CAIs may offer benefit as adjunct to prostaglandin therapy

Emerging evidence is challenging common beliefs when it comes to adding adjunctive therapy to front-line prostaglandins.

ByKuldev Singh, MD, MPH

Kuldev Singh, MD, MPH
Kuldev Singh

Although there is reliable evidence evaluating the efficacy of most glaucoma therapeutic agents when used alone, similar high quality evidence has been lacking when it comes to adjunctive therapy. In particular, selecting an appropriate adjunct to prostaglandin therapy has been a daunting task. There are currently more than 56,000 combinations of glaucoma medications¹ but a relative dearth of head-to-head clinical trials that examine the merits of adding the various agents to prostaglandins.

Beta-blockers have been important therapeutic agents in glaucoma care for almost three decades, but most of the studies that have evaluated the effectiveness of this class of drugs have focused only on the diurnal period. In recent years, nocturnal IOP studies have shown that topical beta-blockers have very little if any effect on IOP during the nocturnal period.^2,3 These findings combined with the lack of evidence supporting significant additional lowering of IOP when beta-blockers are added to prostaglandins have resulted in new questions relating to current treatment paradigms. In particular, there is increasing skepticism that beta-blockers should be the preferred adjunctive agents to prostaglandins in most patients.

Rationale for adjunctive therapy

When advancing glaucoma therapy, there are several limitations that must be considered. Diminishing returns are noted as therapeutic agents are added to each other, partly because of a reduction in baseline IOP. Increasing side effects related to medications and preservatives are also problematic with multiple medications. Both the higher cost and increased complexity of the medical regimen can also impact the success of adjunctive therapy. Finally, tachyphylaxis, or tolerance, is more difficult to assess in patients taking multiple agents.

Increasing side effects related to medications and preservatives are also problematic with multiple medications.
— Kuldev Singh, MD, MPH

Despite these limitations, adjunctive therapy is necessary for many patients. In the Ocular Hypertension Treatment Study, in which the goal of IOP reduction was a modest 20% from baseline, 49% of patients required two or more glaucoma medications to reach this target.⁴ In the Collaborative Initial Glaucoma Treatment Study, where the goal was individualized for each patient and the average IOP reduction was over 35% from baseline, approximately 75% of patients required more than one agent to reach this goal.⁵

Selecting an agent

There is some belief that beta-blockers are the best option for adjunctive therapy. They have been used therapeutically for more than 25 years, are available in once-a-day formulations and are useful for first-line therapy in certain circumstances. There is increasing evidence that these agents, which remain the second most commonly prescribed first-line agents, are not the ideal adjunctive second-line agents when added to prostaglandins. No fixed-combination prostaglandin/beta-blocker agent has been approved by the FDA, presumably because none lowered IOP 2 mm Hg beyond what the prostaglandin lowered alone. One initial explanation for these findings included the possibility that there was a formulation problem. Another explanation is, however, that beta-blockers for some unknown reason, just do not work well when added to prostaglandins.

The data from Liu and colleagues,³ which showed that once-daily timolol was not effective in lowering nocturnal IOP when used alone, suggests that beta-blockers may also not be effective monotherapeutic agents. The study measured patients in a sitting position during the day and in a supine position during the night. Although timolol was effective in lowering IOP during daytime hours, it did not lower IOP at night, and in this study, IOP was highest during the nocturnal period when measured in habitual body positions. These findings are not unexpected, however, if one considers that Brubaker showed approximately two decades ago that timolol does not affect aqueous production at night.⁶

Carbonic anhydrase inhibitors (CAIs)

There is increasing evidence that topical CAIs lower IOP both during the day and night.² Further, a study by O’Connor et al⁷ in 2002 found that CAIs lowered IOP more than beta-blockers or alpha-adrenergic agents in patients inadequately controlled with a prostaglandin. The study was a retrospective chart review of 73 eyes in 73 patients and did not provide the quality of evidence necessary to significantly impact glaucoma care. Nevertheless, the results of this study surprised many and led to further work on the subject.

More recently, Feldman and colleagues presented the results of a prospective trial at the 2006 American Glaucoma Society meeting showing significant reductions in IOP with brinzolamide (Azopt, Alcon Laboratories Inc.) compared with brimonidine tartrate (Alphagan P, Allergan) at two time points.⁸ Patients were started with a 1-month run-in with travoprost, then randomized to brinzolamide or brimonidine, both given twice a day. It is noteworthy that both of these agents are approved only for three-times-daily use by the FDA. At the 3-month final visit, IOP was measured at 8 a.m., noon and 4 p.m. The mean diurnal IOP was also calculated for the two groups.

The IOP-lowering effect was greater in the brinzolamide group at 8 a.m. and 4 p.m. compared with brimonidine (8 a.m., -3.0 mm Hg with brinzolamide vs. -1.7 mm Hg with brimonidine; P = .004; 4 p.m., -2.8 mm Hg with brinzolamide vs. -1.8 mm Hg with brimonidine; P = .032). IOP lowering was about equal at noon (-2.8 mm Hg vs. -2.9 mm Hg with brinzolamide and brimonidine respectively; P = .753). The mean diurnal IOP lowering was -2.8 mm Hg in the brinzolamide group compared with -2.2 mm Hg in the brimonidine group (P = .066). This study has been accepted for publication by Ophthalmology.

It is interesting that IOP reductions at all time points were greater than 2.5 mm Hg with the addition of brinzolamide, which is greater than the 2.0 mm Hg threshold that some have considered to be clinically meaningful. Other reports supporting the additive effect of brinzolamide to prostaglandins are encouraging. Such studies have only provided diurnal data, but most would agree that topical CAIs are more effective than beta-blockers in nocturnal IOP lowering.²

Conclusions

One has to acknowledge that there may be significant inter patient differences with regard to response to medical therapy ...
— Kuldev Singh, MD, MPH

The growing evidence for the use of CAI’s as adjuncts to prostaglandin analogs may well result in a paradigm shift with these drugs challenging beta-blockers for the second position in the algorithm of medical glaucoma therapy. One has to acknowledge that there may be significant inter patient differences with regard to response to medical therapy and that there is no substitute for an individual therapeutic trial. There is likely no single ideal first or second line drug for every patient.

References:

Fechtner RD, Realini T. Fixed combinations of topical glaucoma medications. Curr Opin Ophthalmol. 2004;15:132-135.
Orzalesi N, Rossetti L, Invernizzi T, et al. Effect of timolol, latanoprost, and dorzolamide on circadian IOP in glaucoma or ocular hypertension. Invest Ophthalmol Vis Sci. 2000;41:2566-2573.
Liu JH, Kripke DF, Weinreb RN. Comparison of the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure. Am J Ophthalmol. 2004;138:389-395.
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.
Lichter PR, Musch DC, Gillespie BW, et al. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology. 2001;108:1943-1953.
Topper JE, Brubaker RF. Effects of timolol, epinephrine, and acetazolamide on aqueous flow during sleep. Invest Ophthalmol Vis Sci. 1985;26:1315-1319.
O’Connor DJ, Martone JF, Mead A. Additive intraocular pressure lowering effect of various medications with latanoprost. Am J Ophthalmol. 2002;133:836-837.
Feldman RM, Prager TC, Baker LA, et al. Additivity of brinzolamide vs. brimonidine 0.15% to travoprost 0.004%. Presented at: Annual meeting of the America Glaucoma Society. March 2-5, 2006; Charleston, SC.