Diurnal IOP fluctuation gives clues to glaucoma progression

Leonard A. Levin, MD, PhD, said at the Ocular Surgery News Symposium, Glaucoma: Improving Your Odds that clinical studies of neuroprotection in Alzheimer’s patients may give clues to how the process might work in glaucoma.

LAS VEGAS — Physicians should track the diurnal IOP curves in their glaucoma patients, despite the difficulty in doing so, according to a speaker at a glaucoma meeting here.

“Diurnal fluctuation helps to track progression in glaucoma, although it is a pain in the gizzard to do,” said John R. Samples, MD, here at the second annual Ocular Surgery News Symposium, Glaucoma: Improving Your Odds.

“The curves are important to your patients in terms of their progression,” he said.

Dr. Samples, a program director of the meeting who has researched diurnal curves in glaucoma, explained the circadian rhythm of aqueous flow. He said the curve is at its highest point in the morning, slightly lower in the afternoon and about one-half of the morning level during sleep. Normal flow is about 2.75 µL/minute during the day, he said.

Dr. Samples added that the beta-blocker timolol is “remarkably consistent on suppressing flow during the day but has no effect in sleeping subjects.”

Other factors influencing diurnal variation in IOP include corticosteroids and melatonin levels. Dr Samples said some patients ask him if physical and emotional stress can play a part in the fluctuation of their diurnal curves. He said stress can cause an increase in catecholamines, which cause the curve to fluctuate.

Dr. Samples and co-course director Louis B. Cantor, MD, led the weekend meeting, which drew more than 170 physician attendees. This article recaps some of the highlights of the meeting. These items appeared first in meeting coverage on the OSN SuperSite.

Better IOP measurement needed

If physicians are to make sense of IOP, Dr. Cantor said, “we need better, direct methods of measurement.”

Dr. Cantor spoke on the relationships between tonometry and corneal thickness at the meeting, where he also served as a course director.

He said that to get an accurate conception of IOP, corneal thickness testing should be performed in all glaucoma patients. When a target pressure is set, the treatment should help the patient achieve the target pressure and “not below that,” he said.

Dr. Cantor added that the lower the IOP, the better the prognosis for the patient.

Beta-blockers still vital

Now that prostaglandin analogues are accepted as first-line therapy for glaucoma, beta-blockers are the clear second-line choice, said L. Jay Katz, MD, FACS.

But there are new thoughts on the advantages, limitations and side effects of this “aging king” of glaucoma medical therapy, Dr. Katz said.

For instance, the policy of not prescribing beta-blockers in patients with congestive heart failure has been re-evaluated. “The philosophy has changed in the internal medicine community,” he said.

Earlier restrictions on using beta-blockers in the evening because of fears that ocular circulation may be compromised have also been thrown out, Dr. Katz said, as have concerns about effects such as vasodilation. Physicians should remain cautious about prescribing beta-blockers to patients with asthma and bradyarrhythmia, Dr. Katz said.

“Patients have benefited from new delivery systems that have been formulated for us, whether you are talking suspensions or gel-forming solutions,” Dr. Katz said. He noted that these new features can make beta-blockers safer and easier to use and allow for a better dosing schedule. Patients may benefit from the once-daily formulation of Istalol (timolol, Ista Pharmaceuticals), which was approved for marketing by U.S. regulators in early June, he said.

Istalol is a formulation of timolol maleate with added potassium sorbate. U.S. clinical trials found that use of this once-daily 0.5% formulation with the added sorbate provided pressure control equivalent to timolol solution twice a day. Dr. Katz said it is assumed that the reason for this is that the sorbate increases penetration of the timolol.

Beta-blockers may have been relegated to the role of a second-line alternative to prostaglandins, Dr. Katz said, but they can still be used as first-line therapy, usually in combination with another drug.

Neuroprotection study

Clinical studies of neuroprotection in patients with Alzheimer’s disease may give clues to how the process might work in glaucoma, according to Leonard A. Levin, MD, PhD.

Dr. Levin said that, in the past, physicians did not understand how apoptosis could be induced in an optic nerve disease like glaucoma and that there was no proof from a clinical trial that neuroprotection could work.

“Neuroprotection was difficult to prove because it works in chronic diseases, but not as well for acute diseases,” Dr. Levin said. He said studies to prove that a neuroprotective therapy works would require “many patients and several years.”

But he noted that in a study published in 2003 in the New England Journal of Medicine, neuroprotection was demonstrated in patients with Alzheimer’s disease.

Additionally, he said, a recent study comparing patients who received brimonidine 0.2% twice a day or argon laser trabeculoplasty showed that, after 18 months of follow-up, patients who received brimonidine had a lower mean slope of field loss than those who underwent ALT.

Primary vs. adjunctive efficacy

Physicians cannot assume that when one glaucoma drug is added to another it will be as effective as when it is used as a primary agent, said Steven T. Simmons, MD.

“One can’t add one medication and then expect it to work as well as it does as a primary agent,” Dr. Simmons said. “And you can’t assume that a medication that is effective when added to A will also be effective when added to B.”

The goal of adjunctive therapy is to achieve an additional 15% pressure reduction, Dr. Simmons said. Also, it is hoped that the two medications will work synergistically because each time a therapeutic agent is added there are additional safety concerns, he said.

Clinical trials have shown that adjunctive therapy gives patients the benefits of achieving and sustaining low target pressures, he said.

Dr. Simmons recommended adding another medication or performing argon laser trabeculoplasty when IOP remains uncontrolled on monotherapy. He also recommended that physicians perform monocular trials when adding a new drug to a patient’s regimen.

Other recommendations include considering the long-term efficacy, safety and tolerability of the adjunctive medications, and individualizing treatment to the patient’s needs.

Combination therapies

There are benefits to both fixed and nonfixed combination therapies for the treatment of glaucoma, said George Shafranov, MD. He noted that more than 50% of glaucoma patients need more than one drug to maintain IOP control.

Nonfixed formulations give physicians more freedom in prescribing, while fixed combinations are more convenient for patients and ultimately provide stronger results from a single bottle, he said.

According to Dr. Shafranov, fixed combinations provide the advantages of improved convenience, compliance and efficacy, as well as smaller copayments.

Nonfixed combinations may cause more confusion for patients, he said, as one agent may require once-daily dosing while another requires three-times-daily dosing.

One fixed combination that currently has U.S. regulatory approval is a timolol-dorzolamide combination. Several others are awaiting Food and Drug Administration approval, Dr. Shafranov said.

Dr. Shafranov added that although more fixed combinations are coming, nonfixed combinations allow the most flexibility, and clinicians should not forget that point.

Perimetry strategies

Dr. Shafranov also spoke on the use of advanced glaucoma perimetric techniques at the meeting.

Combining short-wavelength automated perimetry with “more efficient strategies,” such as SITA fast perimetry, can decrease testing time to less than 4 minutes, he said.

Dr. Shafranov said that a new generation of short-wavelength automated perimetry is soon to become available, in which the stimulus size and brightness can be adjusted.

This technology may become available in the United States as soon as the end of the year, he said.

Imaging advantages

Digital imaging technologies can help confirm the presence of subtle ocular defects and thus eliminate the need for repeated confirmatory testing in glaucoma, according to Joel R. Schuman, MD.

Dr. Schuman provided a review of glaucoma diagnostic technologies including the Heidelberg Retinal Tomograph, optical coherence tomography from Carl Zeiss Meditec and the GDx from Laser Diagnostic Technology.

He said that one goal of imaging is to detect glaucomatous loss early to prevent visual loss. He said imaging can also be useful for outcomes evaluation in the study of medical and surgical treatments.