the United Kingdom Glaucoma Treatment Study (UKGTS) are two prospective RCTs comparing treatment versus no treatment in glaucoma patients. Taken together, the results from these trials help us to answer the question of what we should do after diagnosing glaucoma in a patient.

The Early Manifest Glaucoma Trial

The EMGT investigated the effects of medical treatment and laser treatment on glaucoma progression. Two hundred and fifty-five patients were recruited between 1993 and 1997 on a population-screening basis and followed until 2013.

Previously untreated glaucoma patients with repeatable visual field (VF) defect and corresponding optic nerve damage in at least one eye were enrolled, including those with primary open-angle glaucoma (POAG), normal tension glaucoma (NTG) and pseudo-exfoliative (PXF) glaucoma. Patients with advanced VF damage and high intraocular pressure (mean IOP >30 mmHg or IOP >35 mmHg in at least one eye) were excluded.

Participants were randomly allocated to treatment or no treatment. Treatment consisted of a combination of laser trabeculoplasty and topical betaxolol. The primary outcome was glaucoma progression, measured quantitatively by VF deterioration or optic nerve head changes. Mean baseline IOP was 20.7 mmHg and VF mean deviation (MD) was −4.7 dB.

The IOP trend during follow-up was different between the two groups. In the treated arm, IOP decreased from 20.6 to 15.5 mmHg at 3 months, corresponding to a 25% reduction from baseline; this was maintained throughout the follow-up period. No IOP changes were observed in the untreated arm.

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Survival analysis showed that the differences in VF progression between groups arose early and were maintained for the entire follow-up period. Progression was more frequent in the control group at any time point, occurred earlier in controls and increased over time in both arms.

The first analysis (in 2001) showed significantly differently progression in the two groups: 62% in the control group and 45% in the treatment group.² At the end of the study, progression was detected in 59% of treated participants compared with 76% of control participants, with a hazard ratio of 0.6.

An IOP of >21 mmHg, PXF syndrome, glaucoma in both eyes, worse median baseline MD and older age were significantly associated with risk of progression. Among the longitudinal factors, progression was strongly associated with the magnitude of initial IOP change, IOP at 3 months of treatment and mean IOP during follow-up.³ Disc haemorrhages and lower central corneal thickness (CCT) were also associated with risk of progression but the latter only in patients with higher baseline IOP.⁴

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Alongside the valuable data about the impact of treatment on glaucoma progression gained from this study, the untreated group allowed us to follow the natural course of the disease. By analysing data from untreated patients who were followed for at least 6 years, Heijl et al. showed that the majority of subjects experienced minimal yearly IOP changes, with larger IOP changes in those with PXF glaucoma.⁵ Overall, IOP did not increase in the untreated arm and 68% of patients showed glaucoma progression.

Rate of progression, as well as median time to progression, was higher in patients with PXF syndrome, followed by high tension glaucoma and NTG (−3.13 dB/year compared with −1.31 dB/year in high tension glaucoma and −0.36 dB/year in NTG).5 Accordingly, PXF glaucoma has a higher risk of progression if untreated.

The United Kingdom Glaucoma Treatment Study

The UKGTS was conducted in 2014. It was designed to have several similarities to the EMGT (e.g., inclusion criteria), to make the results as comparable as possible. The UKGTS was the first multicentre RCT to evaluate treatment with latanoprost (Xalatan, Pfizer) 0.005% versus placebo in glaucoma patients (POAG, NTG and PXF glaucoma).

Patients were enrolled consecutively between 2007 and 2010 and the primary outcome was VF deterioration within 24 months. Such a short observational period was possible because the frequency interval of VF was clustered at the beginning and the end of the trial, to maximise the power to detect progression.

As in EMGT, enrolled subjects had newly diagnosed and untreated glaucoma, defined by VF defect and corresponding damage to the optic nerve head. Patients with moderate-to-advanced VF damage were excluded, as well as those with elevated IOP (>35 mmHg on two consecutive occasions in either eye or mean baseline IOP of ≥30 mmHg).

Mean IOP was 20.1 mmHg and 19.6 mmHg in the placebo and treated group, respectively. The median MD at baseline was 2.9 dB, which means the glaucoma tended to be at an earlier stage than in the EMGT (median EMGT MD was −4.1 dB).^6,7

Mean IOP reduction from baseline was 5 mmHg (20%) in the treated group and 1.4 mmHg in the placebo group. The strongest initial response was slightly reduced at 6 months and then remained stable during the rest of the study.

At 24 months, the percentage of patients who reached the primary endpoint was significantly different between arms: 25.6% of patients in the placebo group compared with 15.2% in the treatment group. Time to deterioration was also significantly longer in the treated group with consequently longer VF preservation and a hazard ratio of 0.44. These differences were already evident at 12 and 18 months.

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Increased risk of progression was associated with treatment allocation, glaucoma in both eyes, higher mean baseline IOP and disc haemorrhages at the baseline visit. History of heart attack and smoking habits were associated with risk of progression. Unlike in EMGT, age, CCT and severity of VF loss were not associated with risk of progression.⁷

By combining the results from EMGT and UKGTS, common conclusions can be drawn and translated to clinical practice. Lowering IOP is effective in reducing disease progression in previously untreated patients with POAG, NTG and PXF glaucoma; the treatment’s efficacy depends on the patient’s pre-treatment IOP, with a stronger effect on higher baseline IOP values.

The rate of reduction is also crucial: each mmHg of IOP reduction decreases the risk of progression by a specific percentage. The lower the IOP reached—not only immediately after starting therapy but also during follow-up—the better the outcome.

When we analyse the results from RCTs, the statistical variability of data must be taken into account. We strongly need summary measures to draw overall conclusions and mean values of different parameters (such as mean annual IOP change, mean MD change, mean rate of progression), which represent the average behaviour of all participants, are usually reported.

However, there is a certain amount of variability around this value, corresponding to participants who have shown results that differ from the mean. Translating this statistical variability into clinical practice means that one must remember that any patient could be near the average or could be an outlier, showing a different behaviour from that expected, with regard to IOP changes, rate of progression and other parameters.

The EMGT and UKGTS trials provided extensive information on the natural history of glaucoma. When we look at survival analysis, we generally focus on differences between treated subjects and controls, but it also shows patients who progress despite treatment and controls who do not progress despite remaining untreated.

In the UKGTS, two-thirds of participants in the placebo group showed no VF deterioration during 24 months of follow-up and the same happened in 38% of untreated patients in EMGT.^2,6 This suggests that patients with slight VF loss at baseline could be followed without treatment for a period. Then it becomes critical to assess the risk of progression of each patient, keeping in mind that the pattern could be difficult to predict and that the rate of progression may change over the period of observation.

In summary, besides stressing the importance of IOP reduction in preventing glaucoma progression, EMGT and UKGTS have shown that different factors affect the risk of disease progression. Looking for a particular target IOP or percentage IOP reduction is not the best option for all glaucoma subjects. Each patient must be considered as unique; only by quantifying the individual risk will it be possible to best tailor the treatment approach for each patient.

References

1. European Glaucoma Society. Terminology and Guidelines for Glaucoma. 5th ed. 2020.

2. Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268-1279.

3. 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.

4. Leske MC, Heijl A, Hyman L, et al. Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology. 2007;114:1965-1972.

5. Heijl A, Bengtsson B, Hyman L, et al. Natural history of open-angle glaucoma. Ophthalmology. 2009;116:2271-2276.

Garway-Heath DF, Crabb DP, Bunce C, et al. Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial. Lancet. 2015;385:1295-1304.

Lascaratos G, Garway-Heath DF, Burton R, et al. The United Kingdom Glaucoma Treatment Study: a multicenter, randomized, double-masked, placebo-controlled trial: baseline characteristics. Ophthalmology. 2013;120:2540-2545.

Manuele Michelessi, MD

Sara Giammaria, MD

E: manuele_michelessi@yahoo.it

Dr Michelessi is a researcher at the Glaucoma Research Unit of the G.B. Bietti Foundation, Rome, Italy. Dr Giammaria is a research fellow in the Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Canada. Neither author reports any conflict of interest relevant to the subject matter.

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