Therapeutic Options for Glaucoma Patients Who Require More Than 1 Drop

Maintaining appropriate IOPs to minimize the risk of glaucoma progression is not a passive enterprise. Deciding when to add a drop and which drop to add is a challenge every treating physician faces. This article is first in a series on adjunctive therapy.

By William C. Stewart, M.D.

Although glaucoma is most likely a multifactorial disease, the one controllable risk factor is elevated IOP. We know from several trials sponsored by the National Eye Institute that lowering mean IOP does decrease the risk of progression of ocular hypertension (OHT) and primary open-angle glaucoma (POAG).^1-3 Thus, pressure reduction is the chief goal of glaucoma therapy.

Many patients, however, require more than one medication to sufficiently lower IOP. Unfortunately, little consensus exists within the ophthalmic community as to what constitutes routine adjunctive therapy for reducing the pressure. In this article, I will review in brief the current adjunctive topical therapeutic options.

Complex Nature of Target Pressures

What is an appropriate target IOP or pressure reduction goal? This is not known exactly. In the Ocular Hypertension Treatment Study (OHTS), the goal was to reduce pressures by at least 20% and to achieve IOPs ≤24 mm Hg², which was effective in preventing many patients from progressing to POAG. Konstas, Stewart and colleagues showed that 40% of OHT patients with IOPs ≥24 mm Hg, 18% of patients with IOPs of 21-23 mm Hg, 11% of patients with IOPs of 18-20 mm Hg, and 3% of patients with IOPs ≤17 mm Hg progressed to glaucoma.⁴ In patients with glaucoma, target pressures should be even lower.

In our recent meta-analysis, my colleagues and I found evidence that pressures ≤18 mm Hg are most likely to prevent progression in patients with POAG.⁵ The Advanced Glaucoma Intervention Study revealed that patients whose mean IOPs were approximately 12 mm Hg without a peak >18 mm Hg had better visual field preservation than those whose IOPs were above the target.⁶ In contrast, results from the Collaborative Initial Glaucoma Treatment Study suggest pressure reductions as high as 40% may be necessary to prevent progression in patients with POAG.⁷

The body of work in glaucoma therapy over the last 10 years has provided valuable information and guidance. Treatment remains an art, however, as clinicians must evaluate each patient as an individual and be prepared to revise target IOPs and therapy over time.

Undisputed First-line Therapy

My colleagues and I recently published survey results revealing physicians' attitudes toward glaucoma medications.⁸ We found the overwhelming majority of U.S. and European ophthalmologists (98% and 71%, respectively) start with a prostaglandin analogue. This preference is not surprising because medicines in this class are the most effective available. Therefore, for adjunctive therapy, clinicians typically choose medicines from another class to add to a prostaglandin.

In terms of efficacy, I generally place glaucoma medications in two classes. Class 1 includes the pros-taglandins and the beta-blockers. These agents are more efficacious than the class 2 medicines in terms of mean pressure reduction. Further, both class 1 medications can be taken once a day, and both will last more than 24 hours. If a patient forgets a dose, neither medicine gives up its efficacy quickly. They also have favorable peak/trough values, maintaining steady pressures, with lower fluctuations between minimum and maximum pressures.⁹

The alpha agonists, the carbonic anhydrase inhibitors (CAIs) and the cholinergic agents are class 2 medicines. Compared with the class 1 drugs, they are less efficacious in terms of mean pressures; there's a greater difference in their peak/trough readings; they must be dosed more often; and the duration of action for any one drop is limited. If a patient forgets a dose, the pressure returns to pretreatment level. These are good medicines, but they don't have all the advantageous pharmacologic features of those in the class 1 group.⁹

Choosing a medicine to achieve and maintain a target pressure, however, is not a once-and-done decision, as various studies have shown. In the OHTS, for example, approximately 40% of patients needed two or more medicines over 5 years. Although exact figures are not known, some researchers suggest that one-third to one-half of all patients with POAG need a second medicine to reach their treatment goals, whether they're aiming for a certain percentage pressure reduction or a pressure ≤18 mm Hg.^10,11 What this means is: As good as our first-line medicines are, many patients will need at least one more drop to control their pressures long-term.

When Monotherapy Is Not Enough

Despite the efficacy of the prostaglandin analogues, some patients will not reach their target IOPs, either from the start of therapy or as their status changes. Our survey found U.S. doctors are more likely to switch agents before adding a drop to a patient's regimen.⁸ The physician must use his or her judgment if a target pressure for an individual patient can best be attained by switching medications or by adding a second medicine.

Another situation that may prompt a change is when a patient is achieving target IOPs but still showing disease progression. In this case, a lower target is necessary, and adding a drop is the next step.

According to our survey, 45% of U.S. ophthalmologists choose a beta-blocker as second-line therapy. The beta-blockers have some very good features as second-line medicines. They can be dosed once a day, and the generic versions are inexpensive. We know they are additive to prostaglandins, probably because they have a separate mechanism of action.¹² In general, beta-blockers reduce daytime IOPs by 18% to 34%.⁹ In addition, a number of 24-hour studies by Konstas, Stewart and associates have shown reductions in pressure with timolol over the 24-hour pressure curve, including throughout the night.⁵ Unlike the prostaglandins, beta-blockers do not cause red eyes or pigment changes in the iris, lashes and periorbital area.¹³

Beta-blockers may cause side effects, however, some severe. Ophthalmologists know it's critical to take thorough histories from patients with glaucoma to avoid beta-blocker use in patients with reactive airway disease, myasthenia gravis, second- or third-degree cardiac block, or in some patients with a history of heart failure.^14,15 They should be used with caution in diabetic patients because they may mask the symptoms of hypoglycemia. Rare side effects may include depression, mood alterations, memory loss, hallucinations, decreased libido and impotence.

According to our survey, U.S. ophthalmologists choose the alpha agonists next after the beta-blockers for second-line therapy, then the CAI dorzolamide (Trusopt, Merck & Co. Inc.). They typically choose the dorzolamide/timolol fixed combination as third line and combine it with a prostaglandin. It should be noted, however, that this was the only fixed combination available in the United States at the time of the survey.

Generally, as single agents, the CAIs and the alpha agonists are believed to be less effective than timolol. Brimonidine (Alphagan, Allergan Inc.), especially when given twice daily, may lose efficacy in the late afternoon.¹⁶ However, a recent meta-analysis by Tauna, Feldman and Stewart (internal data, 2008) showed that both classes are additive to prostaglandins. When added to a prostaglandin, the CAIs have efficacy similar to that of the beta-blockers, while the alpha agonists are less effective.^17,18

Where do fixed combination therapies fit in? In the United States, the fixed combination market is somewhat limited, with only two products commercially available at this time: dorzolamide/timolol (Cosopt, Merck & Co. Inc.) and brimonidine/timolol (Combigan, Allergan Inc.). A phase 3 trial of the dorzolamide/timolol combination¹⁹ compared the fixed combination with concomitant administration of dorzolamide 3 times a day and timolol twice a day. The regimens were deemed equivalent; however, the non-fixed combination yielded a slightly better outcome (approximately 0.7 mm Hg). Likewise, in phase 3 trials of the brimonidine/timolol combination, this combination was comparable statistically to the individual medications dosed together, but it did show slightly less efficacy.²⁰

Nonetheless, the fixed combinations are generally effective, and I believe they do have an advantage, although as yet unproven, of helping with compliance by simplifying a patient's therapy.

Individualizing Therapy for the Long-term

Ongoing research into the etiology, pathophysiology and pathogenesis of glaucoma will bring us new, more targeted therapies for glaucoma suspects and patients in various stages of the disease process, as well as preventative measures for people at risk for glaucoma. As our knowledge base expands, we will have access to more sophisticated interventions that will help us individualize treatments for our patients.

Given the multifactorial nature of glaucoma, however, it's unlikely that science will produce a one-size-fits-all therapy. Thus, an in-depth understanding of the available agents will guide us toward the most efficacious treatments.

Next month in this series on adjunctive therapy, I will discuss the beta-blockers in greater depth, and provide data from recent studies to aid in your selection process.

Dr. Stewart is a clinical professor of ophthalmology at the Carolina Eye Institute at the University of South Carolina School of Medicine. He is the medical director of PRN Pharmaceutical Research Network LLC, in Dallas.