Target Practice

How IOP sets the tone for glaucoma therapy.

BY LAWRENCE STONE, M.D.

The tools we have to document glaucomatous damage to the optic nerve and functional impairment of vision are sophisticated and precise. Unfortunately, our ability to assess the risk of glaucoma development or progression is far less specific. As a result, it is tempting to invest a lot of faith in intraocular pressure readings. But we must be careful not to overestimate its impact. In recent years, randomized clinical trials examining the effects of IOP lowering on glaucoma control have been tremendously helpful in revealing its strengths as well as its weaknessess. It is critical that we have a grasp of these crucial studies to correctly grasp each patient's case and arrive at a goal for pressure reduction.

In this article, I'll explain how I use these studies — the Ocular Hypertension Treatment Study, the Early Manifest Glaucoma Trial, the Collaborative Intervention Glaucoma Treatment Study, the Collaborative Normal Tension Glaucoma Trial and the Advanced Glaucoma Intervention Study — in daily practice to control my patients' glaucoma successfully. I'll also provide some specific case studies to illustrate my methods.

Study the Studies

The key for glaucoma treatment is early detection. The earlier one detects it, the less aggressive one must be in terms of IOP lowering and the better the long term prognosis. The randomized clinical trials have borne this out.

It is important to know what each study was designed to ask, and what answers or conclusions were found. But take care not to infer too much from the original study design.

Above: Glaucoma flow sheet for patient with monocular advanced pigmentary glaucoma. Meds/comments indicate drops being used on the day of the visit, laser treatments or surgical interventions. A clean version of this form will be available for download at www.ophthalmologymanagement.com to accompany the online presentation of this article.

Be aware that prostaglandins were not yet available at the time most of these studies were initiated. Also, visual field progression in some studies (most notably the CITGS study) was not controlled for cataract progression. For this and other reasons, the study conclusions — while immensely valuable — should not be relied upon as the last word. Here is my summary of each:

• Ocular Hypertension Treatment Study (OHTS). The goal of the trial was to lower IOP by 20% with Timoptic therapy.

Patients had pressure readings of 24 to 32 in the study eye, with fellow eye being above 21. After 5 years, 10% of control eyes developed glaucoma. In treated eyes, only 5% of patients developed glaucoma. Glaucoma was defined by either visual field changes or changes in the optic nerve appearance as judged by stereo photography, or both. In this study, optic nerve progression was found to be the most sensitive way to detect glaucoma. Another interesting conclusion: corneal thickness was related to risk of glaucomatous progression. Patients with thin corneas were at higher risk than those with thick corneas.

• Early Manifest Glaucoma Trial (EMGT). This study examined newly diagnosed high- and normal-pressure glaucoma patients with a mean IOP of 21. The 24-2 Humphrey visual field test averaged minus 4.00 decibels. Treatment with a combination of topical betaxolol and argon laser trabeculoplasty lowered IOP 5.1mm, or 25%, on average. No target pressure was set.

After 6 years, disease progression occurred in 45% of treated eyes vs. 62% of controls. Also, treated eyes had a delayed onset of glaucoma vs. untreated eyes. The authors concluded that the study shows that each additional 1mm of IOP reduction is associated with a 10% reduced risk of disease progression.

One school of thought holds that while this 10%-per-1mm relationship may be valid for a certain range of IOP, lower pressures show diminishing returns. The putative protective value of further lowering beyond a certain level is more debatable. Moreover, you need to consider the effects on patient quality of life from additional medications or incisional surgery, ocular surface problems, difficulties with compliance, or other issues.¹

The EMGT found that visual field deterioration and optic disc hemorrhages were the most sensitive indicators of glaucomatous progression. It also concluded that elevated IOP, but not IOP fluctuation, is a strong risk factor for progression.

• Collaborative Intervention Glaucoma Treatment Study (CIGTS). This study was designed to determine the long-term effect of treating newly-diagnosed primary open-angle glaucoma with trabeculectomy compared to medication. Unlike the EMGT, patients with normal tension glaucoma were excluded from this study.

Think of this as two studies in one. Patients (not eyes) were randomized to either medical or incisional surgery. Aggressive target pressures were set based upon the degree of visual field loss and intraocular pressures using a complex formula. At the time of the study, prostaglandins were not yet available.

Patients had a mean deviation on 24-2 Humphrey visual field of minus 5.00 decibels. The trabeculectomy group achieved pressure reduction to a mean of 14.2mm Hg (average IOP drop was 46%); the medical group achieved reductions to 17.5mm (average IOP drop was 38%). Seventy-five percent of medically-controlled patients required two or more medicines to reach the target IOP. After 5 years, researchers found no difference between the surgically-controlled and the medically-controlled groups on visual field testing. However, the study did not adjust for the higher rate of cataract formation in the surgery vs. the medical group.

Another conclusion was that variability of IOP readings between visits is an independent risk factor for progression (unlike the EMTG study).

CITGS showed us that patients with newly diagnosed glaucoma do well as long as the IOP is lowered by at least 35% (mean reduction from 25 to 17). More aggressive percentage reductions, however, whether achieved through medical, laser or surgery (36% to 48%), allowed for more stability of the visual field.

However, filtration surgery resulted in higher rates of cataract surgery and more local eye symptoms than the medication group, prompting the conclusion that initial trabeculectomy is not recommended at this time.

The CITGS investigators themselves recently concluded that the most valuable lesson from the study thus far is that judicious use of medical therapy is effective in stabilizing vision, visual acuity and the quality of life, at least in the short term.² In addition, "the CITGS is a work in progress, and final opinion about the study and its impact on ophthalmic practice requires longer term follow-up."³

• Collaborative Normal Tension Glaucoma Trial (CNTGT). This group studied patients with normal-tension glaucoma to determine if aggressive IOP lowering slows optic nerve progression and visual field loss. Patients had untreated IOP of less than 24, with 9 of 10 readings equal or less than 21.

A significant lowering of intraocular pressure (30% of more from baseline) significantly arrested progression of field loss in 80% of patients. However, 20% of patients will continue to progress despite this level of pressure lowering. Subgroups of patients more likely to have progression were women, blacks, migraine sufferers and those with disc hemorrhages.

CNTGT showed that visual progression in normal-tension glaucoma is more variable than in primary open-angle glaucoma, with only half of the untreated eyes experiencing visual field progression by 5 to 7 years.

• Advanced Glaucoma Intervention Study (AGIS). The predictive analysis portion of this study taught us that patients with advanced field loss (mean deviation -10.0 decibels) do best with IOPs in the low-normal range. To achieve pressures this low (less than 14.0 mm Hg), filtering surgery must be considered if medicines and laser trabeculoplasty do not adequately lower pressure.

An associative analysis of the AGIS data showed that patients whose IOPs were under 18 during all follow-up visits had mean changes in visual field defect score close to zero, whereas eyes with less than 50% of readings below 18 had significant visual field progression. Many eyes whose pressures were never above 18 in the associative analysis were undoubtably the same eyes as those with the low IOPs seen in the predictive analysis data. The associative analysis also suggests that eyes with advanced optic nerve damage are particularly sensitive to pressure fluctuations.

Setting Target Pressures

So, when you have a patient in front of you for the first time — with all test results and having completed your exam — your first task is to decide how this patient best fits into the glaucoma spectrum and which study is most relevant, then you can set a target pressure for the patient.

Keep in mind that each case needs to be individualized, and issues such as age, family history, appearance of the optic nerve head and numerous other factors that may not have been included in the study data have to be included in the decision-making process. It is as much on an art as a science. Also, advanced imaging technologies were not yet available at the time of most of the studies. See Table 1 above for some guidelines.

Paul F. Palmberg, M.D., Ph.D., of the Bascom Palmer Eye Institute in Miami, Fla., deserves much credit for introducing the concept of target pressures IOP as a means of protecting the optic nerve.

There are numerous factors to consider when establishing a target IOP, but it is also important to remember that any medications can reduce quality of life and compliance. And because maintaining a target IOP can be crucial to successfully managing the disease, you will be tracking IOP over a long range of time. In case you don't already have an efficient record-keeping system for tracking IOP, a handy flow sheet is available for download with the online version of this article at www.ophthalmologymanagement.com.

Case Studies

In the following cases of glaucoma suspects, I'll show you how I used the above-mentioned clinical trials to determine the target IOP and treatment for each. While technology is critical, clinical judgment is paramount in pulling together all the elements in making these diagnoses.

• Case #1. GH is a 42-year-old African-American male referred for second opinion regarding glaucoma. He has been using Travatan qhs in both eyes for 3 to 4 years. His pretreatment pressures were unavailable and he was reluctant to go through a washout period to re-establish them.

Corrected visual acuities were 20/20 OU. IOP was 18 in each eye. Pachymetry was 563μm OD and 560μm OS. Cornea and lenses were clear bilaterally. Visual field exam with SITA SWAP was normal in both eyes Fundus photos showed vertical cup-to-disc ratio of 0.65 OD and 0.45 OS. Cirrus HD-OCT showed no thinning of nerve fiber layer in the right eye and diffuse superior and temporal thinning of nerve fiber layer in the left.

I concluded that the patient had ocular hypertension OD and pre-perimetric glaucoma OS. Travatan drops were maintained in both eyes and consideration is being given for left eye adjunctive therapy or SLT. My target reductions from baseline would be 25-30% OD and 30-40% OS.

• Case #2. BC is a 64-year-old African-American male with chronic angle closure glaucoma and history of bilateral iridotomies. He has asymmetric IOPs: 24 OD and 30 OS. Iridotomies were patent OU. Gonioscopy in ambient light showed 360° open angle OD and 5 clock hours of peripheral synechial closure OS. Visual field testing with SITA standard was mean deviation was right eye -0.77 dB and left eye -4.53 dB.

The right eye showed cup-to-disc ratio of 0.4 with mild thinning of the superior temporal rim. In the left eye, the CD ratio was 0.5. There was vertical elongation of the cup at the 1 and 6 o'clock positions as manifested in the nonstereo photo by bayoneting of the circumlinear vessels. An optic disc cube 200×200 study was normal. In the left eye, generalized thinning of the nerve fiber layer was reflected in the RNFL thickness map and RNFL thickness deviation.

Comment: In the right eye, an OHTS-based risk calculation showed a 12.5% risk of developing glaucoma without treatment after 5 years. After discussion with the patient, therapy for that eye was initiated with a goal of 25-30% reduction based upon the OHTS results. In the left eye, glaucoma was suspected based upon the pressure readings and optic nerve appearance. The nerve fiber layer scan and the visual field findings corroborated the diagnosis. I initiated Travatan-Z therapy, lowering the left eye pressure to 21. Adjunctive therapy for that eye is also being contemplated. With moderate glaucoma, the CITGS results are most relevant to establishing the target pressure and would suggest a 35% to 40% reduction from baseline.

Consider This

What's worked in my practice is catching glaucoma early, when it is much easier to treat. The best time to diagnosis glaucoma is in the pre-perimetric phase, before the patient has lost any visual field, then the patient only needs to be on one drop and your targets don't need to be as aggressive — instead of a 40% reduction, maybe a 25-30% reduction is enough. I credit the spectral domain OCT nerve fiber exam, the 90 diopter optic nerve exam, pachymetry and the 24-2 threshold FTD visual field study as four clinically useful tools in achieving this early detection goal.

The OHTS study had a 20% reduction average, but even with that, 5% of the patients still developed glaucoma. If I think a patient fits into the OHTS group, I will set a target pressure reduction of at least 25%, trying to eliminate the 5% from developing glaucoma. As most PGAs can obtain a 30% reduction with few side effects, this is an easy decision to make.

However, for patients whose glaucoma is detected later in the disease trajectory, I use the other randomized clinical trials (EMGT, CITGS, AIGS and CNTGT) as a guideline. When determining your target pressure for these patients, keep in mind that the reduction percentages researchers tried to achieve in some of the studies were not enough to prevent glaucoma progression. For instance, in the EMGT study, 45% of eyes progressed after 6 years even though they had the target 25% mean IOP reduction level had been reached.

I often refer to a specific randomized trial when explaining my treatment plan to patients. This engenders confidence in the IOP target goal and eye drop recommendations. In dealing with a chronic disease such as glaucoma, the packaging and delivery of the product (i.e., information) is particularly important in enhancing the physician-patient relationship.

A traditional approach in glaucoma has been to treat the patient with a moderate IOP reduction, and then add a second drop if there is progression in the visual field or further cupping. I try to be a little more aggressive with my target pressures in hopes of preventing (or at least delaying) progression and the need for additional therapies. I recommend being proactive by using target pressures based upon the randomized clinical trials or other sources (such as the Delphi group or Table 1) rather than waiting for either structural or functional evidence of disease progression. OM

References

1. Singh, K. Limitations in the assessment of the relationship between IOP and POAG, Ocular Surgery News Special Supplement. May 2007:5-8.
2. Lichter, et al. The Investigators Perspective on the Collaborative Initial Glaucoma Treatment Study. Arch Ophthal 126:122.
3. Pasquale L Optimizing Therapy for Newly Diagnosed open-angle glaucoma. Arch Ophthal 126: 125.

Lawrence Stone, M.D., is chief of ophthalmology at Weiss Memorial Hospital in Chicago, and is founder of Mid-north Eye Center in Chicago. He specializes in glaucoma.