August 01, 2007
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Timing of treatment for ocular hypertension still a critical issue

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A question I am often asked is: “What harm would occur if I wait until my patient with ocular hypertension (OHTN) develops optic nerve damage and visual field loss before I commence therapy?” This question is not easily addressed. The therapeutic approach of waiting until damage occurs was used 20 years ago, using the premise that only 0.5% to 1.0% of individuals with OHTN convert to glaucoma on a yearly basis. Given the low percentage of converters, it was felt that the best approach was a conservative one.

Still, the concept of early intervention was brewing at that time, based in part on information from Dr. Harry Quigley’s optic nerve/visual field histologic studies. In this work, Dr. Quigley showed that 25% to 40% of the retinal ganglion cells in a location must be damaged before a corresponding visual field defect occurs. This led to the recognition that structural and functional loss may develop at different points as glaucoma develops and that perimetry may not detect early loss.

Thus, the concept of therapy for individuals with OHTN at significant risk took shape, but an unanswered question was: “At what point is the risk great enough to warrant therapy”?

For many years, no consensus existed. Some clinicians would begin therapy when the IOP hit 24 mm Hg, others 26 mm Hg, and others waited until the 30 mm Hg mark was broken. Studies exploring this issue published in the 1980s by Epstein, Kass and Schulzer had conflicting results.

Years ago I published a paper titled “Murray’s Rule,” which used a risk factor approach to create an algorithm describing when therapy for OHTN may be indicated. A “chickening out point” of 30 mm Hg was used as the starting point with the level at which therapy was initiated reduced from here depending upon the number of risk factors present including race, age, cup:disc status, secondary glaucoma findings and family history.

My goal was to bring some structure to this difficult question, and, in retrospect, Murray’s Rule was one of the early risk calculators. Still, it was developed using expert opinion but was not evidence based.

Published studies assess risk

Over the past decade, a series of studies investigating ocular hypertension and the risk of developing glaucoma have been published. The initial credit belongs to the Ocular Hypertension Treatment Study (OHTS), with one of its first papers describing the relationship between corneal thickness and IOP measurement. While this finding was not a secret, few understood the clinical relevance until the OHTS corneal thickness paper was published. Suddenly, clinicians had another important parameter to evaluate in at-risk individuals.

Also around this same time, prostaglandins became available, offering a better risk:benefit ratio than previous glaucoma agents. This led to further changes in the therapeutic landscape by allowing clinicians to intervene earlier with a reduced risk of complications.

The OHTS study led to a better understanding of which individuals are at greatest risk to convert to glaucoma. We used to think that the conversion rate was as low as less than 1% per year, but OHTS illustrated that certain individuals have risks exceeding 7% per year. More importantly, OHTS showed that it is not just IOP that is important, but rather a combination of parameters including IOP, age, vertical cup:disc ratio, visual field pattern standard deviation (PSD) and central corneal thickness (CCT).

Risk calculators developed

Using OHTS data and the concept of risk assessment borrowed from the Framingham Heart Study, Steve Mansberger, MD, developed the first of the risk calculators, which he posted on the Internet at www.discoveriesinsight.org. The calculator allows a clinician to assess a patient’s risk of developing glaucoma in a 5-year period.

The publication of the STAR (Scoring Tool for Assessing Risk) calculator, developed by Medeiros and colleagues, further advanced the concept of risk analysis. This calculator, distributed by Pfizer and similar to a slide rule, was quickly adopted.

The expert panel that Pfizer assembled to provide guidance in the area of risk assessment developed guidelines regarding what risk was important. The recommendation was that risk under 5% is small and follow-up is indicated; 5% to 15% risk carries a recommendation that therapy should be considered; and when risk exceeds 15%, therapy is recommended. Interestingly, the STAR calculator included diabetes as one of the parameters even though the Diagnostic Innovations in Glaucoma Study by Medeiros and colleagues did not validate its purported protective effect.

The most recent risk calculator was introduced by the investigators from the OHTS, working in collaboration with colleagues from the European Glaucoma Prevention Study (EGPS). The EGPS has been controversial, in part because there was little difference in IOP reduction between the therapy and placebo arms of the trial. Still, when one evaluates the placebo arm, the results are similar to the untreated arm of the OHTS study. This arm was used to validate the OHTS results and led to the most recent calculator being introduced.

OHTS actually introduced two calculators, the point system and the continuous method for assessing risk. In both, age, IOP, CCT, vertical cup:disc and either the PSD for a Humphrey perimeter (Carl Zeiss Meditec, Dublin, Calif.) or loss variance for the Octopus perimeter (Haag-Streit, Mason, Ohio) are input. Three untreated IOP measurements from each eye are needed, preferably on different days, along with three CCT measures per eye and two visual field tests. The risk is calculated for the patient, not per eye. The OHTS team did not provide guidance as to what level of risk they feel deserves therapy. These calculators are available at http://ohts.wustl.edu/risk.

The STAR expert panel recommended 15% as the point to consider initiating therapy. Still, some practitioners are more conservative and use a 20% point cut-off. I use a 20% level at which to recommend therapy and evaluate individuals in the 15% to 20% ranges closely, looking at several factors such as age.

For example, I recently had a patient who is 43 years old and has an IOP of 24 mm Hg in each eye. Visual fields were full, central corneal thickness is 500 microns in each eye, and the vertical cup:disc ratio is 0.3. The calculated risk is 12.2%, which is low, but the age is one issue that cannot be overlooked. The condition and management options were explained to the patient, including the level of risk for converting to glaucoma over a 5-year period. This particular individual was comfortable in being followed and recognizes that there may come a point in time at which therapy may be needed.

Some patients do not like the unknown and desire therapy, while others are comfortable in being followed. This brings up another important use for the risk calculator, allowing clinicians to better describe their risk. Patients are afforded an opportunity to voice their concerns. In this situation, some individuals with a risk as low as 12% may desire therapy. If therapy is commenced and side effects occur or the medications are ineffective, then going back to careful monitoring is indicated.

Benefits of early intervention questioned

An unresolved question – and the one that started this column – is whether early treatment will spare the patient vision loss over his or her lifetime. Stated differently, is there a difference if we start therapy today when only ocular hypertension is present or next year when a mild field defect may have developed? Does glaucoma decay rapidly and become more difficult to treat with the presence of greater optic nerve damage or visual field loss? Is glaucoma similar to cancer in that early diagnosis and therapy is crucial to the person’s well being? Unfortunately, at this time we cannot answer these questions adequately. We simply do not have enough information.

The Ocular Hypertension Treatment Study II is currently being performed and this should provide some answers to the question of whether early treatment is beneficial. In OHTS II, everyone is now being treated. It is hoped that in several years it will become apparent whether the group that was treated initially will have less visual loss as compared to the individuals in which therapy was delayed.

Finally, some individuals question whether treating OHTN makes sense at all, given that these individuals are disease-free and that therapy is expensive and life altering. Therefore, what should one do? A reasonable approach, given the safety and efficacy of our stable of therapeutic agents, would be to treat those individuals at great risk to convert during their lifetime provided that the care, once initiated, is safe and effective. Until more information is available, this is a prudent course of management.

For more information:
  • Murray Fingeret, OD, is chief of the optometry section at the Department of Veterans’ Affairs Medical Center in Brooklyn and Saint Albans, N.Y., and a professor at SUNY College of Optometry. He is also a member of the Primary Care Optometry News Editorial Board. He may be contacted at St. Albans VA Hospital, Linden Blvd. and 179th St., St. Albans, NY 11425; (718) 298-8498; fax: (516) 569-3566; e-mail: murrayf@optonline.net. Dr. Fingeret has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
Recommended reading:
  • Brandt JD, Beiser JA, Kass MA, Gordon MO. Central corneal thickness in the Ocular Hypertension Treatment Study (OHTS). Ophthalmology. October 2001;108(10):1779-1788.
  • Epstein DL, Krug JH Jr, Hertzmark E, Remis LL, Edelstein DJ. A long-term clinical trial of timolol therapy versus no treatment in the management of glaucoma suspects. Ophthalmology. October 1989;96(10):1460-1467.
  • European Glaucoma Prevention Study (EGPS) Group; Miglior S, Pfeiffer N, Torri V, Zeyen T, Cunha-Vaz J, Adamsons I. Predictive factors for open-angle glaucoma among patients with ocular hypertension in the European Glaucoma Prevention Study. Ophthalmology. January 2007;114(1):3-9.
  • Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: Baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. June 2002;120(6):714-20.
  • Kass MA, Gordon MO, Hoff MR, et al. Topical timolol administration reduces the incidence of glaucomatous damage in ocular hypertensive individuals. A randomized, double-masked, long-term clinical trial. Arch Ophthalmol. November 1989;107(11):1590-1598.
  • 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. June 2002;120(6):701-713.
  • Medeiros FA, Weinreb RN, Sample PA, et al. Validation of a predictive model to estimate the risk of conversion from ocular hypertension to glaucoma. Arch Ophthalmol. October 2005;123(10):1351-60.
  • Ocular Hyptertension Treatment Study Group; European Glaucoma Prevention Study Group; Gordon MO, Torr V, Miglior S, et al. Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension. Ophthalmology. January 2007;114(1):10-19.
  • Quigley HA, Addicks EM, Green WR. Optic nerve damage in human glaucoma. III. Quantitative correlation of nerve fiber loss and visual field defect in glaucoma, ischemic neuropathy, papilledema, and toxic neuropathy. Arch Ophthalmol. January 1982;100(1):135-146.
  • Schulzer M, Drance SM, Douglas GR. A comparison of treated and untreated glaucoma suspects. Ophthalmology. March 1991;98(3):301-307.