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 - 17th Congress of the European Society of Ophthalmology

Amsterdam, The Netherlands / June 13-16, 2009

According to Dr. Antonio Martínez García, Head, Glaucoma Unit, Gallego Institute of Ophthalmology, La Coruña, Spain, “A multitude of different risk factors are important in the pathogenesis of glaucoma. In some patients, intraocular pressure [IOP] may be solely responsible for the disease, but in others, IOP plays only a bit part in the pathogenesis.”

He continued, “There is evidence that lowering IOP will help slow the progression of glaucoma damage, but diurnal IOP fluctuations are as important a risk factor for progression as IOP levels. The Advanced Glaucoma Intervention Study, for example, reported that eyes with a low incidence of IOP fluctuation remain stable, whereas eyes with high IOP fluctuations show deterioration. Fluctuating ocular pressures can result in vasospasm, reperfusion damage and retinal ganglion cell death.”

Perfusion Pressure and Ocular Blood Flow

Noting that individuals with rapidly progressive disease are expected to go blind in a mean of about 14 years, Dr. Martínez observed that among other important vascular risk factors for glaucoma, ocular perfusion pressure is closely linked not only to the prevalence of glaucoma, but also to the progression of glaucomatous damage. Citing an analysis of the probability of developing glaucoma based on diastolic ocular perfusion pressure (DOPP) as opposed to IOP, he said that individuals who present with DOPP >50 mm Hg have a relative risk of essentially 1, whereas those with DOPP <30 mm Hg had a sixfold greater risk. A subsequent study reported that low DOPP is closely linked to the risk of progression. In fact, he said, the risk of progression was significantly higher in patients who have nocturnal dips in diastolic blood pressure than those who do not. Fluctuations of mean ocular perfusion pressure throughout the day are closely connected to visual field damage.

“Many papers have shown that ocular blood flow is reduced in patients with glaucoma who progress despite IOP lowering and some have demonstrated a role for ocular ischemia in the progression of glaucomatous damage,” Dr. Martínez told delegates. “We published a prospective study demonstrating that ocular ischemia is a primary and independent risk factor for glaucomatous progression. At the same level of IOP, the rate of progression was more than 20 times greater in patients with ocular ischemia at baseline compared with patients without ocular ischemia.”

In Dr. Martínez’ view, in order to provide optimal treatment for glaucoma, it is essential to be aware of the different mechanisms involved in the pathogenesis and progression of this multifactorial disease because the vascular factors contributing to glaucoma can now be modified. His Doppler imaging studies demonstrated that the combination of the carbonic anhydrase inhibitor (CAI) dorzolamide and timolol improves ocular hemodynamics and accelerates blood flow in addition to reducing IOP, thereby improving blood perfusion to the retina and optic nerve. The optic neuropathy characteristic of glaucoma is less likely to occur when blood flow is improved, since much of that damage is mediated by reperfusion pressures and ischemia.

Dr. Martínez cited his soon-to-be-published study comparing the efficacy of dorzolamide vs. another CAI, brinzolamide, both in combination with timolol, on retrobulbar blood flow velocity, IOP and visual field progression. He recounted that dorzolamide/timolol significantly reduced the blood flow resistance index in the ophthalmic artery and short posterior ciliary arteries, indicating a lower rate of progression, whereas brinzolamide/timolol had no effect on retrobulbar hemodynamics. IOP reduction was equivalent between the two regimens.

“Kaplan-Meier analysis showed the progression rate to be a statistically significant 46% lower among patients given the dorzolamide/timolol combination at 60 months than those receiving the brinzolamide/timolol combination,” Dr. Martínez reported. He suggested that the difference between the two CAIs in reducing glaucoma progression and damage is mainly due to differences in affinity of the molecules to the 14 different carbonic anhydrase isoforms. Unlike dorzolamide, the affinity of brinzolamide appears to wane after the first year of treatment.

Preservatives

Adverse effects associated with preservatives in topical ocular medications is a growing issue in glaucoma treatment, according to opinion leaders at this meeting. “We must try to use unpreserved medications as much as possible,” stressed Dr. Christophe Baudouin, Quinze-Vingts National Ophthalmology Hospital, Paris, France. “Subclinical inflammation develops in about 80% of patients on long-term topical treatment, especially those on multiple drug regimens, and the preservative is the cause in 90% of cases.”

Most anti-glaucoma medications contain benzalkonium chloride as a preservative, which has consistently demonstrated toxic effects in laboratory, experimental and clinical studies, he reminded delegates. It has been shown to be associated with tear film instability, loss of goblet cells, conjunctival squamous metaplasia and apoptosis, disruption of the corneal epithelium barrier, loss of endothelial cells if introduced into the anterior chamber, and even blood-aqueous barrier disruption in the early phase of pseudophakia. “Moreover, long-term topical drug use can induce ocular surface changes, inflammation and subconjunctival fibrosis, corneal surface impairment and failure of glaucoma surgery, which in most cases are direct toxic effects far from being allergic reactions as has been proposed. Such adverse effects have a negative impact on compliance,” Dr. Baudouin noted. “Care should be taken to avoid preservatives in long-term use when possible and limit their concentration, as their toxicity is dose- and time-dependent.”

Both dorzolamide and the fixed combination of dorzolamide/timolol are presently the only preservative-free glaucoma topical medications in use in Canada.

24-hour IOP Protection

According to Dr. Anastasios Konstas, Chief, Glaucoma Unit, AHEPA University Hospital, Thessaloniki, Greece, glaucoma is a 24-hour disease and fluctuations of IOP over that period are a significant risk factor for progression of disease. He recommended that IOP control be maintained throughout the day and night. Nevertheless, current practice generally involves single pressure readings at each visit which could not possibly determine 24-hour characteristics like diurnal pressure fluctuations and peak pressure, he said.

Dr. Konstas compared the 24-hour efficacy and safety of the dorzolamide/timolol and brimonidine/timolol fixed combinations in patients with primary open-angle glaucoma (POAG) because “a 24-hour study will allow us to elucidate that differences may exist between fixed combinations. IOP pressure readings were carried out every four hours throughout the day and night,” he explained.

Consecutive, newly diagnosed, previously untreated patients with mild to moderate POAG underwent an eight-week run-in period with timolol. Responders who achieved a 20% reduction were then assigned to two months of each fixed combination. Sixty-four glaucoma patients have completed the study so far and four have dropped out. Dr. Konstas reported that the mean morning IOP of patients who completed the protocol was 26.8 mm Hg. With timolol monotherapy, mean diurnal pressure was 20.1 mm Hg. Both fixed combinations significantly reduced pressure compared to timolol alone, with a 9.5% reduction with the brimonidine combination and a 13% reduction with the dorzolamide combination. Peak IOP reductions were 27.7% with timolol and 35% and 38% with the brimonidine and dorzolamide combinations, respectively.

Dr. Konstas also revealed findings on DOPP. “As this study showed, previous 24-hour evidence suggests that dorzolamide was more effective than brimonidine during the night at every time point; consequently, there was a reduction of DOPP during the night [with brimonidine] but there was no difference between the two agents during the day.”

He added, “But the most important result was the significant difference in favour of the dorzolamide/timolol fixed combination at four time points: 06:00, 18,00, 22:00 and 02:00 hours as well as a significant difference for mean 24-hour pressure. Over the 24 hours, the dorzolamide/timolol fixed combination provided significantly lower mean peak (19.6 vs. 20.4 mm Hg, P<0.001) and trough IOP (15.6 vs. 16.1 mm Hg, P=0.03) compared with the brimonidine/timolol fixed combination. These differences may be due to reduced efficacy of brimonidine/timolol in the late afternoon and during the night. The current 24-hour study shows that we get significantly better 24-hour IOP control with the dorzolamide/timolol fixed combination than with the brimonidine/timolol fixed combination in patients with POAG,” he concluded.