Glaucoma therapy: What if a PGA isn’t enough?

Take-home message: In this article, Dr Tanna discusses treatment options for glaucoma patients who do not show satisfactory response to a PGA while taking into consideration the two key therapeutic choice factors: IOP-lowering efficacy and tolerability.

By Dr Angelo P. Tanna

Prostaglandin analogs (PGAs) are the most commonly utilised agents for the initial medical treatment of glaucoma and ocular hypertension. Recently published results from a large multicentre clinical trial showed treatment with latanoprost substantially reduced the risk of visual field progression in patients with glaucoma compared to a placebo control.¹ The clear demonstration of this agent’s beneficial effect with respect to preservation of visual function will strengthen the dominance of PGAs as initial monotherapy.

Capsule opacification with two different IOLs: 3-year results

Despite the high responder rate and efficacy of PGAs with respect to IOP lowering, a large proportion of patients with ocular hypertension and glaucoma require more than one medication to achieve satisfactory IOP control. Indeed, in the above-mentioned clinical trial, 15% of subjects in the latanoprost treatment group progressed in just 24 months. In the Ocular Hypertension Treatment Study² about 40% of subjects required two or more medications to achieve the target 20% reduction in IOP while in the Collaborative Initial Glaucoma Treatment Study, more than 50% of subjects in the medical therapy arm required two or more medications to achieve the stringent target pressures dictated by the study protocol.³

Further treatment options

So, if a PGA does not lower the IOP to a satisfactory level, what should the clinician do? If there is a very poor response, the options are: use another class of medication, advance to laser trabeculoplasty (LTP), or try another PGA.

There are genetic polymorphisms in the PGF-2 alpha receptor that may render an individual non-responsive to one PGA, but not another. If a PGA works well, but not well enough, the options include LTP or the addition of a second topical agent [alpha 2-adrenergic agonist (AA), beta adrenergic antagonist (BB) or topical carbonic anhydrase inhibitor (TCAI); or a fixed combination of agents.

There is growing evidence that LTP is effective in eyes already on a PGA.⁴ Additionally, LTP, unlike many topical ocular hypotensive medications, has been shown to lower nocturnal IOP.⁵ Laser is a good choice for patients on a PGA in whom you need additional IOP reduction.

With respect to the addition of a second topical ocular hypotensive agent, the factors clinicians must consider include the IOP-lowering efficacy, the dosing frequency, the side effect profile and cost.  Additional considerations include the possibility of a neuroprotective effect, the nocturnal IOP-lowering efficacy, and possibly, the impact on ocular perfusion pressure. 

Next: Dosing frequency and side effects

When we as clinicians consider our clinical experience with respect to the magnitude of IOP reduction achieved with AA, BB, and TCAI, we tend to think of the efficacy of these agents when used as monotherapy. When adding any of these agents to a PGA, however, the magnitude of IOP reduction is much smaller than one might expect. A meta-analysis showed no significant difference in the mean diurnal IOP reduction achieved with these agents when added to a PGA that ranged from about 2.3 to 3.0 mmHg.⁶ In that study, at intermediate and trough time points (a longer time period after administration of the adjunctive agent), AA were significantly less effective than BB or TCAIs.

Dosing frequency and side effects

Beta-blockers certainly have the advantage with a once-daily dosing frequency and with excellent tolerability when patients with contraindications are carefully excluded. The side effect profile with AA and BB included fatigue, weakness and dizziness.  Taste disturbance was more frequent with TCAI. Eye pain and burning were significantly more common with AA compared to BB. Although there was a higher incidence of eye pain and burning with TCAIs compared to BB, this did not reach statistical significance.

Fixed combination therapy

Clinicians commonly use fixed combination agents such as dorzolamide-timolol, brimonidine-timolol, and brimonidine-brinzolamide as second line agents in combination with PGAs. Although these agents are, on average, more effective than the addition of either component alone, clinicians must bear in mind that two agents are being added with each fixed combination agent. With that, the risk of side effects increases. The clinician must be sure each component of the fixed combination agent is of benefit to the patient with respect to IOP reduction. Additionally, BB-containing fixed combination agents could potentially have deleterious effects if the BB component causes nocturnal systemic hypotension. The prostaglandin analog and BB fixed combination agents can be used once daily in the morning in patients in whom the additional IOP-lowering benefit of the BB has been established in comparison with the effect of the PGA alone. These agents should be dosed in the morning, ideally upon waking.

Next: Neuroprotection, ocular perfusion pressure, and noctural IOP

There is substantial laboratory evidence that brimonidine is neuroprotective. The LoGTS clinical trial showed a much higher risk of progression in timolol-treated eyes with “normal-tension glaucoma” than brimonidine-treated eyes.⁷ A large number of subjects, especially in the brimonidine arm (55%), dropped out of the study, rendering the results controversial. It has been suggested that timolol may have had a deleterious effect through its possible adverse effect on ocular perfusion pressure. Through its negative chronotropic cardiac activity, ocular perfusion pressure, particularly during sleep, could fall.

Recent studies have shown that when IOP is measured in the habitual position (sitting during the day and supine during sleep), pressures are highest during the nocturnal period. During the entire circadian period, PGAs lower IOP. Timolol and brimonidine, however, do not lower nocturnal IOP.^8,9 The case is controversial with TCAIs, with one strong study showing nocturnal IOP lowering efficacy9 and another that may have been insufficiently powered, showing no nocturnal IOP reduction.¹⁰ As mentioned, it appears LTP does lower nocturnal IOP.

Conclusion

At some point in the future, when these controversial areas are better resolved, we may have a clearer concept of which medication to choose as adjunctive therapy when a PGA is insufficient.  For now, however, the key factors are IOP-lowering efficacy and tolerability.

References

D.F. Garway-Heath et al., Lancet. 2015;385:1295-1304.

M.A. Kass et al.,Arch. Ophthalmol. 2002;120:701-713.

P.R. Lichter et al., Ophthalmology. 2001;108:1943-1953.

D. Singh D et al., Eye. 2009;23:2194-2199.

A.C. Lee et al.,Ophthalmology. 2007;114:666-670.

A.P. Tanna et al.,Arch. Ophthalmol., 2010;128:825-833.

T. Krupin T et al.,Am. J. Ophthalmol., 2011;151:671-681.

J.H. Liu et al., Ophthalmology. 2010;117:2075-2079.

J.H. Liu et al., Ophthalmology. 2009;116:449-454.

C.B. Nau et al., Invest. Ophthalmol. Vis. Sci. 2013;54:7623-7629.

Dr Angelo P. Tanna

e: atanna@northwestern.edu

Dr Tanna is Glaucoma Service Director and Vice Chairman of the Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States.

This article is based on research supported by an unrestricted grant from Research to Prevent Blindness, New York, United States and the Merlau Glaucoma Research Fund.

Dr Tanna is a consultant for Alcon Laboratories, Inc., Apotex, Inc., Sandoz, Inc., and Watson Laboratories, Inc.