[Combination therapy in the medical treatment of glaucoma]. / Stellenwert der Kombinationstherapie in der medikamentösen Glaukombehandlung.

A combination of antiglaucoma medications is indicated if monotherapy is not sufficient to achieve the predefined target pressure and/or in case of a progression of glaucomatous damage or conversion from ocular hypertension to glaucomatous optic neuropathy. Most recently many fixed combinations with two active compounds have become available for the medical treatment of glaucoma. Compared to non-fixed combinations, these drugs offer a much easier use for the patients. Fixed combinations have to be applied less frequently which may improve adherence. Furthermore, they most likely contain a lower amount of toxic preservatives compared to non-fixed combinations. And finally, fixed combinations may eliminate the risk of a "washout" of the first medication by using the second product of a non-fixed combination too soon after the first drop has been installed. This review aims to examine the most important aspects of IOP-lowering fixed and non-fixed combinations in glaucoma management with a clear focus on the results obtained with fixed combinations. In Germany, fixed combinations with the compositions dorzolamide/timolol (FCDT), brinzolamide/timolol (FCBRINT), latanoprost/timolol (FCLT), travoprost/timolol (FCTT), bimatoprost/timolol (FCBIMT), brimonidine/timolol (FCBT), pilocarpine/timolol (FCPT) and metipranolol/timolol (FCMT) are approved for the medical management of glaucoma and ocular hypertension. The results of clinical studies comparing fixed combinations with their active ingredients and with the corresponding non-fixed combinations will be discussed. Furthermore - if available - the results of direct comparisons of the efficacy and safety of different IOP-lowering fixed combinations are summarised.

A review of preserved and preservative-free prostaglandin analogues for the treatment of open-angle glaucoma and ocular hypertension.

Glaucoma affects an increasing number of people worldwide and is the second leading cause of blindness. The aim of antiglaucoma therapy is to maintain a patient's visual function and quality of life. Prostaglandin analogues are first-line topical antiglaucoma therapy. They are effective at lowering intraocular pressure (IOP) and are generally well tolerated, with fewer systemic adverse events compared with the other classes. However, the use of prostaglandin analogues can be associated with ocular adverse effects, such as stinging/burning sensation, dry eyes, iris and periocular hyperpigmentation, and eye lash growth, which can affect patient compliance. Preservatives used in antiglaucoma preparations can have dose-dependent toxic effects, which contribute to adverse effects. The development of preservative-free preparations may reduce such adverse effects and therefore improve patient compliance. Tafluprost is a prostaglandin analogue in a preservative-free formulation that was recently approved for the reduction of elevated IOP in open-angle glaucoma and ocular hypertension.

A European perspective on costs and cost effectiveness of ophthalmic combinations in the treatment of open-angle glaucoma.

PURPOSE: Efficacy, safety, and cost implications are important considerations when choosing an ophthalmic treatment. Fixed-combination glaucoma medications containing brimonidine 0.2% and timolol 0.5%, or dorzolamide 2% and timolol 0.5%, were compared with brimonidine 0.2% and dorzolamide 2% that were used as adjunctive therapy to timolol 0.5%. METHODS: A literature review was conducted to determine the outcome parameters of intraocular pressure reduction and tolerability after 3 months of use of brimonidine or dorzolamide, each together with timolol as a fixed-combination or in concomitant therapy. Modelled cost-minimization and cost-effectiveness analyses were performed to investigate the economic consequences of ophthalmic therapy with brimonidine, dorzolamide, and timolol from a societal perspective. RESULTS: The literature review found that brimonidine and dorzolamide used as fixed combinations with timolol as well as in adjunctive therapy to timolol were equally effective and safe. Furthermore, in the European countries studied, the fixed combination of brimonidine/timolol represented a less costly option when compared to the fixed combination of dorzolamide/timolol evaluated over both a 3-month and a 12-month horizon. CONCLUSIONS: Brimonidine used as a fixed-combination therapy with timolol provided better cost value than dorzolamide/timolol in all the countries studied. For most countries, the fixed combination of brimonidine and timolol also provided better cost value than adjunctive therapy with brimonidine, which was more cost effective than adjunctive therapy with dorzolamide.

A cost-effectiveness analysis of fixed-combination therapies in patients with open-angle glaucoma: a European perspective.

OBJECTIVE: To compare the efficacy and cost implications of the use of the intraocular pressure-lowering prostaglandin analogues bimatoprost, travoprost, and latanoprost as fixed-combination therapies with timolol, a beta-adrenergic receptor antagonist. METHODS: A decision analytic cost-effectiveness model was constructed. Since no head-to-head studies comparing the three treatment options exist, the analysis was based on an indirect comparison. Hence, the model was based on efficacy data from five randomized, controlled, clinical studies. The studies were comparable with respect to study design, time horizon, patient population and type of end point presented. The measure of effectiveness was the percentage reduction of the intraocular pressure level from baseline. The cost evaluated was the cost of medication and clinical visits to the ophthalmologist. All drug costs were market prices inclusive of value-added tax, and visit costs were priced using official physician fees. Cost-effectiveness analyses were carried out in five European countries: Spain, Italy, United Kingdom, Norway and Sweden. The time horizon for the analyses was 3 months. RESULTS: The analysis showed that fixed-combination bimatoprost/timolol was more effective and less costly than fixed-combination travoprost/timolol and fixed-combination latanoprost/timolol in three out of the five countries analyzed. In two countries, bimatoprost/timolol was less costly than latanoprost/timolol, and cost the same as travoprost/timolol. CONCLUSIONS: This cost-effectiveness analysis showed that the fixed combination of bimatoprost 0.03%/timolol 0.5% administered once daily was a cost-effective treatment option for patients with primary open-angle glaucoma. This study was limited by available clinical data: without a head-to-head trial, indirect comparisons were necessary. In the United Kingdom, Sweden, Norway, Italy, and Spain, from a health service viewpoint, bimatoprost/timolol was a slightly more effective as well as less costly treatment strategy when compared to both travoprost/timolol and latanoprost/timolol.

A double-masked, randomized, parallel comparison of a fixed combination of bimatoprost 0.03%/timolol 0.5% with non-fixed combination use in patients with glaucoma or ocular hypertension.

PURPOSE: To compare the safety and efficacy of the fixed combination product with non-fixed combination use of the same active ingredients in separate bottles (bimatoprost once-daily [qd], and timolol twice-daily [bid]). A bimatoprost 0.03% qd treatment arm was used for validation of the study. METHOD: This was a double-masked, randomized, parallel study in 445 patients with open-angle glaucoma or ocular hypertension. They were randomized in a ratio of 2:2:1 to receive bilateral treatment with the fixed combination, non-fixed combination treatment, or bimatoprost alone. RESULTS: Comparing the fixed combination and non-fixed combination, the non-inferiority margin of 1.5 mm Hg was met at all three timepoints for mean intraocular pressure (IOP), and a margin of 1.0 mm Hg for mean diurnal IOP. The incidence of conjunctival hyperemia was statistically significantly lower (p=0.014) in the fixed combination group (8.5%, 15/176) compared with the bimatoprost group (18.9%, 17/90) and the non-fixed combination group (12.5%, 22/176). CONCLUSIONS: The fixed combination of bimatoprost 0.03%/timolol 0.5% administered once daily was comparable in ocular hypotensive efficacy to the non-fixed combination. The lower propensity of the fixed combination to elicit conjunctival hyperemia suggests a superior comparative benefit/risk assessment of the fixed combination in the treatment of elevated IOP.

Direct costs of glaucoma and severity of the disease: a multinational long term study of resource utilisation in Europe.

BACKGROUND: Resource utilisation and direct costs associated with glaucoma progression in Europe are unknown. As population progressively ages, the economic impact of the disease will increase. METHODS: From a total of 1655 consecutive cases, the records of 194 patients were selected and stratified by disease severity. Record selection was based on diagnoses of primary open angle glaucoma, glaucoma suspect, ocular hypertension, or normal tension glaucoma; 5 years minimum follow up were required. Glaucoma severity was assessed using a six stage glaucoma staging system based on static threshold visual field parameters. Resource utilisation data were abstracted from the charts and unit costs were applied to estimate direct costs to the payer. Resource utilisation and estimated direct cost of treatment, per person year, were calculated. RESULTS: A statistically significant increasing linear trend (p = 0.018) in direct cost as disease severity worsened was demonstrated. The direct cost of treatment increased by an estimated 86 for each incremental step ranging from 455 euro per person year for stage 0 to 969 euro per person year for stage 4 disease. Medication costs ranged from 42% to 56% of total direct cost for all stages of disease. CONCLUSIONS: These results demonstrate for the first time in Europe that resource utilisation and direct medical costs of glaucoma management increase with worsening disease severity. Based on these findings, managing glaucoma and effectively delaying disease progression would be expected to significantly reduce the economic burden of this disease. These data are relevant to general practitioners and healthcare administrators who have a direct influence on the distribution of resources.

The cost-effectiveness of bimatoprost 0.03% in the treatment of glaucoma in adult patients--a European perspective.

Glaucoma is a condition affecting one or both eyes with raised intraocular pressure (IOP). IOP should be reduced to prevent progression of visual field loss. This study investigates the cost-effectiveness of bimatoprost compared with latanoprost as first-line monotherapies in the treatment of glaucoma in Austria, Finland and France. On the basis of a single multicentre, randomised, investigator-masked controlled trial, a 6- and 12-month cost-effectiveness model was designed following the treatment recommendations from the European Glaucoma Society. Treatment changes due to insufficient IOP reduction and adverse events were included. The cost-effectiveness analysis showed that the need for adjunctive therapy was the major cost driver. On the basis of evidence from the randomised, investigator-masked clinical trial (RCT), the cost-effectiveness analysis found that bimatoprost was a cheaper and a more effective treatment strategy compared with latanoprost. This was true for all three countries and all IOP targets between 13 and 20 mmHg. The cost-effectiveness result may be generalised to a European setting and perspective.

Unoprostone as adjunctive therapy to timolol: a double masked randomised study versus brimonidine and dorzolamide.

AIMS: To compare the safety and efficacy of unoprostone, brimonidine, and dorzolamide as adjunctive therapy to timolol in patients with primary open angle glaucoma or ocular hypertension. METHODS: This was a randomised, double masked, parallel group, multicentre (14) study. After using timolol maleate 0.5% monotherapy twice a day for 2 weeks, patients (n = 146) with an early morning intraocular pressure (IOP) between 22 and 28 mm Hg, inclusively, received unoprostone isopropyl 0.15% (n = 50), brimonidine tartrate 0.2% (n = 48), or dorzolamide hydrochloride 2.0% (n = 48) twice daily as adjunctive therapy to timolol maleate 0.5% for another 12 weeks. Safety was based on comprehensive ophthalmic examinations, adverse events, and vital signs. Efficacy was based on mean change from baseline in the 8 hour diurnal IOP at week 12. Baseline was defined as values obtained after 2 weeks of timolol monotherapy. RESULTS: Each drug was safe and well tolerated. Burning/stinging was the most common treatment emergent adverse event. No clinically relevant changes from baseline were observed for any ophthalmic examination or vital signs. At week 12, each adjunctive therapy produced statistically significant (p<0.001) reductions from timolol treated baseline in the mean 8 hour diurnal IOP (-2.7 mm Hg, unoprostone; -2.8 mm Hg, brimonidine; -3.1 mm Hg, dorzolamide). The extent of IOP reduction did not differ significantly between unoprostone and either brimonidine (p = 0.154) or dorzolamide (p = 0.101). CONCLUSION: Unoprostone was safe and well tolerated and provided a clinically and statistically significant additional reduction in IOP when added to stable monotherapy with timolol. Furthermore, unoprostone was not significantly different from brimonidine and dorzolamide as adjunctive therapy to timolol.

Scanning laser polarimetry (SLP) for optic nerve head drusen.

Optic nerve head drusen (ONHD) are either clinically invisible or clearly protruding from the disc, in the later case leading to the condition of an irregular, indistinct disc margin or a swollen disc on biomicroscopy. They also may cause visual field defects, even with slow progression. Scanning laser polarimetry (SLP) has been proposed as a rapid, objective and reproducible technology for retinal nerve fiber layer (RNFL) assessment and clinical studies have demonstrated that SLP can help to distinguish between normal and glaucomatous eyes, identify glaucoma suspects and correlates well with visual field defects. The purpose of this study was to evaluate the potential applicability of SLP in 20 consecutive patients with optic nerve head drusen (18 bilateral) that were clinically visible (22 eyes) and invisible (16 eyes). RNFL thickness was studied in patients with and without visual field defects. Patients with visual field defects and ONHD were significantly older and had a small, but significant reduction of visual acuity. Some global SLP parameters (average thickness, ellipse average) were significantly different between subjects with normal and abnormal visual fields. The comparison of the groups with visible and invisible drusen showed that there was no difference in demographic or perimetric data. RNFL thickness measurements were also very similar in both groups. Clinical visibility of drusen was not correlated with RNFL thinning as measured with the GDxTM. SLP assessment, however, was well correlated with functional loss. This objective, non-invasive technology may be an additional option for RNFL evaluation in this condition and an especially useful tool for long-term follow-up.

[Color duplex of retrobulbar arteries in normal pressure and open angle glaucoma]. / Farbduplex der retrobulbären Arterien bei Normaldruck- und Offenwinkelglaukom.

BACKGROUND: Various authors report that the glaucomatous loss of function is due to a chronic anterior ischemic optic neuropathy, being caused by a disturbed relationship between intraocular pressure and perfusion pressure in the posterior short ciliary arteries, which possibly leads to increased resistance in the ciliary vascular system. The authors attempt to test this hypothesis by measuring the vascular resistance (Resistance Index) in the ciliary vessel system by means of color Doppler sonography. PATIENTS AND METHODS: 35 eyes of 35 patients, suffering from open angle glaucoma (OAG), with a mean age of 65.3 years, were examined as well as 35 eyes of 35 patients with normal tension glaucoma (NTG), whose mean age was 65.8 years. Both glaucoma groups were compared to an age- and sex-matched control group of healthy volunteers. The color-Doppler measurements were performed with an Acuson 128 XP/10, which allows imaging of all retrobulbar arteries, the ophthalmic artery, the central retinal artery and the short posterior ciliary arteries, and also guarantees the precise calculation of blood flow velocity and resistive index (RI). The RI was statistically evaluated. RESULTS: The resistance index of all retrobulbar arteries showed a statistically significant increase (p < 0.05) according to Wilcoxon's test in the OAG group as well as the NTG group. CONCLUSIONS: Increased vascular resistance was found in all retrobulbar arteries in OAG and in NTG. These findings point out the pathognomonic importance of perfusion disturbance in glaucoma.

Influence of dorzolamide on corneal thickness, endothelial cell count and corneal sensibility.

PURPOSE: Dorzolamide (Trusopt) is the first topical carbonic anhydrase inhibitor (CAI) that is in clinical use in glaucoma therapy. It is known that CAI have a negative effect on corneal endothelial pumpfunction and therefore on the whole corneal physiology. METHODS: 20 patients with open angle glaucoma or ocular hypertension and an elevated intraocular pressure (IOP) over 21 mmHg and without prior oral CAI-treatment were included in this study. Trusopt was administered t.i.d. as monotherapy and b.i.d. in combination with other topical antiglaucoma drugs. Corneal ultrasound pachymetry, corneal endothelial cell count and aesthesiometry were performed prestudy and on days 1, 8, 15, 30, 60 and 90. RESULTS AND CONCLUSIONS: Mean corneal thickness was slightly increased on day one (statistically non-significant) and returned to baseline measurements at the following visits, no changes in endothelial cell count and corneal anesthesia were found. Topical dorzolamide is not associated with clinically meaningful changes of the cornea.

Treatment of menopausal keratoconjunctivitis sicca with topical oestradiol.

OBJECTIVE: To investigate the effect of 17 beta-oestradiol ophthalmic drops in comparison with a traditional tear substitute in postmenopausal women with keratoconjunctivitis sicca. DESIGN: Randomised prospective trial. SETTING: Menopause clinic. PARTICIPANTS: Eighty-four postmenopausal women suffering from keratoconjunctivitis sicca and necessitating a hormone replacement therapy (HRT) for general climacteric symptoms. METHODS: The women were randomised into two groups and were given 17 beta-oestradiol eye drops (n = 42, group 1) or a tear substitute (n = 42, group 2). Both groups received a systemic HRT. MAIN OUTCOME MEASURES: A Schirmer's test was performed immediately before the beginning of therapy and after four months. In addition, eye symptoms were assessed using a visual analogue scale. RESULTS: A comparison of visual analogue scores at four months in the women who received 17 beta-oestradiol eye drops versus those who received a tear substitute demonstrated a statistically significant difference in all observed ocular symptoms (P < 0.0001). The Schirmer's test revealed a significant difference of results before and after treatment in the oestradiol group (P < 0.0001) while in group 2 no significant difference was found. CONCLUSIONS: Our study demonstrates that topical oestrogen is successful in treating keratoconjunctivitis sicca while it seems that the blood-eye barrier prevents systemic oestrogens from acting on the conjunctivae.

Hormone replacement therapy and intraocular pressure.

OBJECTIVES: To evaluate the effect of hormone replacement therapy (HRT) on intraocular pressure (IOP) in menopausal women. METHODS: The IOP of 25 white menopausal women without an abnormal ophthalmologic history was measured before and during HRT regimen. IOP fluctations were recorded before and 1, 4, and 12 weeks after the beginning of HRT. These measurements were obtained according to a standardized time schedule (08:00, 12:00, 16:00, and 19:00 h). RESULTS: The mean IOP in the left eye decreased from 16.2 +/- 2.4 mmHg before therapy to 14.0 +/- 2.1 mmHg after 12 weeks of therapy (P < 0.001). In the right eye, whose IOP was at 15.3 +/- 2.3 mmHg before therapy there was a decrease to 14.0 +/- 1.9 mmHg after 12 weeks of therapy (P < 0.001). CONCLUSION: Hormone replacement therapy has a positive effect on IOP in menopausal women.

[Multicenter double-blind study with 0.25% timolol in Gelrite (TG) once daily vs. 0.25% timolol solution (TS) twice daily. German Study Group]. / Multizentrische Doppelblindstudie mit 0,25% Timolol in Gelrite (TG) 1mal täglich vs. 0,25% Timolol-Lösung (TS) 2mal täglich. Studiengruppe Deutschland.

In a 12-week double-masked trial we compared the ocular hypotensive effect of 0.25% timolol in Gelrite administered once daily (TG) to that of 0.25% timolol solution administered twice daily (TS). A second objective was to compare the tolerability and the safety of these treatments. Timolol in Gelrite is a new topical formulation of timolol in an anionic heteropolysaccharide gellan gum. A total of 156 patients entered the study after an appropriate wash-out. The medication schedule included one drop of test drug in each eye at 9 a.m. (active drug for both groups) and 9 p.m. (placebo for the TG group, active drug for the TS group). At trough, the mean decrease from baseline intraocular pressure (after appropriate wash-out) ranged from 5.7 to 6.3 mmHg for the TG group and from 5.9 to 6.2 mmHg for the TS group. The difference between the treatment group means ranged from -0.4 to 0.4 mmHg. At peak, the mean decrease from baseline IOP ranged from 5.3 to 6.2 mmHg for TG group and from 5.1 to 6.1 mmHg for the TS group. The difference between the treatment group means ranged from -0.7 to 0.4 mmHg. The results of this study support the hypothesis of a comparable hypotensive effect at peak and trough of 0.25% timolol in Gelrite q.d. to 0.25% timolol solution b.i.d. Furthermore, timolol in Gelrite has an acceptable tolerability profile. The incidence of blurred vision was higher in the Gelrite group, but this different was not statistically significant. The incidence of foreign body sensation was significantly higher in the Gelrite group (P < 0.022).(ABSTRACT TRUNCATED AT 250 WORDS)