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ONTARGET: A Landmark Trial with Immediate Clinical Implications
The Glaucoma Triad: Intraocular Pressure, Blood Flow and Blood Pressure

Comprehensive Care for the Glaucoma Patient

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.

8th Congress of the European Glaucoma Society

Berlin, Germany / June 1-6, 2008

As reported by Dr. Antonio Martinez, Galician Ophthalmology Institute, La Coruña, Spain, research suggests that the carbonic anhydrase inhibitor (CAI) dorzolamide added to timolol not only lowers intraocular pressure (IOP) efficiently, but is also an effective treatment for reducing and/or delaying visual field progression in patients with primary open-angle glaucoma (POAG). This, he explained, is almost certainly due to its effects on improving ocular hemodynamics, accelerated blood flow and superior perfusion in the retina and optic nerve.

Using colour Doppler sonography, Dr. Martinez established a correlation between the rate of visual field progression and blood flow changes in the ophthalmic and short posterior ciliary arteries. He reported the rate of progression to be five times greater in eyes with a colour Doppler-calculated blood flow resistance index (RI) in the pathological range in one vessel and nearly eight times greater with a pathologic RI in both vessels. His group also demonstrated accelerated flow velocity and decreased resistance index in the choroid and central retinal artery, which he characterized as “very probably” related to changes in visual field. Moreover, when the effects of the fixed dorzolamide/timolol combination were compared to latanoprost in POAG patients, although both treatments lowered IOP similarly, only the fixed combination improved ocular blood perfusion in the retrobulbar vessels. Latanoprost had a non-significant effect on retrobulbar hemodynamics, he remarked.

Dr. Martinez recently compared the long-term effect of dorzolamide vs. brinzolamide, each added to timolol, on retrobulbar blood flow velocity, IOP and visual field progression in a 60-month prospective, randomized, blinded study involving 146 POAG patients. He reported, “Whereas dorzolamide added to timolol significantly decreased the resistance index in the ophthalmic artery, brinzolamide did not induce any changes in the retrobulbar hemodynamics when added to timolol. In this study, treatment with the association of dorzolamide 2% and timolol 0.5% reduced the risk of visual field progression by 47% over the brinzolamide fixed combination,” he noted. “Survival rate was 71.4% in the dorzolamide plus timolol group vs. 46.1% of eyes treated with brinzolamide/timolol [P=0.0019].”

There were no statistically significant differences in IOP lowering between the two treatment arms, and brinzolamide/timolol induced no changes in retrobulbar hemodynamics after 60 months. It has therefore been postulated that the marked differences in the effect of the two CAIs on progressive glaucomatous damage are likely due to the vascular activity of dorzolamide, which significantly increased end diastolic velocity in the ophthalmic artery (P<0.0001); the temporal-short posterior ciliary arteries (P<0.0001); and the central retinal artery (P<0.0001). Dorzolamide added to timolol significantly decreased the resistance index in the ophthalmic artery (P<0.0001); temporal-short posterior ciliary arteries (P=0.0037) and central retinal artery (P=0.0028).

The investigators concluded that dorzolamide 2% added to timolol maleate 0.5% twice daily appears to be a more efficacious treatment to reduce and delay visual field progression in patients with POAG than latanoprost or brinzolamide.

Twenty-four-Hour IOP Control

Because glaucoma is a 24-hour disease and IOP fluctuations over 24 hours amplify the risk of progression of glaucoma significantly, Prof. Anastasios Konstas, Associate Professor of Ophthalmology, Aristotle University of Thessaloniki, and Head, Glaucoma Unit, AHEPA University Hospital, Greece, emphasized that IOP must be controlled throughout the day and night. He stated that the dorzolamide/timolol fixed combination provides consistent 24-hour IOP control.

According to Prof. Konstas, “Current glaucoma practice generally involves single readings at each visit, but just by performing single pressure readings, we cannot determine 24-hour pressure characteristics like fluctuating day and night pressure and peak pressure. Around-the-clock IOP evaluation can provide a more complete picture of the real efficacy of all glaucoma treatment options.” He noted, for example, that when all time points in the diurnal curve were evaluated in one of the early studies of 24-hour pressure control, the dorzolamide/timolol fixed combination given twice daily exhibited an approximately 0.6 mm Hg advantage over latanoprost administered as a single evening dose, which was a significant improvement. It is reasonable to assume that better 24-hour IOP control improves glaucoma prognosis in POAG and ocular hypertensive patients, he told delegates.

Prof. Konstas also investigated the 24-hour intraocular pressure-lowering effects of evening latanoprost vs. the fixed combination twice daily. In a study of 39 POAG and 14 ocular hypertension patients after two and six months of treatment, he found that whereas both treatments reduced IOP from baseline at month 2, the fixed combination provided a significant (P=0.002) decrease in mean 24-hour pressure compared to latanoprost, which was driven mainly by significant differences at 10:00 am (P<0.0001) and 10:00 pm (P<0.0001). He reported that at month 6, mean 24-hour pressure was not significantly different between the treatment arms, suggesting that the fixed combination and latanoprost have clinically similar long-term IOP-lowering abilities.

Combination Therapy

The purpose of Prof. Konstas’ most recent study was to evaluate the 24-hour efficacy of three different therapeutic options as second-line adjuvant treatment in a mixed cohort of patients with POAG and exfoliative glaucoma who were insufficiently controlled on latanoprost. The trial did not enrol any non-responders to any glaucoma medication.

Thirty-two patients were randomly assigned to dorzolamide/timolol fixed combination twice daily, latanoprost/timolol fixed combination administered in the evening or latanoprost combined with dorzolamide/timolol for three months, after which all patients were crossed over to the alternative treatments and underwent sitting IOP measurements every four hours for a day. “There were no significant differences in IOP reduction between the two fixed combinations, dorzolamide/timolol [19.9 ± 3.2 mm Hg] and latanoprost/timolol [19.5 ± 3.1 mm Hg], although both provided significantly better 24-hour IOP control than latanoprost monotherapy,” Prof. Konstas reported. “By far, the best 24-hour curve was achieved by the group receiving dorzolamide/timolol plus latanoprost. The addition of dorzolamide/timolol to latanoprost provided the lowest mean 24-hour IOP [16.5 ± 2.8 mm Hg] vs. latanoprost monotherapy [P<0.0001] and the lowest IOP at each individual time point measurement of the day [P<0.0032],” he reported.

Canadian Data

Prof. Konstas cited a Canadian phase IV study headed by Dr. Mark Lesk, Director, Ophthalmology Research, Université de Montréal, Hôpital Maisonneuve-Rosemont, Quebec, which enrolled 350 patients who failed to achieve target IOP after four or more weeks with latanoprost monotherapy, in contrast to his own study which carefully avoided enrolling non-responders. The study objective was to evaluate the efficacy and safety of the dorzolamide/timolol fixed combination alone or with latanoprost in reducing IOP in a real-world setting. Researchers added the fixed combination to latanoprost among 280 patients with POAG or ocular hypertension and 70 other patients were switched from latanoprost to the fixed combination. Outcome measures were absolute and per cent change in IOP from baseline at six and 12 weeks and the proportion of patients achieving a therapeutic response.

After 12 weeks of treatment, 186 of the 280 patients (66.4%) who received dorzolamide/timolol added to latanoprost had achieved therapeutic response >20% IOP reduction from baseline, compared to 37 of the 70 patients (52.9%) who were switched to the fixed combination from latanoprost. Moreover, 116 patients (41.4%) in the add-on group achieved a >30% change from baseline, as did 21 patients (30%) among those in the cohort switched to the fixed combination from monotherapy. There were no serious adverse events reported related to the study compounds. The findings from this phase IV study showed that treatment with dorzolamide/timolol, either alone or with added latanoprost, provided a safe and effective treatment for IOP reduction and attaining therapeutic response.

Prof. Konstas reported that the results of his own recent study demonstrated that the addition of the dorzolamide/timolol fixed combination to latanoprost provided the lowest mean 24-hour IOP (165 ± 2.8 mm Hg) vs. latanoprost monotherapy (P<0.0001) and the lowest IOP at each individual time point (P<0.0032). It showed that dorzolamide/timolol and latanoprost/timolol fixed combinations and the addition of dorzolamide/timolol to latanoprost significantly decreased 24-hour IOP compared to latanoprost, but the latter regimen achieved the greatest 24-hour IOP reduction.

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