Through decades of using IOP to predict disease progression and define effective treatments to lower IOP, target IOP recommendations have changed from ≤21 mmHg to ≤18 mmHg to, most recently, at least a 25% reduction from baseline. But an IOP target is an educated guess; and no single target is meaningful for every patient. How do we customize our treatment plans, and how do we approach “outlier” patients for whom 25% IOP reduction is not the goal?

Reducing IOP

IOP reduction continues to be the only proven intervention for preventing the progression of glaucoma. According to the American Academy of Ophthalmology (AAO) 2016 Preferred Practice Pattern for management of primary open-angle glaucoma (POAG), the goal of therapy is to reduce IOP enough to retard or stop disease progression in an effort to maintain good visual quality of life.¹

Unfortunately, for the individual patient, the amount of IOP reduction necessary to slow or stop glaucoma progression can’t be known for sure, especially at the initiation of treatment. Appropriate management for patients with ocular hypertension is better defined; the 5-year risk for developing glaucoma can be estimated by plugging known risk factors into a validated risk calculator, such as the Glaucoma 5-Year Risk Calculator based on the Ocular Hypertension Treatment Study (https://ohts.wustl.edu/risk ).²

There is no such tool, however, for predicting progression among patients who have established glaucoma (a glaucoma progression calculator has been described, but is considered a research tool rather than a clinical tool).³ Estimating POAG progression risk requires analyzing an array of variables related to patient history, examination, and objective measurements. From this comprehensive risk assessment, one can determine an initial target pressure, initiate therapy, and then monitor for progression over time.

The concept of target IOP has never been a precision tool, and the “magic number” has evolved over the years: from ≤ 21 mmHg 30 years ago, to ≤ 18 mmHg in the 1990s and 2000s when a post-hoc analysis of data from the Advanced Glaucoma Intervention Study demonstrated stability of visual fields in glaucoma patients whose IOP remained consistently below 18 mmHg.⁴ The current AAO recommended target is 25% (or more) lower than baseline for most patients, but that individual risk profiles may warrant different goals for some patients.¹ However, while percent IOP reduction makes more sense than designating a single static pressure as universally acceptable, and while a 25% reduction indeed slows progression for a majority of patients with POAG,⁵ a 25% reduction isn’t a meaningful therapeutic goal for all patients. Each patient is unique. Let’s look more closely at IOP target determination for different types of outliers.

Outlier 1: Very High IOP, No Evidence of Glaucoma

Patients are often referred to tertiary care glaucoma practices, such as mine, for incidentally discovered markedly elevated IOP with no evidence of glaucoma. For example, a man was referred to my office recently by a local optometrist for an IOP of 50 mmHg that was discovered during a routine eye exam. He had no discomfort, blurred vision, or symptoms of any sort, and was unaware that he had elevated IOP. Repeated assessment revealed consistently elevated IOP of 50 mmHg, normal visual fields, and a completely normal nerve fiber layer appearance on OCT.

This scenario presents several questions: First, does he have glaucoma? By the strictest definition, no — he has a risk factor and is a glaucoma suspect.

Second, does he have a problem? Based on his IOP level, probably. Although, if he does, it has yet to cause any noticeable symptoms or detectably impact his optic nerve. This is unusual but not unheard of. Certainly, if one were to follow a population of people with IOP of 50 mmHg, most would go blind if left untreated; however, most would also have other manifestations of the disease.

Third, what is a reasonable target IOP for this patient? In the strictest sense, this patient has ocular hypertension, and the Ocular Hypertension Treatment Study demonstrated that a 20% reduction in IOP would reduce the relative risk of developing POAG over 5 years by about half, but lowering this patient’s IOP to 40 mmHg seems inadequate.⁶ Even assuming he has POAG (which he doesn’t, yet), a 25% reduction from baseline for this patient only reduces IOP to 37.5 mm Hg, which seems equally insufficient to forestall the development of glaucoma. Instinctually, a target in the low 20s feels more appropriate; however, whether this would help him or not is unclear.

So, what is the best course of management for this patient? We elected to begin treatment with a topical ocular prostaglandin analog and follow up in 2 weeks to reassess IOP and recheck visual fields. On follow-up, his IOP was reduced to 28 mmHg and his visual fields remained full. We accepted this IOP level and continue to monitor him on prostaglandin monotherapy.

Outlier 2: Progressive Disease, Very Low IOP

Another outlier is the flip side of the above scenario: a patient with progressive disease despite consistently low IOP. Take, for example, a patient whose pressure is between 12 and 13 mmHg every time it is checked, yet her visual fields are in steady decline. This raises an entirely separate set of questions. First, are her office readings a misrepresentation, in other words, an underestimate of her true IOP? This is plausible if her cornea is very thin, if she has frequent IOP spikes at night or outside of office hours, or if she is experiencing intermittent angle closure. Alternatively, does she only take her IOP-lowering medication the day or two before her office visits in a misguided effort to hide her possible noncompliance? These possible explanations should be investigated further and addressed as appropriate.

Second, does this patient have an IOP-independent disease? It is worthwhile to check her blood pressure and assess for signs and symptoms of reduced ophthalmic perfusion. One might also consult a neuro-ophthalmologist to assess for other forms of optic neuropathy.

With the above possibilities ruled out, one is left with a normotensive glaucoma (NTG) patient who is still progressing at an IOP of 12 mmHg. The question then becomes, would further IOP reduction — say, all the way to single digits — benefit this patient? If so, how might that be achieved?

A retrospective single-center chart review of NTG patients with very low IOP who underwent aggressive trabeculectomy for continuing visual field loss revealed that, based on data from 15 eyes of 14 patients studied, the probability of achieving single-digit or near single-digit (≤10 mmHg) IOP was 87%, 80%, and 66% of eyes at 1, 2, and 4 years respectively, and visual field loss would have been halted in 87% of eyes.⁷ Surgeons must balance the risk for surgical complications — including hypotony, which occurred in 40% of treated eyes in this cohort — with the risk of ongoing disease-related visual compromise.

Other Outliers

A third outlier is a young patient, for example, in his 40s, who has moderate glaucoma and bilateral field defects. Even with a relatively low baseline IOP (<25 mmHg), a 40% or 50% IOP reduction might be more appropriate for such a patient who has potentially decades of life ahead of him. For a higher baseline IOP, even greater percent reductions might be in order.

A fourth scenario we encounter on occasion is a patient who has advanced glaucoma and a terminal disease, such as metastatic lung cancer. One might recommend less aggressive targets and IOP-lowering treatment among those with a shortened life expectancy.

Target Pressure Estimation

Patients with POAG, including outliers, should undergo a comprehensive risk assessment to approximate risk for disease progression. Global risk assessment is a synthesis of relevant factors — including baseline IOP, stage of glaucoma damage (as determined by the degree of structural optic nerve injury and/or functional visual field loss), age of disease onset, current age, and life expectancy — that is used to judge how aggressive to be with treatment.⁸ For example, patients with disease onset early in life or those with more advanced stage disease are at higher risk for vision loss in their lifetime and require more aggressive IOP-lowering treatment compared with older patients with earlier stage disease.

Other clues may be gleaned from family history, prior rate of progression, and correlates of progression. Family history — of both glaucoma and glaucoma-related vision loss — are important considerations in a global risk assessment, with vision loss due to glaucoma being the more significant. Useful information may also be derived from analyzing a patient’s clinical course.

For example, a patient who is noted to be clinically stable at or below an IOP of 17 mmHg but has progressed when IOP is 18 mmHg or above should be maintained at 17 mmHg or below. Weighing these factors, my practice is to determine risk (high, medium, or low) and align risk with a target IOP of low teens (for high-risk patients), mid-teens (medium risk), and high teens (low risk), as a general starting point for target IOP determination in patients with POAG whose untreated IOP is > 21 mmHg. Clearly, as described above, this approach is not appropriate for all patients.

Target IOP may change as a patient’s course unfolds and new information becomes evident. When a target IOP is met and progression stops, there is no problem. But in other scenarios, questioning the initial IOP goal is good practice. Take, for example, a patient on maximum IOP-lowering therapy who is hovering above target IOP but not progressing. Is surgery warranted for this patient? More likely, the initial IOP target was too ambitious, i.e., set too low. Conversely, consider the patient whose IOP may stay consistently below target pressure, yet glaucoma may be progressing. In this instance, you could assume that the initial target pressure was set too high.

Continual Monitoring

In other words, setting an IOP target doesn’t eliminate the need to continually question it. When patients don’t respond as expected, we’re always attempting to reconcile two opposing sets of risk: the risk associated with accepting the current IOP and its risk of further disease progression, and the risk inherent to the next intervention (e.g., surgery) that might conceivably help meet a downwardly revised target.

Remember, too, that risk profiles change as patients age. Thus, in my view, maintaining some flexibility in target IOP is not only justifiable, but good practice. In my practice, I’m most concerned about the effect of treatment on the optic nerve and visual field. Nearly always, if disease is worsening, IOP — whatever the value — needs to be lower. GP

Editor’s note: Medical writing support was provided by Noelle Lake, MD, of Ethis Communications and funded by Bausch + Lomb.

References

1. Prum BE, Rosenberg LF, Gedde SJ, et al for the Glaucoma Preferred Practice Pattern Panel 2014-2015. Primary Open Angle Glaucoma, Preferred Practice Pattern. AAO. 2016.
2. Ocular Hypertension Treatment Study Group; European Glaucoma Prevention Study Group; Gordon MO, Torri V, Miglior S, et al. Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension. Ophthalmology. 2007;114(1):10-19.
3. De Moraes CG, Sehi M, Greenfield DS, Chung YS, Ritch R, Liebmann JM. A validated risk calculator to assess risk and rate of visual field progression in treated glaucoma patients. Invest Ophthalmol Vis Sci. 2012;53(6):2702-2707.
4. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130(4):429-440.
5. 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(10):1268-1279.
6. 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(6):701-713.
7. Iverson SM, Schultz SK, Shi W, Feuer WJ, Greenfield DS. Effectiveness of single digit IOP targets on decreasing global and localized visual field progression after filtration surgery in eyes with progressive normal-tension glaucoma. J Glaucoma. 2016;25(5):408-414.
8. Realini T, Fechtner RD. Target intraocular pressure in glaucoma management. Ophthalmol Clin North Am. 2000;13(3):407-415.

Dr. Realini is professor of ophthalmology at the West Virginia University Eye Institute. His clinical practice and research efforts are focused on improving the lives and preventing blindness in patients with glaucoma. Dr. Realini is a consultant for Alcon, Bausch + Lomb, Inotek, and Novartis and has received research support from Alcon.