SWITCHING VERSUS ADDING
There are more than 40 available therapeutic agents, but only five drug classes. The latter include beta-blockers, prostaglandins, CAIs, adrenergic agonists, and miotics, and these are the focus of this article. Because the selection of secondary therapy is dependent upon primary therapy, this piece builds on the premise that the majority of patients are initially treated with either a beta-blocker or a prostaglandin.
When confronted with a patient whose IOP is inadequately controlled on one agent, the first decision ophthalmologists face is whether to add an agent from a different drug class or to exchange the current agent for one from a different class. To choose, first consider whether you initially achieved the IOP reduction you expected from the primary agent. If not, then perhaps the patient does not respond well to this drug class. Keep in mind that, if beta-blockers lower IOP by an average of 25%, then half of the patients will have a better-than-average response, and half will have a worse-than-average response. If monotherapy did not meet your expectations, I suggest trying monotherapy with an agent from a different drug class. There is probably no value in selecting a different agent within the same class, at least with beta-blockers; head-to-head trials comparing prostaglandins have not yet clarified whether switching between prostaglandins offers a meaningful chance of increased IOP control.
By contrast, if monotherapy initially achieved the IOP reduction you expected but does not bring the patient to the target IOP, then the best option is to add a second drug. Since adding drugs within a class will further reduce the IOP little or not at all (and in the case of prostaglandins, dual therapy can raise IOP1), adjunctive therapy should be from a different class than the primary therapy. Select secondary therapy in the same manner that you select primary therapy—based on safety, efficacy, convenience, tolerability, and cost.
MAKING A SELECTION
Safety
The only absolute in medicine is to do no harm. Consider your patient's complete medical history and eliminate the medication choices that are incompatible with his health status. Take into account ocular and systemic comorbidities and be sure to consider the potential for adverse drug reactions with systemic medications. For instance, brimonidine is contraindicated in patients on systemic monoamine oxidase inhibitors.
Tolerability
Perhaps somewhat artificially, I have separated tolerability from safety. I discuss these topics separately, because their relative impact on my practice patterns is quite different. For instance, airway compromise with a beta-blocker is a safety issue, but eyelash growth with a prostaglandin is a tolerability issue. In the former instance, immediate drug cessation is required; in the latter, a patient may elect—after an informed discussion—to continue the drug and accept the consequences.
Tolerability issues are worth discussing, because the threshold for tolerability varies from patient to patient. Matching drugs to patients requires knowing the tolerability profile of the drug and the tolerance of the patient. For instance, I recently vacillated between a beta-blocker and a prostaglandin for one of my patients. Noting that she had undergone cosmetic blepharoplasty recently, I underscored the primarily systemic side effects of beta-blockers versus the primarily ocular (and typically cosmetic) side effects of prostaglandins. Not surprisingly, she opted for the beta-blocker. Knowing your patients can help you handle these issues.
Efficacy
Of the drugs that would be safe for your patient, select the one most likely to lower his IOP to the target range. The most potent drug is not necessarily the best choice for every patient. If a modest reduction in IOP of 2 to 3 mm Hg will meet your goal, a drug that lowers IOP by 8 mm Hg may not be as appropriate a choice as a cheaper or better-tolerated agent that will meet your patient's needs.
It is important to remember that adjuvant and monotherapy efficacy often differ greatly. For instance, beta-blockers lower IOP by 5 to 6 mm Hg on average when used as monotherapy.2 When added to a prostaglandin, the supplementary IOP reduction is on the order of 1 mm Hg.3,4 As prostaglandins have become common first-line agents (the FDA granted latanoprost first-line status in December 2002), the issue of additive efficacy has become more problematic.
Timolol remains the FDA's gold standard glaucoma medication, so most new medications are studied in combination with this drug. We have very little data on the additive efficacy of various medications to prostaglandins. The only head-to-head comparison of various agents added to a prostaglandin was a retrospective analysis.5 In this study, patients with inadequate pressure control on latanoprost alone underwent adjunctive treatment with a topical CAI, brimonidine, or a beta-blocker. After 1 year, the topical CAI lowered IOP 20% when added to latanoprost, significantly better than beta-blockers (12%) or brimonidine (9%) (Figure 1).
Figure 1. The topical CAI class lowers IOP effectively when used as an adjunct to a prostaglandin.
Convenience
In the majority of cases, glaucoma remains an asymptomatic disease until we treat it. Even if patients never experience a single adverse physical effect of therapy, the need to instill eye drops daily—often repeatedly—takes a toll on their quality of life. It is the ophthalmologist's job to ensure that therapeutic choices impact patients' quality of life as little as possible, and that means striving for convenience as well as safety.
Convenience comprises several issues. All things being equal, select the medication that requires the fewest number of doses per day. This choice will improve both patients' quality of life and their compliance as well. Also, consider that some bottles are harder to squeeze than others, which may be an issue in patients with arthritic hands. Similarly, some patients may not be able to administer eye drops at all due to problems as diverse as tremors and dementia. It is worth noting that argon laser trabeculoplasty is a valid adjunctive therapy in these situations.
Cost
Unfortunately, none of the commonly used glaucoma medications is inexpensive. Depending on the agent, daily glaucoma therapy can cost from $133 to $470 annually.6 The inability to afford medication is a certain cause of noncompliance. For patients with no prescription drug insurance benefits, the cost of medication must be considered during the drug selection process. Because agents within classes tend to be priced similarly due to marketplace competition, a patient's financial constraints often dictate which classes of medications may be prescribed.
Cost can be a factor for patients with a prescription plan as well. Many of these plans operate on a tiered system: First-tier drugs, typically generics, require a small patient copayment or none at all; second-tier or “preferred” drugs are available for a small-to-moderate copayment through bulk-purchase negotiations between the drug plan and the drug manufacturers; and third-tier drugs are least preferred by the drug plan and carry the highest copayment. Often agents within a class will be scattered throughout the tiered system so that, once you select a drug class, your choice of a specific agent will determine your patient's copayment. Encouraging your patients to bring in their drug plan's formulary list will enable you to select the least expensive alternative within your preferred class of agents.
FINAL ANALYSIS
When selecting adjunctive therapy for glaucoma patients, no single agent or class of agents offers the best of all worlds: safety, efficacy, convenience, tolerability, and affordability. The clinical challenge for ophthalmologists is to determine on a patient-by-patient basis which of these parameters are the most and least important. Based on a knowledge of the various agents and classes available, you will subsequently be able to pick the best drug for each patient. Carefully considering each of these issues will lead you to the most appropriate drug for your patients most of the time—but not always.
Unfortunately, the algorithm approach to glaucoma management does not work, because there are so many exceptions to every rule. Occasionally drugs fail to perform as expected, and sometimes uncommon side effects do occur. The selection process outlined here is only a prediction based upon population studies of safety, efficacy and tolerability. The process of drug selection is incomplete until you have performed a therapeutic trial in your patient to ensure that both of you are content with the selection.
Tony Realini, MD, is Director of the Glaucoma Service at the University of Arkansas for Medical Sciences. Dr. Realini may be reached at (501) 686-5150; realinianthonyd@uams.edu.
1. Herndon LW, Asrani SG, Williams GH, et al. Paradoxical intraocular pressure elevation after combined therapy with latanoprost and bimatoprost. Arch Ophthalmol. 2002;120:847-849.
2. Hommer A, Nowak A, Huber-Spitzy V. Multicenter double-blind study with 0.25% timolol in Gelrite (TG) once daily vs. 0.25% timolol solution (TS) twice daily. Ophthalmologe. 1995;92:546-549.
3. Bucci MG. Intraocular pressure-lowering effects of latanoprost monotherapy versus latanoprost or pilocarpine in combination with timolol: a randomized, observer-masked multicenter study in patients with open angle glaucoma. Italian Latanoprost Study Group. J Glaucoma. 1999;8:24-30.
4. Higginbotham EJ, Feldman R, Stiles M, Dubiner H. Latanoprost and timolol combination therapy versus monotherapy: one-year randomized trial. Arch Ophthalmol. 2002;120:915-922.
5. O'Connor DJ, Martone JF, Mead A. Additive intraocular pressure lowering effect of various medications with latanoprost. Am J Ophthalmol. 2002;133:836-837.
6. Vold ST, Riggs WL, Jackimiec J. Cost analysis of glaucoma medications: a three-year review. J Glaucoma. 2002;11:354-358.
