Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Annual Meeting of the Association for Research in Vision and Ophthalmology

Fort Lauderdale, Florida / May 6-10, 2007

The prevalence of glaucoma, the leading cause of blindness in many developed countries, including Canada, is projected to continue to climb steeply due to an aging population. According to the Glaucoma Research Society of Canada, more than 250,000 Canadians have glaucoma with prevalence of 2% over the age of 40 and up to 6% over age 60. Due to the availability of several therapies capable of relieving symptoms and preventing progression, the hurdles have long been considered to be timely diagnosis and appropriate treatment selection. However, new data suggests many patients go untreated even after the diagnosis is made. In data from the US Medicare Current Beneficiary Survey (MCBS), 30% of patients with a diagnosis of glaucoma had not received any form of treatment in the previous year.

According to Dr. Joshua D. Stein, Duke University, Durham, North Carolina, “We have knowledge that consistent use of effective medical therapies reduces patients’ risk for blindness due to glaucoma, yet we found that many patients are not benefiting from the availability of these increasingly effective therapies.” Suggesting that physicians who are not following patients rigorously may be as much at fault as patients who are not complying with therapy, Dr. Stein cautioned, “Glaucoma will continue to be a leading cause of blindness in older populations,” unless more rigorous efforts are employed to offer state-of-the-art therapies that control intraocular pressure (IOP) and help reperfuse the optic nerve.

Enhanced Duration of IOP Control

While prescribing an IOP-lowering agent is the critical first step in any form of glaucoma, including primary open-angle glaucoma (POAG), which is the most common type, there is increasing evidence that treatments and strategies differ for important measures, such as 24-hour IOP control. While many clinicians rely on in-office measures of IOP, which are often taken at near peak activity of a morning treatment, a randomized, placebo-controlled study comparing a fixed-dose combination to a single agent demonstrated that the combination was significantly more efficacious, particularly when IOP was assessed over the full 24 hours. “Although we now know that IOP is not the only cause of optic nerve damage in patients with glaucoma, it is still considered to be among the most important. It is therefore reasonable to seek the best 24-hour control of IOP to provide the best protection against progressive vision loss,” stated Dr. Robert M. Feldman, Hermann Eye Center, University of Texas Medical School, Houston.

Study Findings

In a trial for which Dr. Feldman was the lead investigator, 232 patients with POAG who had insufficient control of IOP after a six-week run-in with timolol were then randomized to the combination of 2% dorzolamide and 0.5% timolol or to remain on timolol.

Over the course of eight weeks, the fixed-dose combination not only provided significantly greater control at several time points, including 10 a.m. (-1.3 mm Hg, P=0.003) and 2 p.m. (-1.07 mm Hg, P=0.016), but the average daytime IOP was also significantly lower (-0.8 mm Hg, P=0.025). The persistence of the greater relative control with the combination over the course of the study suggests the potential for a cumulative advantage over time. These data are particularly reassuring because of the growing consensus that most patients will eventually require combination therapy if a combination is not indicated first-line.

In another double-blind study that compared the same fixed-dose combination to latanoprost monotherapy in patients who are timolol responders, the study demonstrated that the fixed-dose combination provided additional IOP control. In this study, 29 patients who had been treated with latanoprost for at least four weeks were switched to twice-daily dosing of dorzolamide and timolol in a fixed dose. After the switch, there was a 2.7 mm Hg reduction in IOP (P<0.0001 vs. baseline). Eleven patients (37%) reported burning upon instillation of the fixed dose, but the senior author of the study reported that this was highly transient and diminished with repeated dosing in most patients. Only two patients discontinued therapy due to the burning.

“The study was really designed to test the strategy of improving control of IOP in patients on a single agent by using the fixed-dose combination,” Dr. Sriram Sonty, Department of Ophthalmology, University of Illinois, Chicago, told delegates. “Here we have two mechanisms of action and this is attractive when trying to achieve sustained reductions in IOP over each dosing period.”

In the study design, patients considered to be insufficiently controlled on latanoprost therapy were administered a single drop of timolol in one randomly chosen eye. If the eye demonstrated at least a 15% reduction in IOP or a decrease of ³3 mm Hg two hours after timolol, latanoprost was discontinued and the patient was started on the fixed-dose dorzolamide/timolol combination. Safety and efficacy were evaluated at weeks 4 and 12. The substantial reduction in IOP was combined with a high degree of tolerability.

“The study demonstrates that the fixed-dose dorzolamide/timolol combination does provide further reductions in IOP in patients insufficiently controlled on latanoprost therapy,” reported Dr. Sonty, indicating that this approach is an attractive next step in this population.

Possibility of Increased Perfusion to the Optic Nerve

“Following treatment with dorzolamide, there was a 5% increase in mean retinal arteriolar diameter, a 17% increase in blood velocity and a 25% increase in blood flow in response to isoxic hypercapnia,” reported Dr. Subha Venkataraman, Department of Ophthalmology and Vision Science, University of Toronto, Ontario. Consistent with earlier experimental work, “these findings suggest treatment with dorzolamide improves retinal arteriolar and capillary vascular reaction independent of the change in IOP.”

Compliance Is Key

However, keeping patients compliant with therapy has been a challenge regardless of any relative benefit from one strategy over another. Most patients do not recognize an immediate change in symptoms when they begin to skip therapies. If daily therapies are considered cumbersome, they are more easily abandoned. While patient education is considered to be the key to adherence, a study of claims data revealed that hyperemia may be an important and poorly recognized obstacle to remaining on treatment. In an analysis of adverse events by drug classes, hyperemia was the most cited adverse event. Of the 65% of patients on a prostaglandin for glaucoma who complained on an adverse event, 70% reported hyperemia. Conversely, hyperemia was less common with alpha adrenergics and uncommon with dorzolamide, a carbonic anhydrase inhibitor.

“Only 69% of patients reporting hyperemia recalled mentioning the problem to a physician, but 10% acknowledge skipping doses due to hyperemia, which is likely an underestimate,” reported Dr. Thom J. Zimmerman, Chair, Department of Ophthalmology, University of Louisville, Kentucky. He noted that in a survey of physicians, hyperemia was cited as the adverse effect from glaucoma agents most likely to affect adherence. More than 70% of physicians felt that adherence was worse for prostaglandins than other classes due to adverse events.

Adverse effects on patient appearance are a powerful deterrent to compliance, but hyperemia also has implications for surgery due to concern among some surgeons that uncontrolled hyperemia may adversely affect outcome. However, the key to overall outcome in patients with glaucoma is effective control of IOP, a goal that must include treatment selection for both efficacy and for relative adherence.

While more data are needed to explore potential differences between therapies for IOP-independent benefits, the full spectrum of modern strategies, including fixed-dose combinations, should be considered in providing persistent IOP control.

Summary

Glaucoma, the leading cause of blindness in Canada, is an insidious process that requires aggressive therapy to prevent adverse outcomes. Although there is now an array of therapies for controlling IOP, a major source of optic nerve damage, the differences in the mechanisms of action with the dorzolamide/timolol combination may offer opportunities to achieve additive effects. Additionally, regardless of the relative advantages of available strategies, an important goal is to also achieve persistent compliance, which may depend on selecting therapies with a low risk of adverse effects, including red eyes, which reduce the likelihood of daily dosing by patients.