Natural History of Intraocular Pressure in the Early Manifest Glaucoma Trial: A 6-Year Follow-up

Objectives  To characterize intraocular pressure (IOP) changes during 6 years of follow-up among patients with early, newly diagnosed glaucoma randomized to no initial treatment in the Early Manifest Glaucoma Trial (control group) and to evaluate factors associated with IOP changes in this group.

Methods  Early Manifest Glaucoma Trial control patients, aged 50 to 80 years at baseline, were followed up for 6 years or to the time of progression, when treatment could be initiated. After baseline, patients were followed up every 3 months with comprehensive ophthalmologic examinations, including Goldmann applanation tonometry. Change in IOP over 6 years was assessed by linear regression analyses.

Results  At baseline, the median IOP of this cohort (N = 118) was 20.8 mm Hg and was higher for the 15 patients with exfoliation glaucoma (24.0 mm Hg vs 20.0 mm Hg for others; P = .005). In patients without exfoliation glaucoma, IOP remained stable during follow-up (median IOP change of −0.01 mm Hg/y; interquartile range, 0.85 mm Hg/y). In comparison, patients with exfoliation glaucoma showed a significantly larger median change of 0.96 mm Hg/y (interquartile range, 3.11 mm Hg/y) (P = .004). In the overall cohort, the only factor related to IOP change was exfoliation glaucoma (P < .001). Among patients without exfoliation glaucoma, no factors were associated with IOP change.

Conclusions  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, where IOP increased by almost 1 mm Hg annually. No factors, aside from exfoliation glaucoma, were related to longitudinal changes in IOP. These new natural history data may be useful in guiding management decisions for glaucoma treatment, particularly in patients with early disease or with exfoliation glaucoma.

Elevated intraocular pressure (IOP) is a major documented risk factor for the incidence and progression of primary open-angle glaucoma (OAG)^1-5 Yet, OAG occurs in persons with all IOP levels, as shown repeatedly in population-based studies.^6-9 Furthermore, questions remain about the long-term IOP measures that are most influential in glaucoma progression, eg, mean IOP and IOP fluctuation. Diagnosis of OAG is typically followed by the immediate initiation of IOP-lowering treatment, eg, topical medications and/or laser trabeculoplasty, with the goal of slowing disease progression. As a result, limited information exists on the natural course of IOP in patients with untreated OAG and the factors that influence this course over time. The few observational studies that have reported longitudinal changes in IOP have mainly involved persons without glaucoma.^10-12 Furthermore, most clinical trials evaluating glaucoma treatment compare different methods for reducing IOP and do not include an untreated arm.^13-15 Understanding changes in IOP over time and their related factors in the absence of treatment is valuable, both because of scientific interest and for clinical reasons. Such information can be useful in guiding management decisions for patients with glaucoma at early stages of disease.

The Early Manifest Glaucoma Trial (EMGT) is a randomized clinical trial that demonstrated the effectiveness of immediate therapy to lower the IOP, vs no initial treatment, on progression of early, newly detected OAG (including primary, “normal-tension,” and exfoliation glaucoma types).² The EMGT results demonstrated that treated patients had half the risk of progression compared with controls; in addition, each millimeter of mercury higher of mean IOP during follow-up was associated with a 13% increased risk of progression.³ These findings confirm the role of IOP and its reduction in glaucoma progression. By design, EMGT has an untreated control arm and includes patients with various glaucoma types. These design features provide a unique opportunity to evaluate the natural history of IOP in untreated patients with early disease, as well as with different levels of baseline IOP.

The aims of this report were to (1) characterize IOP changes in patients with newly diagnosed glaucoma randomized to no initial treatment in EMGT and (2) evaluate factors associated with IOP changes in this group of control (untreated) patients during 6 years of follow-up. These analyses aimed to explore whether factors related to IOP or to glaucoma progression also influenced the natural history of IOP in early glaucoma. A separate article¹⁶ has reported results of visual field progression among this same group of EMGT control patients.

The EMGT design and methods have been described in detail previously.¹⁷ Two hundred fifty-five patients aged 50 to 80 years with newly detected and untreated chronic OAG (all types, including exfoliation glaucoma) were recruited through a population-based screening. Patients were included if they had repeatable glaucoma visual field defects by Humphrey threshold perimetry in at least one eye that were compatible with glaucoma and not explained by other causes. Patients with angle-closure glaucoma were excluded. All patients provided written informed consent and the trial was approved by the Ethics Committee of the University of Lund, Malmö, Sweden, and the Committee in Research Involving Human Subjects of the State University of New York at Stony Brook. Eligible patients were randomized to treatment with laser trabeculoplasty and betaxolol hydrochloride twice daily in eligible eyes (n = 129) or to no initial treatment (control group, n = 126) and followed up every 3 months. Study visits included comprehensive ophthalmologic examinations with Humphrey full-threshold 30-2 visual field tests and tonometry, as well as fundus photographs every 6 months. Tonometry was performed with calibrated Goldmann applanation tonometers by technicians masked to study group and to earlier IOP values. The measurements for each patient were performed by certified, masked technicians at the same time of the day during follow-up, whenever possible. The EMGT progression criteria, described elsewhere, were based on significant worsening in visual fields, as detected by computerized analysis in glaucoma probability maps, and optic disc cupping, as detected by an independent disc photography reading center.¹⁷ Control patients were followed up without treatment until progression occurred or IOP exceeded 35 mm Hg at 2 consecutive follow-up visits; at that time, patients were informed and options discussed, with decisions made following the usual patterns of glaucoma treatment.

Natural history was assessed among control patients who were followed up for at least 6 years or progressed by EMGT criteria within 6 years. The cohort was limited to 6 years of follow-up to achieve a balance between having a sufficiently long duration of follow-up to provide meaningful information and having an adequate sample size to provide stable values. Follow-up data were considered only up to the time of progression, as patients could be treated at that time. Analyses were based on eligible eyes for the trial. For the one-fifth of patients with 2 eligible eyes, the first eye to show progression was included in the analyses, or if neither eye progressed, the eye with the largest field defects at baseline (ie, worse mean deviation values) was used.

The rate of change for each patient was calculated as the slope of linear regression of IOP on time and then summarized across patients. This approach, which assumed a linear trend of IOP change, was selected after conducting various exploratory analyses and by plotting the longitudinal course of IOP for each individual EMGT patient over time. Results generally followed a linear pattern and supported the linearity assumption. Furthermore, good agreement was found between actual IOP changes and modeled IOP changes by linear regression.

Descriptive statistics were tabulated to provide IOP change summaries among different subgroups. Factors associated with IOP change were formally evaluated using linear regression models and their statistical significance was based on Wald z statistics.¹⁸

Baseline factors evaluated for possible association with IOP change were (1) demographic (age, sex); (2) ocular (number of eligible eyes, IOP [average of 2 baseline Goldmann measurements], perimetric mean deviation [average of 2 baseline field measurements], exfoliation glaucoma [dilated examination], refractive error [automated refractor], and clinically observed disc hemorrhages); and (3) medical/family history and related measurements (systolic and diastolic blood pressure [BP]; hypertension [systolic BP>160 mm Hg or diastolic BP>95 mm Hg or use of antihypertensive medication]; systolic, diastolic, and mean ocular perfusion pressures [the respective BP minus IOP]; and self-reported history of cardiovascular disease, hypertension medication use, low BP, migraine, Raynaud disease, smoking, and glaucoma in parents or siblings).

Of the 126 patients randomized to the control group, 118 were followed up for 6 years or progressed by EMGT criteria within that time frame. Among the 80 control patients who progressed during the 6 years of follow-up, the median time to progression was 48.2 months.

Baseline characteristics of the 118 controls by exfoliation glaucoma status are presented in Table 1. Overall, this group had a mean age of 68 years, was predominantly female, had a median IOP of 20.8 mm Hg, and a median mean deviation (mean deviation) of −3.4 dB. Median central corneal thickness was 548.6 μm and 20.3% had both eyes eligible. Exfoliation glaucoma was present in 15 patients or 12.7% of the total group. Patients with exfoliation glaucoma were significantly older (P = .02) and had higher IOP (P = .005) than the other controls. Mean deviation was slightly, but not significantly, worse in these patients.

Overall, IOP was stable up to 6 years (median change, 0.01 mm Hg). The average annual change in IOP is depicted for all EMGT controls in Figure 1 and by exfoliation glaucoma status in Figure 2. For presentation purposes, these figures exclude 5 patients with annual change greater than 6 mm Hg who had progressed within 10 months of study enrollment and had very few IOP measurements. As seen in Figure 1, the vast majority of control patients experienced minimal annual IOP change during 6 years, with IOP changes limited to within ±1 mm Hg/y for about two-thirds of controls. Figure 2 indicates that larger IOP changes were observed among patients with exfoliation glaucoma, as most of these patients had IOP increases; in contrast, IOP changes were symmetric around zero for patients without exfoliation glaucoma.

The first row of Table 2 presents detailed data on annual IOP change for the total group, as well as for patients with and without exfoliation glaucoma. Annual IOP change was +0.03 mm Hg/y for all 118 patients and was similar for the 103 patients without exfoliation glaucoma. The latter group had a median annual IOP change of −0.01 mm Hg (range, −12.03 to 3.87 mm Hg/y). In comparison, the 15 patients with exfoliation glaucoma showed a significantly larger and more positive median IOP change of almost +1 mm Hg/y (range, −16.22 to 12.32 mm Hg/y; P = .004).

Factors significantly associated with annual IOP change were explored first by descriptive statistics and then by linear regression modeling. The univariate results of these analyses found no factors, other than exfoliation glaucoma, to be associated with annual IOP change among all controls.

Table 2 presents the univariate results according to exfoliation glaucoma status; it also shows that no factors were identified in controls without exfoliation glaucoma. Among all controls and controls without exfoliation glaucoma, little variation was observed across the factors examined, with comparable results by age and sex. Control patients with higher and lower baseline IOP had similar median annual IOP changes of 0.02 and 0.04 mm Hg, respectively. In the absence of exfoliation glaucoma, controls with lower baseline IOP had a median IOP increase of 0.01 mm Hg/y (range, −12.03 to 3.70 mm Hg/y) and those with higher baseline IOP had a median IOP decrease of −0.08 mm Hg/y (range, −8.69 to 3.87 mm Hg/y). The annual IOP changes among patients without exfoliation glaucoma were also small for the other factors. Although comparisons were limited by the small number of patients with exfoliation glaucoma, particularly in some subcategories, Table 2 indicates that these patients tended to have larger annual IOP changes than others according to most of the factors examined, but these differences were not statistically significant.

In a linear regression model that included the entire 6-year cohort (N = 118), the presence of exfoliation glaucoma was the only factor associated with IOP change (P < .03) after adjustment for age, sex, and baseline IOP. No associations were found between IOP change and other factors in this cohort.

Because patients with exfoliation glaucoma had substantial differences from patients without exfoliation glaucoma regarding baseline IOP and age (Table 1) and exfoliation glaucoma was significantly associated with IOP change, additional linear regression analyses were conducted excluding these 15 patients. These analyses explored whether any factors were associated with IOP change in the majority of patients (n = 103), without the influence of exfoliation glaucoma. However, no specific factor was found to be associated with IOP change among control patients without exfoliation glaucoma. Because of the small number of patients with exfoliation glaucoma, no further regression analyses were conducted in this group.

By including an untreated control arm in its design, EMGT is uniquely suited to evaluate IOP natural history in glaucoma. In this cohort of 118 control patients, IOP remained stable for 6 years, regardless of IOP baseline levels, except in the presence of exfoliation glaucoma. The overall median IOP change over the follow-up period was 0.0 mm Hg and the median annual change was 0.03 mm Hg/y.

Controls with exfoliation glaucoma had significantly higher IOP at baseline than patients without exfoliation glaucoma and a larger median change of almost 1 mm Hg annually. When all 118 patients were considered, only exfoliation glaucoma was related to IOP change in various analyses. When the 103 patients without exfoliation glaucoma were analyzed separately, none of the factors evaluated influenced IOP change. These results highlight the importance of exfoliation glaucoma in the natural history of IOP in glaucoma.

To our knowledge, there are no directly comparable studies that evaluated IOP change in patients with untreated glaucoma. Although the Collaborative Normal-Tension Glaucoma Study included an untreated arm, this study only enrolled patients with normal-tension glaucoma and did not report changes in IOP over the course of the study.^19,20 Most other glaucoma trials have not included an untreated arm or reported changes in IOP. The Ocular Hypertension Treatment Study, the one clinical trial to provide data on IOP changes in an untreated group, randomized persons with ocular hypertension to medication or observation.⁵ Ocular Hypertension Treatment Study patients in the untreated arm showed a small decrease in IOP of 4% or approximately 1 mm Hg after 5 years. This finding is consistent with the minimal IOP change observed in the EMGT controls. The observation that IOP remains stable over time was also supported by results of the Malmö Ocular Hypertension Study, which randomized patients with untreated ocular hypertension to treatment with timolol or placebo and followed them up for up to 10 years.²¹

As noted in the legends for Figure 1 and Figure 2, 5 control patients had IOP changes larger than 6 mm Hg and progressed within the first 10 months of follow-up. While these results appear extreme compared with all other controls, the large slopes are based on only a few IOP measurements during a limited period. Therefore, linear regression is not an appropriate method to assess IOP yearly change in these patients, as confirmed by the examination of their individual longitudinal IOP profiles.

Long-term IOP change in general populations has been reported in some large observational studies. Despite substantial differences in study designs, study populations, age groups included, length of follow-up, and other methodological differences, IOP changes were small in all studies. For example, Wu et al¹² found a median 9-year change of 0.0 mm Hg in an African-origin population in Barbados, West Indies, and Klein et al²² reported a 5-year mean (SD) change of 0.0 (3.2) mm Hg in the Beaver Dam Eye Study. These findings are consistent with our median 6-year change of 0.0 mm Hg in the control patients with glaucoma in EMGT and suggest that IOP levels are fairly steady over time in persons with and without glaucoma.

Control patients with exfoliation glaucoma had higher IOP at baseline and showed more IOP change than control patients without exfoliation glaucoma. Three of the 5 patients with IOP changes greater than 6 mm Hg/y had exfoliation glaucoma (all 5 patients progressed in their first 10 months). As shown in Figure 2 and Table 2, the patients with exfoliation glaucoma had consistently greater IOP change than others. When considering all patients, exfoliation glaucoma was an important factor affecting IOP change, although the number of affected patients was small. When patients without exfoliation glaucoma were analyzed separately, no factors were related to longitudinal IOP change, further confirming the importance of exfoliation glaucoma in influencing this change.

Despite the small sample size, exfoliation glaucoma also was a strong risk factor for glaucoma progression in all EMGT patients, both after the initial and the long-term follow-up.^3,4 Since IOP and exfoliation glaucoma were independently associated with progression, the higher risk of patients with exfoliation glaucoma was not explained fully by their higher IOP. When the untreated group was considered separately, exfoliation glaucoma again was an important factor affecting progression.¹⁶ Exfoliation glaucoma is believed to have a more serious course and a worse prognosis.^23-28 The EMGT findings support these observations and indicate that these patients have higher IOP, more IOP change, and more glaucoma progression.

Because IOP is a major risk factor for OAG, identifying predictors of high IOP and IOP change has long been of interest. While factors such as BP, baseline IOP, older age, sex, diabetes mellitus, and obesity have also been associated with IOP in different population studies,¹ no such significant relationships were found between IOP change and any of these factors, including BP, in the current study. The absence of such associations in EMGT may be due to its smaller sample size, which limits detection of significant relationships; a more limited range of IOP values; or the nature of the EMGT population itself given its selection to meet eligibility criteria for a clinical trial.

We also explored whether IOP change was related to factors associated with OAG or its progression, eg, age, family history of glaucoma, central corneal thickness, perimetric mean deviation, exfoliation glaucoma, and perfusion pressure.^1,4,29 Although the results linked IOP change to exfoliation glaucoma, no relationships were observed with the other variables examined. These negative findings may be due to the small magnitude of the IOP changes observed. They could also be explained by the smaller sample size of EMGT than the other studies, which may not have allowed for detection of significant associations. However, the IOP changes were comparable across the various categories of factors examined and no relationships were suggested, except for exfoliation glaucoma. Alternative explanations may be found in the differences in study populations or other aspects of research design. In sum, only exfoliation glaucoma was associated with IOP change in EMGT, a factor not always considered in population-based and other studies.

A major asset to achieve the aims of the current evaluation is the EMGT design itself. The positive design features include the presence of an untreated control arm and the inclusion of patients with different OAG types and different IOP levels. Furthermore, since the main EMGT results firmly documented the effectiveness of treatment,² no similar studies with an untreated group are likely to be undertaken, thus making its data unique. An additional advantage is the availability of carefully collected data at baseline and follow-up visits every 3 months, which were obtained according to a structured protocol. Furthermore, to avoid any potential effects of IOP fluctuations during a 24-hour period, efforts were made to conduct follow-up measurements during the same time of the day. The very high retention achieved, with minimum losses to follow-up over an extended period, further strengthens the natural history evaluations.

One important limitation is the sample size available, which reduced the power for analyses. In particular, the small number of patients with exfoliation glaucoma precluded separate study of this group and for this reason, most of the data presented are descriptive only. Another limitation is the length of follow-up. Patients included in these natural history analyses were followed up for 6 years or up to progression, as treatment could be initiated at that time. Our finding of IOP stability may not apply with longer follow-up, that is, beyond 6 years, or if the linearity assumption is not valid. Since patients with angle-closure glaucoma were excluded, our results do not pertain to these patients, who may well have IOP increases over time. Another point is that our ability to identify factors associated with IOP change, other than exfoliation glaucoma, is likely to be limited by the small amount of median IOP change in the majority of the EMGT control cohort. Finally, the question of general applicability of these natural history results has to be considered. Although most EMGT patients were recruited through a large population-based study, which enhances generalizability, the study was conducted in Sweden and results may not pertain to other ethnic groups. Furthermore, EMGT required specific criteria for inclusion, eg, an average IOP lower than 30 mm Hg at baseline and early glaucoma defects. The natural history of IOP changes in patients with glaucoma may differ in patients with higher IOP, more severe disease, or outside the other EMGT enrollment criteria.

This study provides new information on the natural history of IOP in patients with early glaucoma. Contrary to common belief, these findings indicate that in the absence of treatment the course of IOP in these patients showed minimal change over 6 years, except for those with exfoliation glaucoma. Other than exfoliation glaucoma, no factors were associated with IOP change during follow-up. These natural history data may be useful in guiding management decisions for glaucoma treatment, particularly in patients with early disease or who have exfoliation glaucoma.

Correspondence: Leslie Hyman, PhD, Division of Epidemiology, Department of Preventive Medicine, Stony Brook University, Stony Brook, NY 11790-8036 (lhyman@notes.cc.sunysb.edu).

Submitted for Publication: March 20, 2009; final revision received August 21, 2009; accepted August 27, 2009.

Author Contributions: Dr Hyman had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: This study was supported by grants U10EY10260, U10EY10261, and K2002-74X-10426-10A from the National Eye Institute (Bethesda, Maryland) and the Swedish Research Council (Stockholm).

Group Information: A list of the Early Manifest Glaucoma Trial Group was published in Arch Ophthalmol. 2002;120(10):1268-1279 and Arch Ophthalmol. 2003;121(1):48-56.