feature
Clinical Considerations of the Latest Research for Better Glaucoma Management
With new trial results in hand, doctors will better understand how the different glaucoma agents fit into the therapeutic spectrum.
By Murray Fingeret, O.D.

For several years, clinicians have considered prostaglandin analogues as the primary therapy for open-angle glaucoma (OAG). These agents are easy to use, have few side effects and are safe and effective.

New research continues to support the efficacy of prostaglandins for lowering IOP associated with OAG and ocular hypertension (OHT) and provides us with additional information to help us manage the disease. What's more, we now have additional data on the best adjunctive therapies to use with them.

In this article, I'll discuss the latest findings and put them into context for clinicians.

Unique, lasting effects

In a recent study by Sit, Weinreb and colleagues,¹ travoprost 0.004% (TRAVATAN^® solution) was shown to have lasting effects on diurnal and nocturnal IOP even after it was discontinued for several days.

When patients stopped using travoprost for approximately 2 days, their IOPs remained low, although not as low as when they were taking the medication regularly.

Surprisingly, the reduction was greatest during the nocturnal period, a time of day when IOP is normally higher. Although we don't want to condone noncompliance, these results are reassuring because we can prescribe travoprost knowing that if our patients occasionally miss a dose, their IOPs won't increase dramatically.

Adjunctive therapies

Approximately 40% of patients who use prostaglandins for glaucoma therapy need a second medication to lower IOPs further.^2,3 They either don't reach their target IOPs, or they show disease progression in the optic nerve or visual fields.

Adjunctive therapies can include topical beta-blockers, alpha2 agonists and topical carbonic anhydrase inhibitors (CAIs).

In the past, conventional wisdom said topical beta-blockers were the most potent agents when added to a prostaglandin. Yet, surprisingly, a study by O'Connor and Martone⁴ found that dorzolamide was more effective in lowering IOP (additional 19.7%) than timolol (12.3%) or brimonidine (9.3%) when added to latanoprost (XALATAN*). These results ran counter to popular opinion, although they were of no surprise to glaucoma specialists.

When the results of the Ocular Hypertension Treatment Study (OHTS) were reviewed, topical CAIs were the third most commonly used agent, ahead of alpha2 agonists.⁵

To examine the issue further, Tsukamoto and colleagues⁶ compared the additional IOP-lowering effects of topical brinzolamide and dorzolamide when given to patients using latanoprost and a beta-blocker. The study found the two CAIs identical in terms of efficacy, although ocular irritation was less common with brinzolamide.

A study by Silver and the Brinzolamide Primary Therapy Study Group⁷ showed that brinzolamide and dorzolamide were equally efficacious when used as primary agents, although ocular irritation, again, was less common with brinzolamide.

In other research, Reis and colleagues⁸ looked at the hypotensive efficacy of timolol 0.5%, brinzolamide 1% and brimonidine 0.2% ophthalmic solution when given to patients using travoprost. Timolol and brinzolamide were most effective in lowering IOP when added to travoprost while brimonidine showed the least
efficacy.

In a more recent, prospective, double-masked study that compared the efficacy of brinzolamide 1% and brimonidine 0.15%, Feldman and colleagues found that brinzolamide proved to be the most effective in lowering IOP when added to travoprost.⁹

This evidence reinforces the earlier findings that CAIs, such as brinzolamide, are more effective secondary agents that should encourage clinicians to combine them with travoprost in patients who don't meet their target IOPs or show progression.

Efficacy minus BAK

Preservative use in glaucoma drugs is becoming an important issue because the disease is chronic, requiring patients to take the medications for long periods of time. And many of them have some form of ocular surface disease.

Research shows BAK and other types of preservatives can cause a myriad of ocular problems from irritation and hyperemia to allergy, inflammation and toxic reactions.^11,12

BAK can destabilize the tear film and may cause filtration surgery failure, cystoid macular edema and even cataract development.¹² Some of these side effects may lead to poor compliance. Patients may either reduce the use of their medications or stop taking them altogether.

Until recently, clinicians have had little choice but to manage the side effects since all prostaglandins contain BAK in different concentrations.

The question for doctors whose patients experience nonspecific side effects has become, "Do we continue to prescribe prosta-
glandins, which happen to be the most effective class of drugs for reducing IOP, or do we switch to a less effective agent that does not contain BAK?"

With all this in mind, Lewis and colleagues¹⁰ conducted a double-masked, randomized clinical trial that compared the safety and efficacy of a newly formulated travoprost 0.004% made without BAK to the currently marketed travoprost made with the preservative in patients with OAG or OHT.

Study results, presented at the 2006 meeting of The Association for Research in Vision and Ophthalmology, showed that travoprost BAK-free lowered IOPs as effectively as the original travoprost and was considered a safe alternative.

The incidence of ocular hyperemia associated with the BAK-free travoprost was 6.4%.

The significance of the Lewis study is that it gives clinicians new insight into drugs being developed without BAK that do not compromise safety and efficacy.

As new formulations made without BAK become available in the future, doctors will have better therapeutic options to offer glaucoma patients.

Looking ahead

Given all the recent data, clinicians now have the information they need to prescribe a regimen for each individual patient, including those who develop side effects, who need adjunctive therapy and may be noncompliant.

*Trademark is the property of its owner.

References

1. Sit AJ, Weinreb RN, Crowston JG, et al. Sustained effect of travoprost on diurnal and nocturnal intraocular pressure. Am J Ophthalmol. 2006;141:1131-1133.

2. Kass MA, Heuer DK. The Ocular Hypertension Treatment Study. Arch Ophthalmol. 2002;120:701-713.

3. Wolters Kluwer Health, Concomitancy Analysis, May 2006.

4. O'Connor DJ, Martone JF, Mead A. Additive intraocular pressure-lowering effect of various medications with latanoprost. Am J Ophthalmol. 2002;133:836-837.

5. 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. 2002;120:701-713.

6. Tsukamoto H, Noma H, Matsuyama S, et al. The efficacy and safety of topical brinzolamide and dorzolamide when added to the combination therapy of latanoprost and a beta-blocker in patients with glaucoma. J Ocul Pharmacol Ther. 2005;21:170-173.

7. Silver LH, and the Brinzolamide Primary Therapy Study Group. Clinical efficacy and safety of brinzolamide (Azopt), a new topical carbonic anhydrase inhibitor for primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol. 1998;126:400-408.

8. Reis R, Queiroz CF, Santos LC, et al. A randomized, investigator-masked, 4-week study comparing timolol maleate 0.5%, brinzolamide 1%, and brimonidine tartrate 0.2% as adjunctive therapies to travoprost 0.004% in adults with primary open-angle glaucoma or ocular hypertension. Clin Ther. 2006;28:552-559.

9. Feldman RM, Prager TC, Baker L, Chuang AZ, Additivity Study Group. Additivity of Brinzolamide vs. Brimonidine 0.15% to Travoprost 0.004%. Presented at The Association for Research in Vision and Ophthalmology; April 30-May 4, 2006; Fort Lauderdale, FL.

10. Lewis RA, Weiss MJ, Landry TA, et al. Travoprost 0.004% With and Without Benzalkonium Chloride: A Comparison of Safety and Efficacy. Presented at The Association for Research in Vision and Ophthalmology; April 30-May 4, 2006; Fort Lauderdale, FL.

11. Noecker RJ, Herrygers LA, Anwaruddin R. Corneal and conjunctival changes caused by commonly used glaucoma medications. Cornea. 2004;23:490-496.

12. Miyake K, Ota I, Ibaraki N, et al. Enhanced disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema by topical timolol and its preservative in early postoperative pseudophakia. Arch Ophthalmol. 2001;119:387-394.