Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - World Glaucoma Congress 2009

Boston, Massachusetts / July 8-11, 2009

In some patients, glaucoma progresses slowly and is unlikely to lead to blindness over a patient’s lifetime; in others, it is rapidly progressive and can be expected to lead to visual disability within the foreseeable future. “Glaucoma is also multifactorial,” Dr. Antonio Martínez Garcia, Head, Glaucoma Unit, Galician Ophthalmology Institute, La Coruña, Spain, reminded delegates, “and different risk factors are involved in the pathogenesis and progression of the disease as well.” For example, elevated intraocular pressure (IOP) may be the dominant etiological factor in one patient’s glaucoma, while in others, IOP may play a marginal role, with other factors including ocular ischemia being the larger contributor.

Given that one meta-analysis found that approximately 40% of patients with glaucoma will progress over a period of five years, the question Dr. Martínez and colleagues asked is: Do treatments variably reduce the risk of progression and if so, what might explain this difference? To answer this, investigators randomized 40 treatment-naïve patients (80 eyes) with asymmetric glaucoma to either timolol 0.5% or timolol 0.5% plus the carbonic anhydrase inhibitor (CAI) dorzolamide 2%. Both colour Doppler imaging and visual field were evaluated in a masked fashion.

At 48 months’ follow-up, 29% of the cohort had evidence of visual field progression for a global survival rate of 71%. When investigators compared survival rates according to treatment, however, they found a significant difference in survival rates at 83% for the dorzolamide/timolol arm—in other words, only 17% of the eyes in the combination arm progressed over the 48-month follow-up—vs. a 60% survival rate for the timolol monotherapy arm, where 40% of the eyes progressed over the same treatment interval (P=0.0392). “This suggests that the addition of dorzolamide to timolol reduced the relative risk of progression by 58% compared with timolol alone, so dorzolamide seems to be effective in reducing the risk of progression,” Dr. Martínez observed.

In a second study, the same investigators randomized 146 patients with primary open-angle glaucoma (POAG) to either dorzolamide 2% added to timolol 0.5% or to another CAI, brinzolamide 1%, also added to timolol. Two different methods were used to evaluate visual field progression while ocular blood flow was assessed with colour Doppler imaging.

At 60 months’ follow-up, 60% of the overall cohort had no evidence of visual field progression. Intriguingly, however, there was again a statistical difference in survival curves between the two treatment arms: 73% of patients receiving dorzolamide/timolol had no signs of visual field progression at five years compared with only 50% of those receiving the brinzolamide/timolol combination (P=0.0008), representing a 52% lower relative risk of progression in favour of the dorzolamide/timolol combination.

Asked how results could be so discrepant when dorzolamide and brinzolamide are both CAIs, Dr. Martínez explained that there are some 15 different carbonic anhydrase isoforms in the body, all controlling different functions. For example, carbonic anhydrase isoform II is responsible for the IOP-lowering effects of the CAIs, whereas carbonic anhydrase isoform IV regulates vascular effects. It has been demonstrated that dorzolamide’s affinity for vascular-regulating carbonic anhydrase isoform IV is six times higher than that of brinzolamide. “This suggests that dorzolamide not only significantly reduces IOP when added to timolol, it also increases ocular blood flow, [thereby reducing] the risk of progression in glaucoma patents,” Dr. Martínez concluded.

Ocular Surface Disease

Another factor that is gaining attention in the current management of glaucoma is ocular surface disease (OSD). As speakers here indicated, OSD involves not just the cornea and the conjunctiva but the inside of the eyelids as well as the eyelid margin. It is also highly prevalent; it contributes to non-compliance—and subsequent disease progression—and is largely iatrogenic. Itchy, dry, scratchy, uncomfortable red eyes are the primary symptoms of OSD and up to 60% of glaucoma patients experience mild to moderate symptoms; 30% report symptoms are severe (Leung et al. J Glaucoma 2008;17(5):350-5).

Benzalkonium chloride (BAK), the most commonly used preservative in topical anti-glaucoma medications, is used to prevent microbial contamination. BAK has, however, detergent-like activity and it serves to destabilize the lipid layer of the eye. Among its demonstrable cytotoxic effects, BAK shrinks conjunctival cells after only brief contact and promotes subclinical inflammation; the greater the number and the longer the duration the medications are used, the greater the appearance of inflammatory infiltrates in conjunctival biopsies.

Subclinical inflammation may also lead to surgical failure when attempts are made to correct glaucoma surgically, as noted by Dr. Christophe Baudouin, Professor of Ophthalmology, Quinze-Vingts National Ophthalmology Hospital, Paris, France. The most obvious manifestations to BAK are allergic reactions seen after initial exposure. Not uncommonly, patients can develop a toxic reaction to preservative-containing products many months and even years after initiating treatment so symptoms may occur relatively distant to initial use, Dr. Baudouin noted. Laboratory studies have also confirmed that it is largely BAK and not the active ingredient in the medication that is associated with dose-dependent toxicity.

In a comparison of preservative-containing vs. preservative-free beta blocking eye drops, Dr. Baudouin and colleagues found that all palpebral, conjunctival and corneal symptoms were significantly more frequent (P<0.0001) in the group that used a preservative-containing eye drop and that there was a significant decrease (P<0.0001) in all ocular signs and symptoms in patients who reduced their use of preservative-containing drops or who were switched to a preservative-free drop (Jaenen et al. Eur J Ophthalmol 2007;17(3):341-9). Dr. Baudouin also emphasized that claims suggesting preservatives facilitate penetration of the drug into the eye are not supported by efficacy data, as there is no indication from clinical studies to date that preservative-free topical medications are any less effective at lowering IOP than those which contain a preservative.

Prospective Multicentre Study

In Canada, there is now a preservative-free form of dorzolamide/timolol and both the tolerability and efficacy of the new formulation was recently evaluated in a prospective multicentre study. A total of 170 patients with OAG or ocular hypertension completed the study. At baseline, mean IOP was 29.6 mm Hg while the mean Glaucoma Symptom Scale (GSS)-SYMP-6 was 73.5. The primary objective of the study was to evaluate changes in the GSS-SYMP-6 in newly-diagnosed patients treated with preservative-free dorzolamide/timolol for eight weeks.

At study end point, the mean GSS-SYMP-6 score at 75.9 had not appreciably changed from baseline, suggesting that the preservative-free treatment was not associated with a worsening of OSD symptoms, as pointed out by lead author Dr. Cindy Hutnik, Associate Professor of Ophthalmology and Pathology, University of Western Ontario, London. Eight-five per cent or more of both physicians and patients also indicated they were either satisfied or very satisfied with the treatment, she added.

As a secondary end point, treatment also led to a highly significant 38% decrease in IOP to a mean of 18.1 mm Hg (P<0.001) at week 8. Only two serious adverse events were attributed to study medication, a signal that treatment with the new formulation was both safe and well tolerated. Commenting further on the study’s implications, Dr. Hutnik felt that OSD contributes to poor outcomes in glaucoma patients. “We have more and more evidence, including from my basic science lab, that preservatives can be harmful to the surface of the eye and that perhaps one of the reasons patients do not like using their eye drops is that they just do not feel good,” she told delegates.

While preservative-free topical medications may not be required by all patients with either glaucoma or ocular hypertension, “If there is a medication that brings your pressure down very effectively, reduces your risk of converting to glaucoma by 50% and does not cause any side effects, it is something I would certainly consider,” Dr. Hutnik suggested.