The Tonometry Tightrope
Should IOP Dictate Treatment Decisions?

Studies demonstrate that intraocular pressure is no longer sacrosanct in glaucoma care.

BY NATHAN RADCLIFFE, MD

While elevated intraocular pressure is not used to define glaucoma, IOP reduction is the only proven treatment for this blinding disease.¹ Additionally, while elevated IOP is no longer a criterion for the diagnosis of glaucoma, it is still useful in identifying patients who are at a higher risk of developing glaucoma or in identifying established glaucoma patients who are at a higher risk of progression.

For example, in the Early Manifest Glaucoma Trial (EMGT), where patients were randomized to ocular hypotensive therapy or observation based on visual field and optic disc criteria, the average IOP upon inclusion was 20.6 mm Hg and 80% of eyes had an IOP of less than 25 mm Hg.²

Consider the Ocular Hypertension Treatment Study (OHTS), in which patients with IOPs between 24 mm Hg and 32 mm Hg (but with normal optic nerves and visual fields) were randomized to placebo or to achieve 20% IOP-lowering with medical therapy.³ This study was performed in order to better understand the value of IOP reduction in ocular hypertensive patients. While pressure reduction was effective in halving the development of POAG, 92.4% of the patients (across both the treatment and observation groups) did not develop glaucomatous optic disc or visual field deterioration five years into the study.⁴

While it is true that in both the EMGT and OHTS studies IOP reduction was effective in reducing the proportion of patients with progressive glaucoma, IOP alone is not particularly useful in diagnosing glaucoma. For example, in OHTS, the mean IOP of patients who went on to develop POAG was 25.6 mm Hg versus 24.9 mm Hg in those that did not develop POAG.⁵ However, having a central corneal thickness (CCT) that was 40 microns thinner than average led to a POAG risk that was equivalent to having an IOP 8 mm Hg higher than average.

Re-evaluating Risk Factors

As clinicians, it is likely that we overestimate the contributions of tangible glaucoma risk factors, such as IOP, and underestimate the influence of more nebulous risk factors, such as CCT. I use the online ocular hypertension risk calculator (Figure 1) to provide more reliable risk information when discussing treatment decisions with my patients (available at ohts.wustl.edu/risk/calculator.html).

Part of the reason that IOP has become less useful in the management of POAG is the recognition that CCT is a confounder of IOP measurement with Goldmann applanation tonometry; however, there is more to the story. Consider the Barbados Eye Study, a study in which over 3,000 patients without any glaucoma at baseline were followed for nine years.⁶ Again, CCT was a strong risk factor for the development of POAG, but this time in a study of entirely untreated glaucoma patients, demonstrating that CCT values could not possibly be influencing treatment decisions. The true nature of how CCT relates to glaucoma risk has yet to be determined. However, the weight of current evidence suggests that CCT increases glaucoma susceptibility independent of IOP.

Benefits of IOP Reduction

Despite the weakness of IOP as a diagnostic criteria for glaucoma, all major IOP-lowering clinical trials have found that IOP lowering is the only proven method of preventing, delaying or stopping the progression of glaucoma. These major IOP-lowering studies have also consistently demonstrated that most glaucoma patients progress. And whether you are considering the effect of medicines, laser or surgery, the beneficial effects of IOP reduction on progression are reasonably consistent for high and low pressure glaucomas.^1,4,7-10 For example, in the Canadian Glaucoma Study, patients with an IOP 1 mm Hg higher during the follow-up period had a 19% higher risk for visual field progression.⁷

In 1984, the Collaborative Normal-tension Glaucoma Study (CNTGS) was conceived to determine the role that IOP plays in visual field loss in normal-tension glaucoma and to further understand the value of IOP reduction in this challenging group of patients. Only patients with progressive or fixation-threatening glaucoma were treated. In the untreated arm of the CNTGS, the mean time to progression in the untreated patients was greater than 2000 days and only one half showed progression by seven years, emphasizing that glaucoma can be a slow disease that in some circumstances may not warrant treatment.⁹

Dangers of Elevated IOP

Given the strong role that elevated IOP plays in glaucoma progression, it is natural to wonder which type of elevated IOP is most damaging: consistently elevated pressure, or equally high but fluctuating IOP.

IOP fluctuation can be thought of as short-term (diurnal) fluctuation or as long-term (inter-visit) fluctuation. Nouri-Mahdavi et al. evaluated subjects in the Advanced Glaucoma Intervention Study (AGIS) and found that increasing age and greater inter-visit fluctuation in IOP (but not greater mean IOP) were associated with visual field progression.¹⁰ In a follow-up paper considering patients with only a single surgical intervention, Caprioli and Coleman found that the relationship between IOP fluctuation and visual field progression was particularly significant in patients with a low mean IOP.¹¹ Since patients in the EMGT had lower average IOP values than the AGIS patients, it is interesting to note that the EMGT investigators could not confirm the fluctuation-progression relationship in their patient population.¹²

While the results of these two studies may seem contradictory, it has been proposed that in the AGIS study, patients with higher IOP and/or worsening visual fields were more likely to have more aggressive medical and/or surgical interventions, which could result in greater IOP fluctuations. Many astute clinicians will note that in their own practice, IOP fluctuation may be a marker of poor patient compliance or of escalating medical or laser intervention.

Time Management

Another side of both diurnal and intervisit IOP fluctuation is the effect that such fluctuations may play on our ability to manage glaucoma. Dr. Bhorade and the OHTS investigators recently evaluated intervisit IOP fluctuation in 810 untreated patients with ocular hypertension.¹³ They found that 24% of patients had a 15% or greater IOP increase or decrease between study visits. The investigators noted that these IOP fluctuations could mask or mimic the efficacy of glaucoma therapy, complicating our efforts to judge therapeutic efficacy. The same problem can occur with diurnal IOP fluctuations. For example, on average, IOP drops about 2 mm Hg between 8am and 4pm. For example, if one starts therapy at 8am and then judges its efficacy at 4pm on another day, on average one will get a 2 mm Hg or 10% “effect” just based on anticipated diurnal change. This is why it is important to check the pressure at the same time of day when changing therapy, but it is also why it is important to check the IOP at different times of the day in patients under stable IOP treatment. Our patients often choose to come to see us at times that are habitually convenient for them. For example, a patient may always present for evaluation on Monday mornings before he or she heads in to work. It is our job as glaucoma doctors to be aware of these habits and to break them when appropriate.

Figure 1. The calculator estimates POAG risk using the patient's clinical data over several visits (above) or by comparing data to averages for several risk factors and assigning point values to each (below).

Additionally, consider the monocular trial: the act of initiating therapy in one eye in order to evaluate its efficacy in comparison to the IOP in the fellow, untreated eye. This treatment paradigm assumes that IOP fluctuates symmetrically between eyes — it doesn't. This paradigm also assumes that two eyes of the same person will respond similarly to a given drug — not always true, and that the fellow eye is unaffected by the medication applied to the first eye. This is untrue in particular for beta-blockers.¹⁴ Tony Realini, MD, recently evaluated this strategy in 26 patients and found that it is difficult, in general, to predict an eye drop's long-term effects.¹⁵ In addition, he found that one would do no better gauging a drop's efficacy by looking at how well the treated eye responded in comparison to the follow-up IOP of the untreated fellow eye. One would do just as well assessing a drops efficacy in comparison to that eye's untreated/baseline IOP.

Putting IOP in Perspective

In my practice, I try to place IOP into an appropriate perspective based upon the data above. I believe that IOP is a truly noisy data point that is constantly tempting us to make a type I error by drawing too large a conclusion from a limited data point. I avoid the temptation to draw any conclusions from a single IOP data point and instead try to collect many data points at different times of day when evaluating patients on stable therapy, and at the same time of day, when evaluating patients whose therapy I am changing.

When I am trying to determine if a given patient has undetected IOP “spiking,” rather than check a diurnal curve I play the odds and try to evaluate the IOP as early in the day as possible. In patients where a high trough IOP may be problematic, I try to check the IOP prior to the instillation of morning eye drops, particular if the AM agent is indicated for TID dosing where trough effects may be more prevalent. In normal-tension glaucoma patients, where the untreated IOP may be low at baseline, I initiate therapy that I know to be effective based on my review of the literature, typically a prostaglandin analogue.

On follow up, if the treated IOP is similar to that of the untreated IOP, I may switch medications within the PGA class to maximize efficacy without abandoning monotherapy; however, I try not to add medications without evidence of further visual field or optic nerve deterioration unless the IOP is consistently and significantly above target. I believe that the slowly progressive nature of normal tension glaucoma demonstrated in the CNTGS supports a prudent, rational and cautious approach to this disease. OM

References

1. Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M; Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268-1279.
2. Leske MC, Heijl A, Hyman L, Bengtsson B. Early Manifest Glaucoma Trial design and baseline data. Ophthalmology. 1999;106:2144-2153.
3. Gordon MO, Kass MA. The Ocular Hypertension Treatment Study: design and baseline description of the participants. Arch Ophthalmol. 1999;117:573-583.
4. Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK 2nd, Wilson MR, Gordon MO. 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;120:701-713; discussion 829-830.
5. Gordon MO, Beiser JA, Brandt JD, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK 2nd, Wilson MR, Kass MA. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:714-20; discussion 829-830.
6. Leske MC, Wu SY, Hennis A, Honkanen R, Nemesure B; BESs Study Group. Risk factors for incident open-angle glaucoma: the Barbados Eye Studies. Ophthalmology. 2008;115:85-93.
7. Chauhan BC, Mikelberg FS, Balaszi AG, LeBlanc RP, Lesk MR, Trope GE; Canadian Glaucoma Study Group. Canadian Glaucoma Study: 2. risk factors for the progression of open-angle glaucoma. Arch Ophthalmol. 2008;126:1030-1036. Erratum in: Arch Ophthalmol. 2008;126:1364.
8. 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;130:429-440.
9. Anderson DR, Drance SM, Schulzer M; Collaborative Normal-Tension Glaucoma Study Group. Natural history of normal-tension glaucoma. Ophthalmology. 2001;108:247-253.
10. Nouri-Mahdavi K, Hoffman D, Coleman AL, Liu G, Li G, Gaasterland D, Caprioli J; Advanced Glaucoma Intervention Study. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology. 2004;111:1627-35.
11. Caprioli J, Coleman AL. Intraocular pressure fluctuation a risk factor for visual field progression at low intraocular pressures in the advanced glaucoma intervention study. Ophthalmology. 2008;115:1123-1129.e3. Epub 2008 Feb. 20.
12. Bengtsson B, Leske MC, Hyman L, Heijl A; Early Manifest Glaucoma Trial Group. Fluctuation of intraocular pressure and glaucoma progression in the early manifest glaucoma trial. Ophthalmology. 2007;114:205-209.
13. Bhorade AM, Gordon MO, Wilson B, Weinreb RN, Kass MA; Ocular Hypertension Treatment Study Group. Variability of intraocular pressure measurements in observation participants in the ocular hypertension treatment study Ophthalmology. 2009;116:717-724. Epub 2009 Feb 25. Erratum in: Ophthalmology. 2009;116:822.
14. Piltz J, Gross R, Shin DH, Beiser JA, Dorr DA, Kass MA, Gordon MO. Contralateral effect of topical beta-adrenergic antagonists in initial one-eyed trials in the ocular hypertension treatment study. Am J Ophthalmol. 2000;130:441-453.
15. Realini TD. A Prospective, randomized, investigator-masked evaluation of the monocular trial in ocular hypertension or open-angle glaucoma. Ophthalmology. 2009;116:1237-1242.

Nathan Radcliffe, MD, is an assistant professor of ophthalmology and director of the glaucoma service at Weill Cornell Medical College and New York-Presbyterian Hospital in New York.