According to best estimates, more than 200,000 people in the United States are blind from glaucoma, out of about 4 million with the disease. Worldwide, 6 million people out of 67 million with the disease are blind. Glaucoma is the second leading cause of irreversible blindness in the United States, number one worldwide. Among African Americans and Latinos in the United States, it is the leading cause of blindness.1

Why do people become blind from glaucoma? We can look to society, patients themselves, and physicians for some of the reasons, namely

1. Lack of access to health care

2. Nonadherence to medical therapy

3. Inadequate treatment

To date, the only factor we have been able to modify to regulate this disease is IOP. We are aware, however, that there may be IOP-insensitive factors, such as blood flow or neurodegeneration, that may be amenable to treatment in the future.

In this enduring material, we discuss evidence-based best practices for glaucoma care, using representative cases that demonstrate how new data from recent studies may influence our clinical decisions.

CASE 1: SIMPLIFYING A COMPLEX REGIMEN

A 76-year-old woman with glaucoma is evaluated for poorly controlled IOP. She is using latanoprost once a day, timolol twice a day, brimonidine three times a day, and pilocarpine four times a day, but she has not reached her target IOP. She has rheumatoid arthritis, and her hands are deformed because of that. When we review her schedule and ask her to show us how she instills her medications, we see that she has a great deal of difficulty getting the drops—any of the drops—into her eyes. She mentions that her husband is available to help with her drops in the morning and the evening.

To help this patient gain better IOP control, our most reasonable options include trabeculectomy, reviewing and simplifying the regimen, adding brinzolamide three times a day, or continuing the same medications, while encouraging adherence.

Any of these options is potentially correct, but reviewing and simplifying the regimen would be my preference. Knowing the patient's husband can help her in the morning and the evening, we should be able to simplify her regimen to twice-a-day dosing, possibly using fewer bottles, which may solve the problem. In this case, it did.

If we could be certain of a perfect outcome, trabeculectomy would be a good choice. There are always risks with surgery, however, and we prefer to try to control pressures medically.

Adding another medication might be beneficial if the patient were able to get the drops in her eyes. The concern is that adding a drop makes the regimen more complex and even more difficult for her.

Keeping the same medications and encouraging adherence may help in some cases. With constant prodding and re-education, patients sometimes improve their adherence but only if you provide this kind of feedback constantly. In this instance, however, the patient's regimen is so complex and it is so difficult for her to instill the medications herself that encouraging adherence probably will not be successful.

Adherence and Persistence

In a 2008 study, more than half of the patients surveyed did not adhere to their glaucoma therapy regimen, or they instilled their drops improperly.2 Other studies have reported similar findings.3,4We can also look at persistence by reviewing prescription renewal rates through pharmacies and formularies. If patients are renewing their prescriptions regularly, they are more likely to be using their medications than if the renewals are sporadic and infrequent. This appears to be a more reliable measure of adherence and persistence than asking patients directly.5 Studies using electronic monitors often found that patients said they used their medications much more regularly than they actually did.6

Studies have also shown that persistence and adherence are best with the prostaglandin analogues, which are oncea- day drugs.7 When a second medication is added, not only does adherence decrease for the second medication compared to the first, but when a patient is using two medications, he or she is less likely to use the first one than when it was prescribed as monotherapy.8

Adding more medications really does affect patients' adherence to their medical regimens. Therefore, we need to aim for the simplest regimen possible. Patients admit that if they take one medication a day, as opposed to two or more, they are more likely to use it on a regular basis.9 The cost of a medicine can affect adherence to medical therapy, and that is important. In a 2009 study, however, nearly 45% of patients using an electronic monitoring device who knew they were being monitored and were provided free medication used their drops less than 75% of the time.10

Educating patients is another important factor in improving adherence. This should involve emphasizing the importance of glaucoma care, ensuring that patients understand the purpose of their medications, and being sensitive to side effects.

CASE 2: ADDING A FIXED-COMBINATION AGENT

An 82-year-old man is evaluated for treatment of primary open-angle glaucoma. His visual acuities are 20/25 OD and 20/30 OS. Central corneal thickness measurements are 545 and 540 μm, with some asymmetry. The right optic nerve has a smaller cup than the left, and there is a small disc hemorrhage inferiorly in the left eye (Figure 1). Baseline pressures were 29 mm Hg in the right eye and 34 mm Hg in the left eye. Although a prostaglandin ana analogue and a ß-blocker reduced the pressures, they were still above the target of 20 mm Hg. We continued the prostaglandin, stopped the ß-blocker, and added the fixed combination of brimonidine and timolol. With that additional medication (but the same number of bottles), pressures were reduced to 17 mm Hg and 19 mm Hg. The patient tolerates this regimen well and appears to be using his drops as prescribed. His discs and visual fields have been stable for 2 years.

CASE 3: EXTREME NONADHERENCE

A 58-year-old man, a physician, has ocular and systemic hypertension. Baseline IOPs were 43 mm Hg and 30 mm Hg, and visual acuities were 20/30 OD and 20/35 OS. The patient had undergone cataract extraction in both eyes, somewhat complicated in the right. Figure 2 shows vertical cupping and loss of the rim inferiorly in the right eye and a healthier-looking optic nerve head in the left eye. Visual fields showed a defect on the right and possible early visual field loss on the left.

The patient was started on timolol monotherapy, but he did not return for follow-up. Five years later, the patient returned for evaluation. He was still using timolol, which he self-prescribed. His pressures were 32 mm Hg and 26 mm Hg, and he was legally blind with markedly excavated cups. Which of the following is the best treatment for this patient?

a. Start with monotherapy and add more medications as needed

b. Prescribe multiple medications, including a fixed combination (timolol-dorzolamide or timolol-brimonidine) and a prostaglandin analogue

c. Perform laser trabeculoplasty

d. Perform filtering surgery

Starting with monotherapy and adding more medications as needed is a reasonable option, and that was done in this case, although we would have to ask ourselves: How likely is it that this patient will achieve target pressures with one medication?

In retrospect, prescribing multiple medications, including a fixed-combination and a prostaglandin analogue, would have been a better choice for this patient. With this regimen (along with regular follow-up visits), he would have been more likely to reach target pressures. Another important consideration is that this regimen is close to maximum medical therapy, so if target pressures were not reached, the treating physician could move quickly beyond medical therapy.

Laser trabeculoplasty helps with adherence. Unfortunately, its effect is modest, similar to using a single medication, and it is not likely this patient will reach target pressures with laser trabeculoplasty alone.

Filtering surgery alone can quickly reduce pressures, but when IOPs are extremely high, there are risks, such as choroidal detachment and suprachoroidal hemorrhage. Going straight to filtering surgery is an option for this patient, especially if the treating physician is convinced he will not use anything medically. In most cases, however, patients and doctors prefer to start with medication before moving to surgery.

CASE 4: PROSTAGLANDIN INTOLERANCE

A 58-year-old woman has ocular hypertension, a family history of glaucoma, and low diastolic blood pressure. Her visual acuity is 20/20 OU, IOPs are 34 mm Hg and 32 mm Hg, with central corneal thicknesses of 520 and 515 μm. She has small cups with some asymmetry.

After discussing the risks of glaucoma progression with her doctor, the patient opted for treatment, even though her discs are relatively healthy and her visual fields are good. She started using a prostaglandin analogue, but she did not tolerate it because of hyperemia. A ß-blocker alone reduced her pressures, but she did not achieve her target pressure of 22 mm Hg. The ß-blocker was stopped, and the patient started using a fixed combination of brimonidine and timolol twice a day. Her pressures were reduced to 20 mm Hg and 19 mm Hg, with excellent tolerability, and she has remained stable on that regimen.

Is there something more?

Are there factors other than pressure that cause progression in glaucoma? We have discussed this possibility for more than 100 years, and we have evidence from some large, well-accepted studies suggesting there must be something more we can do for our patients with glaucoma.11 The landmark Normal Tension Glaucoma Study showed that patients who were treated and achieved a marked pressure reduction, at least 30% below baseline, did much better than the untreated control group.12 What is important to note, however, is that 12% of the patients who were treated aggressively still progressed during this study. The question is: Did the glaucoma progress because pressures were not low enough, or was there something more than pressure causing progression in this population?

This famous graph from the Advanced Glaucoma Intervention Study (Figure 3) shows high-tension glaucoma patients whose target pressures were below 18 mm Hg.13 In subgroup analysis, subjects in the group with a mean IOP of 12.3 mm Hg seem to have an incredibly stable course when we look at their perimetry results, compared to the other subgroups, where there was definite progression over the course of the trial. Keep in mind, however, that the flat graph with the mean IOP of 12.3 mm Hg is showing an average of the entire group. When we look more closely, we see that, within that group, about one-fourth had sustained progressive change in their visual field, which means that one-fourth got worse. We can also imagine then that onefourth seemed to get better on serial perimetry, and they averaged out. This would suggest, however, that perhaps certain individuals with very low IOPs progress. So, whether a patient has normal-tension or high-tension glaucoma, something more than pressure regulation may be necessary.

In an editorial more than a decade ago, Caprioli noted that, during the course of the disease, various factors seem to have different degrees of importance in different patients.14 In one patient, for example, a pressure of 60 mm Hg is an important predictor of progression, more so than anything else. Someone else, however, may have a pressure of 11 mm Hg and be continually getting worse. This seems to suggest we should be looking at—and potentially treating—something other than pressure in those individuals. Whether that treatment is neuroprotective or something to improve blood flow, we are all looking for that next step beyond pressure regulation.15,16

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