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Tolerability and effectiveness of preservative-free dorzolamide–timolol (preservative-free COSOPT) in patients with open-angle glaucoma or ocular hypertension
Abstract and Figures
To assess the effect of preservative-free dorzolamide-timolol on nonvisual symptoms and intraocular pressure (IOP) in newly diagnosed and untreated patients with open-angle glaucoma or ocular hypertension.
This was a prospective, 8-week, open-label, Canadian multicenter study. All patients were treated with preservative-free dorzolamide-timolol formulation. The primary outcome was the change in the nonvisual symptom score of the Glaucoma Symptom Scale (GSS-SYMP-6) from baseline to 8 weeks. Secondary effectiveness outcome measures were absolute and percent changes in IOP from baseline to 4 and 8 weeks.
One hundred and seventy-eight patients were enrolled. Mean (SD) age was 65.6 (12.1) years and 90 (50.6%) were females. There were 92 patients diagnosed with open-angle glaucoma, 62 with ocular hypertension, and 23 with both diseases (diagnosis was missing for one patient). The mean (SD) GSS-SYMP-6 score increased from 73.6 (21.8) at baseline to 76.1 (20.7) at 8 weeks (P = 0.097). Mean (SD) IOP significantly decreased by 11.7 (5.1) mmHg at 4 weeks (P < 0.001) and by 11.5 (5.3) mmHg at 8 weeks (P < 0.001), representing reductions of -38.5% (P < 0.001) and -38.0% (P < 0.001), respectively.
Preservative-free dorzolamide-timolol does not increase eye discomfort while significantly reducing IOP in patients with open-angle glaucoma or ocular-hypertension.
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... CI = Confidence Interval; SD = standard deviation. . The superscript letter a indicates a statistically significant difference compared to baseline; the superscript letter b indicates a clinically significant difference compared to baseline (difference in GSS score greater than 7, which is the amount of change used as surrogate for clinically significant improvement) [23] . Data presented as means and 95% confidence interval. ...
... Figures in parentheses indicate percentages. The superscript letter a indicates a statistically significant difference compared to baseline; the superscript b indicates a clinically significant difference compared to baseline (difference in GSS score greater than 7, which is the amount of change used as surrogate for clinically significant improvement) [23]. SYMP = symptomatic; FUNC = functional. ...
... CI = Confidence interval; SD = standard deviation; TDFC UD = preservative-free unit dose timolol/dorzolamide fixed combination; GSS = Glaucoma Symptom Scale; SYMP = symptomatic; FUNC = functional. The superscript letter a indicates a statistically significant difference compared to baseline; the superscript b indicates a clinically significant difference compared to baseline (difference in GSS score greater than 7, which is the amount of change used as surrogate for clinically significant improvement) [23]. ...
Purpose: To assess a change in visual-related quality of life (QoL) in glaucoma patients after switching from preservative-containing medical therapy to preservative-free unit dose timolol/dorzolamide fixed combination (TDFC UD). Methods: Prospective, noninterventional, multicenter 8-week study. Primary outcome was a change in visual symptoms at week 8, as assessed by the Glaucoma Symptom Scale (GSS). Results: 80 patients completed the study. There was a clinically significant increase in the scores of all GSS-related categories at week 8 when compared to baseline (GSS symptom week 8: +21.15 ± 37.9%, GSS function week 8: +10.3 ± 31.6%, both p < 0.001 vs. baseline). Comparison between patients taking only TDFC UD and patients taking TDFC UD plus concomitant medications did not detect differences in any GSS category (p > 0.50 in all comparisons). Conclusions: Switching to TDFC UD significantly improved the self-reported QoL of glaucoma patients. This can be seen even in patients who are taking concomitant ocular treatments. © 2013 S. Karger AG, Basel.
... Often, patients with glaucoma require lifetime topical therapy and OSD has been reported in up to 59% of patients [4,5]. Preservatives in topical antiglaucoma drops disrupt the ocular surface by a variety of mechanisms resulting in decreased tear film stability and increased evaporation [6,7]. The side effects of preserved eye drop administration include ocular hyperemia, burning, stinging, and itching that are exacerbated by an unstable tear film [7]. ...
... Preservatives disrupt the ocular surface by numerous mechanisms including cellular apoptosis and neurotoxicity causing OSD and reducing patient tolerability [6,7,19,20]. Furthermore, preservatives may cause some local corneal anesthesia masking the symptoms of OSD that may increase severity over time [17,21,22]. ...
Introduction:
To compare the tolerability and efficacy of a preservative-containing latanoprost (PCL) to a preservative-free formulation of latanoprost (PFL) in patients with open-angle glaucoma or ocular hypertension.
Methods:
A pooled analysis was performed of data from five published studies. The primary outcome was tolerability as evaluated by the severity of hyperemia. The secondary objectives were patient tolerance based on a composite ocular surface disease (OSD) score arising from ocular signs and symptoms, patient and investigator satisfaction, and a comparison of IOP-lowering efficacy.
Results:
There were three randomized controlled trials and two observational studies included in the analysis. Conjunctival hyperemia improved significantly in 25.6% (388) of patients switched to the PFL group versus 11.7% (117) of patients switched to the PCL group (p < 0.001). PFL was two times superior to PCL in reducing ocular hyperemia (odds ratio = 1.96; p < 0.001). The mean OSD composite score decreased by 32.2% in patients switched to the PFL group and 14.1% in the PCL group (p < 0.001). At 3 months, the mean IOP was similar between groups (p = 0.312).
Conclusion:
This post hoc pooled analysis confirmed the findings of the individual studies that PFL is as efficacious at reducing IOP as PCL but better tolerated. After switching to PFL, there was twice the improvement in the OSD composite score. PFL was twice as effective at reducing ocular hyperemia and other ocular signs. These findings suggest that PFL has features that may improve patient compliance, thereby potentially improving the IOP-lowering efficacy on a long-term basis.
... In contrast, most available data about the tolerability and safety of PF DTFC derives from open-label studies [30,100,101]. To date, head-to-head evidence for the tolerability profile of the unit-dose PF DTFC formulation versus preserved DTFC has been limited. ...
... The tolerability and efficacy of PF-DTFC has also been investigated by Hutnik et al [101] in an 8-week, open label, multicentre study that included 187 treatment-naïve patients with open-angle glaucoma, or ocular hypertension. The tolerability of PF DTFC was assessed using the nonvisual symptom score of the Glaucoma Symptom Scale (GSS-SYMP-6), which evaluates the following: a) burning, smarting and stinging, b) tearing, c) dryness, d) itching, e) soreness and tiredness, and f) feeling of something in the eye. ...
Introduction: Preservative-free (PF) medications represent a valuable treatment strategy in the lifelong management of glaucoma. By removing preservative toxicity, PF formulations provide tangible clinical benefits to glaucoma patients worldwide. They improve tolerability and adherence, leading to a positive impact in long-term intraocular pressure (IOP) control.
Areas covered: A critical review of the subject is provided, including selected evidence on the safety and tolerability of currently available topical PF formulations. Cumulative evidence confirms that topical PF medications are at least equally efficacious to their preserved equivalents. There is convincing short-term evidence for superior tolerability and safety of PF formulations compared to preserved medications. The long-term benefits and success of PF therapy requires further elucidation.
Expert opinion: Successful stepwise administration of medical therapy for glaucoma remains elusive. There is a greater risk for ocular toxicity and therapy failure with preserved topical glaucoma therapy. Currently available and emerging PF therapy options potentially optimize lifelong stepwise glaucoma therapy and may enhance outcome. To avert complications from preservatives leading to poor adherence, ideally, future antiglaucoma therapy should become 100% PF. There are still key aspects of PF therapy that warrant further investigation.
... Указанный эффект можно объяснить отсутствием консерванта Бензалкония Хлорида (БХ) и его токсического действия на ткани переднего отрезка глаза. Так, например, согласно данным экспериментального исследования, выполненного Kwon и соавт., повреждение эндотелия роговицы вызвано именно БХ, а не составляющими компонентами ФК Д/Т [21]. Применение ФК Д/Т, не содержащей консервантов, заметно повышает качество жизни больных глаукомой [22]. ...
Topical and systemic carbonic anhydrase inhibitors (CAIs) are widely used in the treatment of glaucoma for reducing intraocular pressure. This part of the review describes the characteristics of systemic CAIs, their side effects and the ways to overcome them, as well as contraindications. The use of CAIs during pregnancy is considered. Particular attention is paid to the antioxidant activity of CAIs and the promising development of hybrid forms based on the existing CAIs as a part of a multipurpose glaucoma treatment strategy.
... Preservative-free Cosopt® has been developed as an alternative for those patients allergic or sensitive to the commonly used preservative benzalkonium chloride (BAK). One study has shown that this formulation lowers IOP by 38% from baseline at 8 weeks without significantly increasing ocular discomfort (as measured by the Glaucoma Symptom Scale [GSS-SYMP-6]).21 A second report demonstrated that both the preservative-free and preservative-containing formulations of dorzolamide–timolol fixed combination were equivalent in efficacy in IOP changes at peak and trough. ...
Glaucoma is a collection of diseases characterized by multifactorial progressive changes leading to visual field loss and optic neuropathy most frequently due to elevated intraocular pressure (IOP). The goal of treatment is the lowering of the IOP to prevent additional optic nerve damage. Treatment usually begins with topical pharmacological agents as monotherapy, progresses to combination therapy with agents from up to 4 different classes of IOP-lowering medications, and then proceeds to laser or incisional surgical modalities for refractory cases. The fixed combination therapy with the carbonic anhydrase inhibitor dorzolamide hydrochloride 2% and the beta blocker timolol maleate 0.5% is now available in a generic formulation for the treatment of patients who have not responded sufficiently to monotherapy with beta adrenergic blockers. In pre- and postmarketing clinical studies, the fixed combination dorzolamide-timolol has been shown to be safe and efficacious, and well tolerated by patients. The fixed combination dorzolamide-timolol is convenient for patients, reduces their dosing regimen with the goal of increasing their compliance, reduces the effects of "washout" when instilling multiple drops, and reduces the preservative burden by reducing the number of drops administered per day.
The key clinical attributes of preserved dorzolamide/timolol fixed combination (DTFC) and the emerging potential of preservative-free (PF) DTFC are reviewed with published evidence and clinical experience. The indications and role of DTFC in current glaucoma management are critically discussed. Preserved DTFC became the first intraocular pressure (IOP)-lowering fixed combination (FC) approved by the US Food and Drug Administration (FDA) and remains one of most commonly used medications worldwide. The pharmacological properties of DTFC reflect those of its two time-tested constituents, i.e., the carbonic anhydrase inhibitor dorzolamide and the non-selective beta-blocker timolol. In regulatory studies DTFC lowers IOP on average by 9 mmHg (32.7%) at peak and by 7.7 mmHg (27%) at trough. In trials DTFC shows equivalence to unfixed concomitant therapy, but in real-life practice it may prove superior owing to enhanced convenience, elimination of the washout effect from the second drop, improved tolerability, and better adherence. PF DTFC became the first PF FC approved, first in unit- dose pipettes, and more recently in a multidose format. Cumulative evidence has confirmed that PF DTFC is at least equivalent in efficacy to preserved DTFC and provides a tangible clinical benefit to patients with glaucoma suffering from ocular surface disease by improving toler- ability and adherence. Finally, we identify areas that warrant further investigation with preserved and PF DTFC.
To evaluate the safety and efficacy in intraocular pressure (IOP) reduction of increasing Cosopt dosage from twice to three times a day.
The study included patients with primary open-angle glaucoma or ocular hypertension. After a washout period, IOP was measured at baseline, after 4 weeks of treatment with Cosopt twice a day, and after another 4 weeks of treatment with Cosopt three times a day. Blood pressure, heart rate, and oxygen saturation levels were also recorded.
Twenty-nine eyes of 29 patients were included. Increasing Cosopt dosage resulted in a statistically significant (P < 0.001) additional reduction in IOP of 2.2 ± 1.58 mmHg (10.69% ± 7.49% of the baseline IOP values). There were no local or systemic adverse effects.
Treatment with Cosopt three times a day was more effective in reducing IOP than twice a day, with no effect on safety.
The purpose of this study is to compare the safety and intraocular pressure (IOP)-lowering efficacy of travoprost/timolol in a benzalkonium chloride (BAK)-free fixed combination preserved with polyquaternium-1 (TRA/TIM BAK-free), with travoprost/timolol-fixed combination preserved with BAK (TRA/TIM), in patients with open-angle glaucoma or ocular hypertension.
In this prospective randomized controlled trial, subjects with IOP of at least 22 mm Hg in one or both eyes at 0900 h, and IOP of at least 21 mm Hg in one or both eyes at 1100 h and 1600 h at two eligibility visits were randomly assigned to receive either TRA/TIM BAK-free (n=195) or TRA/TIM (n=193), dosed once daily in the morning (0900 h) for 6 weeks. IOP was assessed at 0900 h, 1100 h, and 1600 h at each scheduled visit (baseline, 2 and 6 weeks after randomization).
Mean IOP reduction across all visits and time points was 8.0 mm Hg in the TRA/TIM BAK-free group and 8.4 mm Hg in the TRA/TIM group (P=0.0943). The difference in mean IOP between groups ranged from 0.2 to 0.7 mm Hg across visits and time points, with a mean pooled difference of 0.4 mm Hg (95% CI: -0.1 to 0.8), demonstrating equivalence of the two formulations. The most common drug-related adverse event was hyperemia of the eye (ocular hyperemia and conjunctival hyperemia combined), occurring in 11.8% of the TRA/TIM BAK-free group and 13.0% of the TRA/TIM group.
Travoprost/timolol BAK-free demonstrated equivalence to travoprost/timolol preserved with BAK in efficacy. No clinically relevant differences in the safety profiles of travoprost/timolol BAK-free and travoprost/timolol preserved with BAK were identified.
This paper reviews the burden and economic consequences of glaucoma upon healthcare systems and patients, especially elderly patients. An extensive review of the literature was conducted, primarily using MEDLINE, but also by examining selected article reference lists, relevant websites and the proceedings of specialised conferences. All relevant articles and documents were analysed.
Glaucoma is characterised by destruction of the optic nerve. It is most often a continuous, chronic eye disease and the most frequent diagnosis is primary open angle glaucoma (POAG). POAG is mostly associated with intraocular hypertension which can be delayed by medication, surgery or laser therapy.
The prevalence rate of glaucoma is about 1% in the population >50 years of age. The rate increases with age and is higher in Black and Hispanic populations. Glaucoma affects more than 67 million people worldwide. Cost-of-illness studies have shown the importance of this disease, on which more than £300 million was spent in the UK in 2002. Most of the costs (45%) were associated with direct medical costs, but direct nonmedical costs (20%) and indirect costs (35%) were also not negligible. Recent economic studies have shown a dramatic increase in the number of patients with glaucoma receiving treatment but a reduction in use of surgical procedures to treat the condition, especially as first-line therapy. The greater part of medical expenditure is now on medication, with new, more potent, better tolerated, but more costly drugs replacing older and less expensive medications. Treatment costs are directly related to the severity of disease and the number of different treatments used; they are also negatively correlated with treatment efficacy in reducing intraocular pressure. However, long-term economic benefits that may be associated with use of more potent new drugs (by delaying institutionalisation) have never been documented. Glaucoma screening has also been found not to be cost effective, although these results should be reconsidered in the light of new data.
Topically administered dorzolamide 2%/timolol 0.5% (dorzolamide/timolol ophthalmic solution; Cosopt®) is a fixed combination of two ocular hypotensive drugs (the carbonic anhydrase inhibitor dorzolamide and the β-adrenoceptor antagonist timolol) that have an additive effect on lowering intraocular pressure (IOP) when administered together. This product is indicated for the treatment of elevated IOP in patients with open-angle glaucoma or ocular hypertension (OH) who are insufficiently responsive to topical β-adrenoceptor antagonist monotherapy. As such, it can be considered for use in individuals who, as a consequence of failing to achieve target IOP with β-adrenoceptor antagonist monotherapy, require the addition or substitution of another class of topical antiglaucoma medication. Clinical trials have demonstrated that dorzolamide/timolol (1 drop per eye twice daily) is an effective and generally well tolerated fixed combination for lowering IOP in patients with open angle glaucoma or OH, including individuals uncontrolled on β-adrenoceptor antagonist monotherapy. Compared with concomitant therapy with the individual components, the primary advantage of fixed combination dorzolamide/timolol is convenience.
Pharmacological Properties
Dorzolamide/timolol comprises dorzolamide, a highly selective inhibitor of carbonic anhydrase isoenzyme II, and timolol, a nonselective β-adrenergic antagonist. Both components decrease elevated IOP by inhibiting aqueous humour production; they each achieve this by a different mechanism of action and have an additive effect when administered together. Dorzolamide/timolol also improves some markers of ocular blood flow (an effect likely attributable to the dorzolamide component).
After topical administration, both components enter the systemic circulation. Systemically absorbed dorzolamide undergoes slow hepatic metabolism; both the single N-desethyl metabolite and the parent drug accumulate in erythrocytes, although the resulting inhibition of carbonic anhydrase isoenzyme I and II (by N-desethyldorzolamide and dorzolamide, respectively) is not sufficient to disrupt normal physiological function. Dorzolamide and its metabolite are eliminated primarily by the kidneys.
Timolol has a high systemic bioavailability via the ocular route and may cause typical systemic β-adrenoceptor antagonist effects. The mean peak plasma timolol concentration was 0.46 and 0.35 μg/L after the morning and afternoon dose, respectively, in six subjects who received topical timolol 0.5% twice daily.
Therapeutic Efficacy
Randomised clinical trials of 1.5–6 months’ duration have compared the IOP-lowering efficacy of dorzolamide 2%/timolol 0.5% 1 drop per eye twice daily with that of other topically administered ophthalmic therapies in patients with glaucoma (almost exclusively primary open angle glaucoma) or OH enrolled at one or more centres. All of these studies were preceded by a run-in period on timolol 0.5% twice daily or an ocular hypotensive medication washout period.
When evaluated in large, single- or double-masked, parallel-group comparisons, the IOP-lowering effect of dorzolamide/timolol was superior to that of monotherapy with each of the individual components (administered at their recommended dosing frequencies), equivalent to that of dorzolamide 2% two or three times daily plus timolol 0.5% twice daily given concomitantly, equivalent to that of monotherapy with latanoprost 0.005% once daily, and generally equivalent to that of brimonidine 0.2% twice daily plus timolol 0.5% twice daily given concomitantly. Whereas reductions in IOP significantly favoured monotherapy with bimatoprost 0.03% once daily (in patients inadequately controlled on β-adrenoceptor antagonist monotherapy) and fixed combination therapy with latanoprost 0.005%/timolol 0.5% once daily in large, double-masked, parallel-group comparisons, the IOP-lowering effect of dorzolamide/timolol was generally similar to that of these agents in small, single- or double-masked, cross-over comparisons. The IOP-lowering effect of dorzolamide/timolol was less than that of latanoprost 0.005% once daily plus brimonidine 0.2% twice daily given concomitantly in small, double-masked, parallel-group, comparisons.
Variable results were seen when dorzolamide/timolol was compared with monotherapy with travoprost 0.004% once daily or with fixed combination therapy with brimonidine 0.2%/timolol 0.5% (brimonidine/timolol) twice daily in small, single-blind, cross-over or parallel-group studies. Dorzolamide/timolol was either more or less effective than travoprost 0.004%, but similarly or less effective than brimonidine/timolol, in lowering IOP.
Reductions in IOP seen with the fixed combination were maintained for up to 1 year in a non-blind extension of one study.
Tolerability
Topically administered dorzolamide/timolol is generally well tolerated and has an adverse event profile reflecting that of the individual components. No additional tolerability issues specific to the fixed combination have been identified. The most common adverse events in patients with glaucoma or OH who received dorzolamide/timolol in large, randomised clinical trials were ocular and local reactions, including burning and/or stinging of the eyes (mostly of mild or moderate intensity and transient; likely due to the dorzolamide component) and dysgeusia.
In large comparative trials, the incidences of drug-related ocular burning and/ or stinging and dysgeusia with dorzolamide/timolol were mostly higher than those with latanoprost 0.005% and consistently higher than those with bimatoprost 0.03% or brimonidine 0.2% plus timolol 0.5% given concomitantly. Similarly, ocular burning, ocular stinging and unusual taste were reported more often by dorzolamide/timolol recipients than brimonidine/timolol recipients, based on preliminary reports of small comparative studies. More dorzolamide/timolol than latanoprost/timolol recipients experienced transient eye pain, although conjunctival hyperaemia was less common with dorzolamide/timolol than with bimatoprost 0.03%. The tolerability profile of dorzolamide/timolol was similar to that of brimonidine 0.2% plus latanoprost 0.005% given concomitantly in small comparative studies.
Systemic adverse events such as headache, nausea and urolithiasis (likely due to the dorzolamide component) and bradycardia/sinus bradycardia, cardiac failure, heart block, hypotension, and respiratory symptoms/failure (likely due to the timolol component) have been reported, albeit infrequently, with dorzolamide/ timolol during clinical trials or post-marketing experience.
Purpose: Enhance recognition by the external disease specialist of the conjunctival changes associated with glaucoma therapy and the reported association with glaucoma filtration surgery. Methods: Literature search with emphasis on the cellular and subcellular changes induced by antiglaucoma medications, the definition and diagnosis of drug-induced cicatricial conjunctivitis (DICC), and the implications for future glaucoma therapy or surgery. Results: Significant conjunctival and subconjunctival changes occur associated with the use of antiglaucoma medications that affect the success of glaucoma filtration surgery. The extreme form of change is the DICC, which is clinically and pathologically identical to ocular cicatricial pemphigoid. The autoantigen in the basement membrane probably differs in these two disease processes. Conclusions: There is a movement toward an earlier approach to glaucoma filtration surgery, in large part based on the literature reviewed here. The external disease specialist needs to be cognizant of these conjunctival changes to best consult on patients receiving antiglaucoma medications.
Objective
To compare the dorzolamide-timolol fixed combination twice daily to its components, timolol maleate and dorzolamide hydrochloride, given in their usual monotherapy regimens in patients whose intraocular pressure (IOP) was not controlled on timolol twice daily alone.
Purpose:
To compare the intraocular pressure (IOP) lowering effect of concomitant administration of 0.5% timolol and 2% dorzolamide and a fixed combination dorzolamide-timolol (Cosopt) To critically evaluate discrepancies between phase 3 clinical trials and prior replacement studies.
Design:
A prospective, randomized, controlled clinical trial and a prospective, non-randomized comparative replacement trial.
Participants/interventions:
In a national multicentre trial, 131 patients were randomized to dorzolamide-timolol or a topical carbonic anhydrase inhibitor (CAI) and non-selective beta-blocker following a 1-month run-in using the separate components. Peak (maximal drug effect) and trough (minimal drug effect) IOPs were measured at baseline and 1 month after treatment. The replacement therapy study enrolled 404 consecutive glaucoma patients using a non-selective beta-blocker and dorzolamide and changed treatment to the fixed combination. Mean IOPs at the same time of day were compared before and 1 month after changeover.
Main outcome measure:
The main outcome measure was IOP, comparing baseline and on-therapy measurements at study conclusion between the two arms of the randomized trial and before and after switching therapy in the replacement trial.
Results:
In the randomized trial, the mean baseline peak and trough IOPs were 18.4 and 21.0 mmHg in the group randomized to combination therapy and 17.6 and 19.8 mmHg in the dual drug group. After randomization and treatment for four weeks, the peak and trough IOPs were 17.6 and 19.5 mmHg in the combination group and 17.3 and 19.0 mmHg in the concomitant group. The percentage change in IOP was -3.2% at peak and -6.5% at trough for the combination and -0.3 and -3.2% for the concomitant group. These differences did not show statistical significance. In the replacement study, mean baseline IOP was 19.4 mmHg. Four weeks after initiation of treatment on the fixed combination, a significant additional IOP reduction of 1.7 mmHg (-8.8%) was observed (P < 0.0001). Overall, 81% of eyes exhibited equal or lower IOP on the fixed combination compared with concomitant therapy.
Conclusion:
The results of the randomized trial indicate that the fixed combination dorzolamide-timolol (Cosopt) was as effective as its components in controlling IOP, confirming results seen in phase 3 clinical trials. However, in the replacement study, utilization of the combination drug offered a statistically significant additional IOP reduction (P < 0.0001), which duplicates results from previous replacement studies.
This study assessed the long-term effects of dorzolamide 2% BID added to timolol maleate 0.5% BID on intraocular pressure (IOP), retrobulbar blood flow, and the progression of visual field damage in patients with primary open-angle glaucoma.
This was a prospective, 4-year, open-label intervention study. All consecutive patients with a clinical diagnosis of open-angle glaucoma in both eyes (mean defect greater than -6 dB) who presented for a regular check-up between January and July 2001 at the Instituto Galego de Oftalmoloxía were screened for study eligibility. All participants had been treated with timolol 0.5% BID in both eyes for at least 6 months before the screening visit. Dorzolamide 2% BID was added to timolol 0.5% BID in the eye with the larger visual field defect (study eye), whereas timolol 0.5% BID was continued in the eye with the smaller visual field defect (control eye). Variables evaluated at baseline and every 6 months for 48 months included retrobulbar hemodynamic parameters (using color Doppler imaging), progression of visual field damage, and IOP. Progression of visual field damage was defined according to modified Anderson criteria. Visual field progression-free survival rates for the study and control eyes were plotted using Kaplan-Meier analysis and were compared using a log-rank test.
Forty-five patients met the inclusion criteria, of whom 5 were lost to follow-up. Thus, 80 eyes of 40 patients were included in the analysis. Patients' mean (SD) age was 68.0 (7.1) years; all patients were white and 21 (52.5%) were male. Mean baseline IOP was 19.18 (1.34) and 18.23 (1.64) mm Hg in the study and control eyes, respectively (P=0.006). The combination of dorzolamide and timolol was associated with significant increases from baseline in enddiastolic velocity in the ophthalmic and short posterior ciliary arteries (P<0.001) and significant decreases in the resistivity index in both arteries (P<0.001). Twenty-three of the 80 eyes (28.8%) had progression of visual field damage (7 study eyes and 16 control eyes). On Kaplan-Meier survival analysis, the risk of progression was significantly lower in the eye treated with dorzolamide and timolol compared with the eye treated with timolol alone (hazard ratio=0.41; 95% CI, 0.17 to 0.94; P=0.035). Mean changes in IOP from baseline to month 48 were -1.10 mm Hg in the dorzolamide and timolol group (95% CI, -1.73 to -0.51; P<0.001) and 1.27 mm Hg in the control group (95% CI, -2.74 to 1.72; P=NS).
In this 4-year, open-label study in patients with primary open-angle glaucoma, dorzolamide 2% BID added to timolol 0.5% BID was associated with a significant reduction in IOP and significant increases in retrobulbar hemodynamic parameters in both the ophthalmic and short posterior ciliary arteries. Dorzolamide added to timolol may be effective in preventing progression of glaucomatous visual field damage.
The only proven strategy to prevent primary open-angle glaucoma (POAG) is the use of ocular hypotensive therapy among people diagnosed with ocular hypertension. In this review, various modifiable lifestyle factors, such as exercise, diet, and cigarette smoking, that may influence intraocular pressure and that have been studied in relation to the risk of developing POAG are discussed. Epidemiologic studies on lifestyle factors are few, and the current evidence suggests that there are no environmental factors that are clearly associated with POAG; however, a few factors merit further study. This review also outlines future directions for research into the primary prevention of POAG.