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.

Annual Meeting of the Association for Research in Vision and Ophthalmology

Fort Lauderdale, Florida / April 30-May 5, 2006

The multicentre EXACCT trial examined the impact of dorzolamide/timolol fixed combination (DTFC) in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT) who had responded inadequately or were unresponsive to initial treatment with latanoprost. The open-label trial involved a total of 343 patients enrolled by 33 Canadian physicians. EXACCT investigators reported initial findings from 243 patients, 196 of whom had an inadequate response to treatment with latanoprost and 47 whose condition was unresponsive (defined as an intraocular pressure [IOP] reduction <15%). If IOP remained inadequately controlled after four weeks of treatment with latanoprost monotherapy, DTFC was added to the regimen while latanoprost non-responders were switched to DTFC. The primary end point was the proportion of patients who achieved an IOP reduction of 3 mm Hg or 10% after 12 weeks of DTFC treatment.

Following the initial four-week trial of latanoprost, the IOP for the study population averaged 22 to 23 mm Hg. After six weeks of treatment with DTFC, mean IOP was 15.8 mm Hg among patients who received DTFC as add-on therapy to latanoprost and 17.19 mm Hg among latanoprost non-responders who had switched to DTFC. IOP values remained stable during the additional six weeks of follow-up, as the mean IOP was 15.78 mm Hg (-28.31%, P=0.001) in the DTFC/latanoprost group and 17.29 mm Hg (-24.4%, P=0.001) in the patients who switched from latanoprost to the fixed combination.

Among patients who received DTFC as add-on therapy, 93.1% had at least a 10% further decrease in IOP after the addition of the fixed combination. Among patients who switched from latanoprost to DTFC, 90.6% had at least a 10% reduction in IOP. For the two groups combined, 92.6% of patients achieved clinically significant reductions in IOP after starting DTFC therapy.

“The reduction in IOP after [the addition of the] DTFC was almost double what we had expected. We were really surprised to see how effective the treatment strategy was. The severity of adverse events was generally mild in nature and did not lead to discontinuation by any patients,” researchers reported.

The improvement in IOP observed in latanoprost non-responders suggests that DTFC might be an alternative to latanoprost for that subset of patients, they added. According to EXACCT investigator Dr. Mark Lesk, Université de Montréal, Hôpital Maisonneuve-Rosemont, Quebec, “Results from this study bring a different perspective on the use of DTFC. We now have clinical evidence that DTFC helps patients who are not controlled to target; those who are not responding to latanoprost achieve their target IOP and bring their pressure under control.”

Twenty-four-Hour IOP Effects

A second study reported here during the scientific sessions compared the 24-hour IOP effects of the dorzolamide/timolol fixed combination and latanoprost in patients with POAG or OHT. The study involved 53 patients with a mean baseline 24-hour IOP of 25.2 mm Hg. They were randomized to six months of treatment with the fixed combination or latanoprost. Curve testing by Goldmann applanation tonometry was performed at 6 a.m., 10 a.m., 2 p.m., 6 p.m., 10 p.m. and 2 a.m. at baseline and six months.

At the end of the study, 24-hour IOP averaged 18.1 mm Hg in the fixed-combination group and 18.3 mm Hg in the latanoprost group, reported a multinational group headed by Dr. Vassilios P. Kozobolis, Democritus University, Thrace, Greece. The difference between treatment groups was not significant. Dorzolamide/timolol was associated with significantly greater IOP reduction at 10 a.m. (P=0.01) and 10 p.m. (P<0.0001). Comparison of mean diurnal IOP at two months and six months revealed fewer statistical differences between latanoprost and DTFC at the later time point. Dr. Kozobolis interpreted the observation as a reflection of “the stability of the IOP reduction with DTFC during the active treatment period. This indicates that DTFC may demonstrate less long-term drift than observed previously with timolol alone.”

Dr. Kozobolis and colleagues concluded that dorzolamide/timolol and latanoprost have similar 24-hour IOP-lowering efficacy over six months of treatment, but DTFC might offer improved efficacy at specific time points.

Significance of Ocular Blood Flow

In addition to OHT, impaired ocular blood flow (OBF) has emerged as a potentially major contributor to the pathogenesis of POAG. As such, OBF has attracted clinical researchers’ attention as a potential target for agents used to treat POAG. Investigators at the University of Vienna have evaluated the ocular hemodynamic effects of dorzolamide and timolol in patients with POAG and OHT. Initial data from the study showed that dorzolamide but not timolol increased blood flow in the optic nerve head and choroid (Fuchsjager-Mayrl et al. Br J Ophthalmol 2005;89(10):1293-7).

A new report from the Vienna study focused on the effects of dorzolamide and timolol on underlying vascular dysregulation in patients with POAG or OHT. Dr. Leopold Schmetterer and colleagues reported results at six months.

As previously documented, patients with POAG or OHT, compared to age- and sex-matched controls, exhibit an abnormal association between choroidal blood flow (as measured by fundus pulsation amplitude [FPA]), mean arterial blood pressure (MAP), Bfrim and BFcup (Fuchsjager-Mayrl et al. Invest Ophthalmol Vis Sci 2004;45(3):834-9). Both dorzolamide and timolol significantly altered the association between BFrim, BFcup, FPA and MAP toward normalization (P<0.05). The effect was dependent on the IOP reduction achieved and was not associated with an increase in OBF parameters. The results indicated that dorzolamide and timolol reduced vascular dysregulation in POAG or OHT, Dr. Schmetterer and colleagues concluded. The effect on vascular dysregulation appears unrelated to the treatment’s effects on OBF but is associated with IOP-lowering efficacy.

Investigators in a small multinational study evaluated the association between retinal oxygen saturation and retrobulbar blood flow in patients with POAG. Fourteen patients underwent retinal oximetry imaging, followed immediately by colour Doppler imaging (CDI) assessment of peak systolic velocity, end diastolic velocity and resistive index of the ophthalmic artery and central retinal artery. CDI ophthalmic artery systolic velocity correlated significantly with superior venular optical density ratio (P=0.038) and diastolic velocity had a weak correlation with superior arteriolar optical density ratio (P=0.06).

Higher ophthalmic artery blood flow is associated with higher levels of oxygen saturation in the superior retinal arteries and veins, stated Dr. Alon Harris, Indiana University, Indianapolis, and multicentre international collaborators. The results indicated that retinal oximetry images may reveal oxygen delivery to retinal tissues in proportion to corresponding blood flow.

A study from the Université de Montréal and Hôpital Maisonneuve-Rosemont examined the relationship between changes in the optic nerve head (ONH) and long-term visual field stability in patients with glaucoma. Previous work has shown that glaucoma and OHT patients who have thin corneas experienced greater reductions in ONH cup depth and smaller improvements in neuroretinal rim blood flow during sustained IOP reduction, stated Dr. Lesk and colleagues.

The study involved 26 patients with glaucoma and preperimetric glaucoma. The ONH was assessed by retina tomography and scanning laser Doppler flowmetry before treatment and two to six months after sustained IOP lowering. Peripheral vasospasticity was measured by finger Doppler during cold-water immersion and ultrasound pachymetry was performed. Visual field stability was monitored over 4.2 years by means of modified Hodapp-Anderson-Parrish criteria.

During follow-up, eight patients progressed, 16 remained stable and two were indeterminate. Patients who progressed had greater movement of the base of the ONH cup, indicating a more compliant lamina cribrosa. Additionally, vasospasticity was greater in patients who progressed. The two findings may suggest markers that identify patients at increased risk for disease progression.