Better alternatives to standalone prostaglandin analog therapy

Physicians have the option of various adjunctive therapy when prostaglandin analog therapy alone is not sufficiently potent to lower IOP, i.e., they can add one agent, a fixed-combination therapy, or perform selective laser trabeculoplasty (SLT).

“We need to add a second-line agent when the target IOP is not achieved or the target has to be reset when pressure is not lowered enough and progression of glaucoma at the current IOP is noted,” said Sanjay G. Asrani, MD.

But there are a number of considerations surrounding addition of a second-line agent: patient compliance, side effects, allergic reactions, contraindications, and call backs.

Dr. Asrani sets the target IOP range according to the guidelines of the Canadian Society.

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Specifically, for patients with advanced glaucoma, the target is in the low teens with the least fluctuation tolerance, i.e., less than 3 mm Hg; for moderate glaucoma, the target range is the mid-teens with acceptable fluctuations of less than 4 mm Hg; and for mild glaucoma, the target range is the high teens with acceptable fluctuations of less than 5 mm Hg, he outlined.

Dr. Asrani, professor of ophthalmology; Head, Glaucoma OCT Reading Center; and director, Duke Eye Center of Cary, Duke University, Durham, NC, enumerated some important considerations.

He noted that roughly a third of patients who are newly treated require adjunctive therapy within one year. When the adjunctive therapy is combined with a prostaglandin, the patients are typically instilling drops twice daily, once in the morning and again in the evening.

When a single drug agent is added, the mean IOP-lowering effect is similar, but the side effects and nocturnal IOP-lowering efficacy differ.

Side effects

For example, when a topical carbonic anhydrase inhibitor (CAI) is added to a prostaglandin, the benefits include a good nocturnal IOP-lowering effect, no impact on systemic blood pressure (BP), and a low allergy rate; however, there can be corneal endothelial toxicity.

The CAIs are better at lowering the IOP when they are used with prostaglandins rather than beta-blockers.

When considering use of a beta-blocker in addition to a prostaglandin, the important factors are ruling out asthma, emphysema, and bundle branch block; the moderate IOP-lowering efficacy, the possibility for tachyphylaxis, and the limitation of once-daily use in the morning.

When combining alpha agonists with prostaglandins, the red flags are the 28% allergy rate (mostly follicular conjunctivitis), contraindicated use in infants and young children and elderly adults, and the effect on the systemic BP (decreased ocular perfusion pressure), according to Dr. Asrani.

Low diastolic ocular perfusion pressure (DOPP), which is defined as the difference between the diastolic BP and the IOP, he emphasized, is the major risk factor for the genesis and progression of glaucoma.

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“The DOPP must be kept at about 55 mm Hg. Below that level, it becomes a major risk factor. The prostaglandins and CAIs are the only ones that increase the perfusion pressure,” he said.

With beta-blockers, the DOPP remains unchanged because the drugs do not work as effectively at night; with alpha agonists the DOPP decreases significantly.

Another option when a prostaglandin is not as effective as desired is adding a fixed-combination therapy. Dr. Asrani noted that a fixed-combination drug is often used as the initial adjunctive therapy.

Prescribing trend

There is a prescribing trend toward earlier more aggressive therapy for better IOP control. A fixed-combination drug may improve treatment adherence.

He commented that the reasons for the trend toward adding a fixed-combination drug to a prostaglandin are the greater IOP lowering effect, fewer copays and visits to measure the IOP if there are no allergic reactions, more consistent IOP lowering during the day, and the complementary action of inflow inhibition to the prostaglandin’s outflow enhancement.

In addition, with a fixed-combination therapy there is less exposure to preservatives, reduced washout effects, fewer total drug instillations, and the dosing is still twice daily as with single agents added to a prostaglandin.

A third option to add to prostaglandin therapy is SLT, which eliminates a number of potential problems by reducing compliance issues, side effects, allergies, and drug costs in young patients who may not understand the need for treatment compliance and in elderly patients who may have impaired memory, arthritis, and a large medication burden.

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SLT may be applied in patients with narrow angles with elevated IOP with compression gonioscopy after laser iridotomy. Finally, the procedure can reduce IOP fluctuations, which is important because the risk of glaucoma progression in five years is six times greater in eyes in which the IOP fluctuates 5.5 mm Hg compared with 3 mm Hg, Dr. Asrani explained.

SLT also can be beneficial in patients with low and normal tension glaucoma, in whom lowering the IOP and controlling fluctuations are vital.

“I typically perform SLT as the second-line therapy if the patient is already taking a prostaglandin,” he said, adding that topical CAIs can be considered as a second-line therapy in these patients because the CAIs do not affect the BP while they increase the DOPP.

“The considerations for the choice of a second-line agent are side effects, compliance, cost, effect on IOP fluctuations, effects on DOPP, and quality of life,” Dr. Asrani said. “Rho kinase inhibitors will soon be available for adjunctive therapy and they show great promise. A recently completed study of Rhopressa [Aerie Pharmaceuticals] showed stable efficacy at three months and the drug was not inferior to timolol instilled twice daily.”