Long-term effect of latanoprost/timolol fixed combination in patients with glaucoma or ocular hypertension: A prospective, observational, noninterventional study
© Schwenn et al; licensee BioMed Central Ltd. 2010
Received: 15 April 2010
Accepted: 8 September 2010
Published: 8 September 2010
Prospective, observational studies that enroll large numbers of patients with few exclusion criteria may better reflect actual ongoing clinical experience than randomized clinical trials. Our purpose was to obtain efficacy and safety information from a cohort of subjects exposed to latanoprost/timolol fixed combination (FC) for ≥18 months using a prospective, observational design.
In all, 577 office-based ophthalmologists in Germany switched 2339 patients with glaucoma or ocular hypertension to latanoprost/timolol FC for medical reasons. Follow-up visits were scheduled for every 6 months over 24 months; physicians followed usual care routines. Intraocular pressure (IOP), visual field status, optic nerve head findings, and adverse events were recorded. Efficacy parameters were evaluated for the per protocol (PP) population; the safety population included subjects receiving ≥1 drop of FC. Physicians rated efficacy, tolerability, and subject compliance at month 24.
Of the 2339 subjects switched to latanoprost/timolol FC (safety population), the primary reasons for switching were inadequate IOP reduction (78.2%) and desire to simplify treatment with once-daily dosing (29.4%; multiple reasons possible). In all, 1317 (56.3%) subjects completed the study, and 1028 (44.0%) were included in the PP population. Most discontinuations were due to loss to follow-up. Change in mean IOP from baseline to month 6 was -4.0 ± 4.31 mmHg, a reduction that was maintained throughout (P < 0.05 for change at all time points). By investigator assessments, optic disc parameters and visual field were stable over 24 months, and there was no relationship between IOP reduction over 24 months and development of a visual field defect. More than 90% of physicians rated latanoprost/timolol FC as "very good" or "good" for efficacy (PP population), tolerability, and compliance. The FC was safe and well tolerated. No change in iris color was reported by most subjects (83.1%) at month 24.
Over 24 months, latanoprost/timolol FC effectively lowers IOP levels and is well tolerated in patients with glaucoma or ocular hypertension who change from their previous ocular hypotensive therapy for medical reasons. Investigator assessments found optic disc parameters and visual field to be stable throughout 24 months of follow-up.
In patients with glaucoma or ocular hypertension who do not reach their target intraocular pressure (IOP) level with ocular hypotensive monotherapy, the European Glaucoma Society  recommends adding a second medication when the original agent showed some effectiveness. In fact, many patients with these conditions must use more than one ocular hypotensive therapy to reduce IOPs to levels that may be expected to slow or stop disease progression . In these individuals, a fixed-combination (FC) formulation may be preferred to multidrug regimens in order to maximize patient compliance and quality of life .
In Europe, the FC of the prostaglandin analogue latanoprost and the beta-blocker timolol is approved for the treatment of open-angle glaucoma or ocular hypertension in patients insufficiently controlled on monotherapy. Latanoprost, the first prostaglandin F2a analogue to be commercially available in Europe and the United States, acts primarily by increasing outflow [3, 4] while the beta-adrenergic receptor antagonist timolol lowers IOP by reducing aqueous humor production [5, 6]. The combination of the two agents has been shown to have an additive IOP-lowering effect [7–10], and several prospective, randomized clinical trials have demonstrated that latanoprost/timolol FC is effective and well tolerated [11–16].
Although such prospective, randomized trials are the gold standard for evaluating the safety and efficacy of new medical treatments, their strict designs may not reflect community practice patterns thereby limiting the generalizability of findings. Prospective, observational studies that include large numbers of patients with few exclusion criteria may better reflect actual ongoing clinical experience. The present prospective, noninterventional, observational study was designed to obtain efficacy and tolerability information about a cohort of subjects exposed to the latanoprost/timolol FC for at least 18 months.
The study was conducted in general ophthalmology practices in Germany between August 2005 and December 2008. The study met all standards for ethical approval in Germany. It was planned and conducted and data were analyzed in accordance with guidelines issued by the Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Drugs and Medical Devices). German law does not require patient informed consent in observational studies in which treatment is medically indicated by the physician regardless of study participation and in which treatment use is restricted to approved indications.
Procedures and measurements
In all, 577 office-based ophthalmologists treated and provided information for 2339 subjects with glaucoma or ocular hypertension who were being switched for medical reasons to once-daily latanoprost/timolol FC from another ocular hypotensive medication (monotherapy, FC, or unfixed combination). Participating ophthalmologists followed their usual care practices. At the baseline visit, the reason(s) for switching the subject to latanoprost/timolol FC was noted, and demographic data, medical and ocular histories, visual field status (Aulhorn stage and mean defect), and optic nerve head findings were recorded. Prior to pupil dilation, best-corrected visual acuity was determined, and IOP level was measured once by pulse air tonometry or calibrated Goldman applanation tonometry.
Study-related follow-up visits were scheduled to occur at approximately 6-month intervals for 24 months. At each visit, IOP was measured, optic disc excavation and visual field (Aulhorn stage) were assessed, and glaucoma damage/progression was evaluated by investigators. Any decision to withdraw FC therapy before 24 months was made at the discretion of the treating physician.
All observed or volunteered adverse events and serious adverse events were recorded throughout the study. Serious adverse events were those that were life-threatening, resulted in death, required or prolonged hospitalization, or resulted in disability or congenital anomaly. Suspected causal relationships to latanoprost/timolol FC were recorded by treating physicians. Version 12.0 of the Medical Dictionary for Regulatory Activities (MedDRA) was used to code diagnoses, previous/concomitant diseases, and adverse events.
Physicians assessed the overall efficacy and the overall tolerability of latanoprost/timolol FC at month 24 as "very good", "good", "moderate", or "insufficient". Subject compliance with the FC was evaluated by physicians using the same four categories. At month 24, subjects evaluated change in iris color from baseline as "none", "slightly", "distinctly", or "very distinctly" and were asked whether they wished to remain on the FC.
Endpoints and analyses
Statistical analyses were descriptive and exploratory. Percentages for categorical variables as well as means, standard deviations (SDs), and, where appropriate, two-sided 95% confidence intervals (CIs) for continuous variables were calculated based on nonmissing observations. Associations between pairs of variables were assessed using Pearson correlation for continuous variables, Spearman rank correlation where one or both variables were ordinal, or tetrachoric correlation for two binary variables.
If both eyes were treated with the FC, the IOP value for the right eye was used; otherwise, the value for the treated eye was used. If the physician did not indicate which eye was treated, it was assumed that both eyes were prescribed FC therapy. Mean changes in IOP levels at months 6, 12, 18, and 24, and at the last visit were assessed. In the analysis of changes in IOP, the last visit was defined as the last postbaseline visit at which an IOP level was recorded. In addition, mean change in corrected IOP from baseline to last visit was assessed using the formula developed by Kohlhaas et al.  (corrected IOP = raw IOP + [-0.0423 × central corneal thickness in μm + 23.28]), and for the subset of subjects in whom IOP was measured using applanation tonometry and for subjects stratified by diagnosis and by baseline ocular hypotensive therapy.
Mean changes from baseline in horizontal and vertical cup/disc ratios were evaluated across visits. Aulhorn stage and mean defect at each visit and change in stage from baseline were summarized. A stepwise analysis of variance (ANOVA) of mean change in visual field defect (last visit at which the parameter was recorded - baseline) included the following potential explanatory variables: age, gender, baseline mean defect, change in IOP (last visit at which the parameter was recorded - baseline), number of postbaseline optic disc hemorrhages, treatment duration, primary diagnosis, history of hypertension, history of hypotension, and history of diabetes. The significance level for variable entry was set at 0.05 and for retention at 0.10; no interaction terms were fitted.
A 6-item composite variable reflecting progression of glaucomatous damage from baseline to last visit was defined as any of the following: (a) increase in horizontal or vertical cup/disc ratio by ≥0.2; (b) occurrence of ≥1 postbaseline optic disc hemorrhage; (c) decrease in rim area, rim volume, and/or mean retinal nerve fiber layer thickness by 0.2 mm2, 0.1 mm3 and 0.1 mm, respectively, as measured by Heidelberg Retina Tomograph; (d) progressive visual field deterioration noted by the physician at ≥1 postbaseline visit; (e) increase in Aulhorn stage by ≥1 stage; or (f) decrease in mean defect by ≥2.5 dB. A stepwise logistic regression analysis of the binary variable presence/absence of progression included the following potential predictors: age, gender, baseline IOP, change in IOP (last visit - baseline), primary diagnosis, history of hypertension, history of hypotension, and history of diabetes. The significance level for variable entry was set at 0.05 and for retention at 0.10; no interaction terms were fitted. In addition, progression of optic disc excavation (present if either criteria [a] or [c], above, was met) and progression of visual field (present if criteria [d] and if criteria [e] and/or [f] were met) were evaluated.
Efficacy parameters were analyzed for the per protocol (PP) population which included subjects treated with latanoprost/timolol FC for ≥18 months who had a baseline and ≥1 postbaseline IOP measurement (≥18 months apart), did not have a refractive error ≤ -8 diopters or ≥ + 8 diopters at baseline, and did not administer ocular hypotensive medication in addition to latanoprost/timolol FC medication during the study period. This definition of the PP population was appropriate given that the primary objective of this noninterventional study was to obtain information about a cohort of subjects exposed to the latanoprost/timolol FC for at least 18 months. In addition, key efficacy analyses were reproduced using the full analysis set (FAS) population, which included all subjects with ≥1 postbaseline IOP measurement, in order to evaluate the robustness of the PP analyses. The safety population included all subjects who received ≥1 drop of study medication.
No. (%) subjects
Received latanoprost/timolol FC
Completed 24 months of follow-up
Discontinued prior to 24 months
Per protocol population
Reason(s) for exclusion:*
Not treated for ≥18 months
No baseline and ≥1 postbaseline measure for IOP ≥18 months apart
Additional ocular hypotensive medication during study
Ametropy at baseline
Full analysis set
Excluded (no postbaseline IOP measurement)
Baseline characteristics, N = 2339
Mean ± SD
65.5 ± 11.7
Male gender, n (%)*
Ocular hypotensive therapy reported by ≥50 subjects
Reason(s) for switching to latanoprost/timolol FC,‡ n (%)
Inadequate IOP reduction on prior therapy
Desire to simplify treatment with once-daily dosing
Side effects/hypersensitivity reactions with prior therapy
Prior therapy contraindicated due to subject's signs/symptoms
Mean IOP* and mean change in IOP from baseline† by visit (mmHg), PP population
Mean ± SD
Change from baseline, mean ± SD
20.3 ± 4.20
16.4 ± 3.04
-4.0 ± 4.31
16.4 ± 3.04
-3.9 ± 4.53
16.4 ± 2.99
-4.0 ± 4.43
16.2 ± 3.17
-4.2 ± 4.69
16.2 ± 3.16
-4.1 ± 4.66
Mean IOP and mean change in IOP from baseline to last visit* (mmHg), alternate populations
Mean ± SD
Change from baseline, mean ± SD
PP population: corrected IOP
20.5 ± 3.94
16.3 ± 3.30
-4.2 ± 4.21
Full analysis set: raw IOP
20.4 ± 4.25
16.4 ± 3.42
-3.9 ± 4.65‡
PP population with applanation tonometry data: raw IOP
20.3 ± 4.31
16.2 ± 3.02
-4.0 ± 4.59§
Mean change from baseline* in horizontal and vertical cup/disc ratios by visit, PP population
Mean ± SD (95% CI)
Horizontal cup/disc ratio
0.0003 ± 0.13117
0.0039 ± 0.13286
0.0092 ± 0.13860
0.0041 ± 0.14078
0.0079 ± 0.14645
Vertical cup/disc ratio
0.0040 ± 0.12772
0.0075 ± 0.13726
0.0152 ± 0.14613
0.0088 ± 0.13534
0.0127 ± 0.15155
Information concerning mean visual field defect measurement method was available for 744 subjects, and the most commonly used measurement method was the Humphrey Visual Field Analyzer (n = 337). At month 24, 72 of the 122 subjects (59.0%) with valid data for the Aulhorn stage based on the Humphrey Visual Field Analyzer at both baseline and month 24 had no change in stage; 15.6%, 2.5% and 0.8% of subjects increased by 1, 2 and 3 stages, respectively, whereas 15.6%, 4.9%, 0.8% and 0.8% of subjects decreased by 1, 2, 3, and 4 stages, respectively.
In the PP population, there were no statistically significant changes in mean defect from baseline to months 6, 12, 18, and 24 or to the last visit. In the multivariate analysis, change in mean defect from baseline to the last visit was related only to baseline mean defect. This analysis only involved subjects with nonmissing data for the response variable and all potential explanatory variables (n = 355). The final model was reduced to a simple linear regression with intercept -0.718 and slope -0.283 (95% CI: -0.354, -0.211; P < 0.0001). Hence, subjects with a lower baseline mean defect experienced a higher change in mean defect from baseline to last visit. In addition, the correlation between changes from baseline to last visit in mean defect and in IOP was estimated at 0.0276 (95% CI: -0.0603, 0.1156; P = 0.5956; n = 371), providing no evidence of a relationship between IOP reduction and reduction in mean defect.
Changes in progression measures by last visit* and month 24, n/N (%), PP population
Increase in horizontal or vertical cup/disc ratio by ≥0.2 (visit - baseline)†
≥1 postbaseline optic disc hemorrhage‡
Decrease in ≥1 rim area, rim volume, and/or mean RNFL thickness by HRT (visit - baseline)†
Visual field deterioration rated as progression by physician at ≥1 postbaseline visit‡
Increase in Aulhorn stage§ by ≥1 stage (visit - baseline)†
Decrease in mean defect by ≥2.5 dB†
Adverse events, N = 2339
All adverse events
Number of events
≥1 adverse event
≥1 serious adverse event
≥1 severe adverse event
Discontinued FC due to adverse event
Dose reduced/temporarily discontinued FC due to adverse event
All Ocular Adverse Events
Number of events
≥1 adverse event
≥1 serious adverse event
≥1 severe adverse event
Discontinued FC due to adverse event
Dose reduced/temporarily discontinued FC due to adverse event
At month 24, the majority of responding physicians rated the overall efficacy of latanoprost/timolol FC as "very good" or "good" (PP population: 922/997 [92.5%]; FAS population: 1312/1504 [87.2%]). Among subjects for whom physicians provided evaluations at month 24, the overall tolerability of the FC was assessed as either "very good" or "good" in 1503/1584 (94.9%) subjects and compliance with the FC as "very good" or "good" in 1439/1580 (91.1%) subjects. More than three-quarters (1123/1351 [83.1%) of responding subjects reported no change in iris color at month 24, and nearly 90% (n = 1343/1520 [88.4%]) indicated a desire to continue FC treatment after the completion of study. At month 24, change in visual acuity from baseline was not statistically or clinically significant.
Results of this long-term observational study of latanoprost/timolol FC demonstrate that the combination effectively reduces IOP levels and is well tolerated in patients with glaucoma or ocular hypertension who change from their previous ocular hypotensive therapy for medical reasons. The significant IOP-lowering effect of the FC was seen early, at the month 6 visit, and was sustained throughout the 24-month follow-up period. Moreover, no significant changes in optic disc and visual field defect were noted by investigators, and structural and functional parameters remained stable over 24 months. Investigator assessments revealed no significant association between IOP reduction over two years and change in visual field.
Previous research has demonstrated that progression of glaucoma or ocular hypertension can be delayed or halted by lowering IOP levels through the use of ocular hypotensive agents [2, 18–21]. Herein, the mean IOP reduction of approximately 4 mmHg sustained over 24 months was somewhat greater than reductions reported in previous short-term observational studies of patients switched to the FC [22, 23]. For example, a prospective, multicenter study  of patients switched to latanoprost/timolol FC and followed for at least two months found mean IOP reductions from baseline of 2.9 mmHg in those with primary open-angle glaucoma or exfoliation glaucoma and of 3.1 mmHg among patients with ocular hypertension (P < 0.001 for all). A multicenter, observational study  of patients with glaucoma or ocular hypertension who were switched to the FC and followed for six months reported mean IOP reductions from baseline of 3.3 mmHg, 4.1 mmHg, and 3.4 mmHg among patients with open-angle glaucoma, exfoliation glaucoma, and ocular hypertension, respectively (P < 0.001 for all).
As has been shown previously [11–16], the FC was well tolerated. In all, 99/185 (53.5%) adverse events were ocular in nature, half of treatment-related adverse events related to the eye, and two of the three reported treatment-related serious adverse events were ocular. Fewer than 3% of subjects discontinued the FC due to an ocular adverse event. The tolerability of an ocular hypotensive agent is important given the negative impact of ocular adverse events on patient continuation with therapy [24, 25].
At month 24, physician evaluations of latanoprost/timolol FC were overwhelmingly positive with regard to efficacy, tolerability, and patient compliance. In addition, nearly 90% of patients expressed a desire to remain on the FC after the end of the study. These positive evaluations are tempered, however, by the fact that they were made for and by patients who stayed on therapy for the full follow-up period; it is not known how many of those for whom efficacy, tolerability, or compliance were issues discontinued FC therapy prior to that time point. Conversely, nearly 90% of discontinuations in the present study were unrelated to latanoprost/timolol FC, with the vast majority attributable to loss to follow-up. Moreover, a prior study  of patients switched to latanoprost/timolol FC found that 97% of patients (1008/1042) remained on treatment after the 6-month study period.
Benefits of prescribing a FC agent for patients with glaucoma or ocular hypertension may include improved adherence, persistence, convenience, and reduced exposure to preservatives. Improved adherence and persistence, in particular, are critical since the use of an effective ocular hypotensive agent over the long term may be expected to increase the likelihood of delaying or stopping glaucomatous damage. Poorer compliance has been demonstrated in those treated with more complex medication regimens [26–30]. Comparative studies of medication compliance in patients prescribed alternative FC therapies are needed.
This study has both strengths and limitations. The observational design may have better reflected actual clinical practice than controlled clinical trials, but the absence of a control group limits our ability to draw conclusions, and the PP population included fewer than half the number of subjects treated, primarily due to loss to follow-up. Given the observational design, it was not possible to standardized the timing and method of measuring IOP levels and visual field defects. It is notable, however, that IOP reductions from baseline to last visit among the 687 subjects evaluated by applanation tonometry were similar to those observed for the total population. Although the design did not include a washout period between termination of baseline therapy and initiation of latanoprost/timolol FC combination, this would not be expected to impact the long-term outcomes evaluated herein. The 24-month follow-up period may have been too short to detect changes in visual fields. Moreover, last visit data for individual progression measures reflected a time point prior to month 24 for between 15% (for cup/disc ratio data) and 32% (for rim area/volume/retinal nerve fiber layer data) of evaluable subjects. Strict adherence to study procedures and reporting requirements could not be affirmed given the large number of participating physicians and the prolonged follow-up period. Finally, while 17% of patients reported a change in iris color from baseline to month 24, evaluations relied on recollections of baseline color. The Ocular Hypertension Treatment Study  found that 17.1% of subjects prescribed a prostaglandin analogue for at least six months and 7.6% of those in the observation group reported a change in iris color, darkening of the eyelids, or growth of eyelashes.
This 24-month study demonstrated that latanoprost/timolol FC effectively reduces IOP levels and is well tolerated in patients switched from other ocular hypotensive therapies for medical reasons. Investigator assessments showed optic disc parameters and visual field to be stable throughout the follow-up period.
The results of this study were presented in part at the 8th International Symposium on Ocular Pharmacology and Therapeutics, December 3-6, 2009; Rome, Italy.
Editorial support, including contributing to the first draft of the manuscript, revising the paper based on author feedback, and styling the paper for journal submission, was provided by Jane G. Murphy, PhD, of Zola Associates and was funded by Pfizer Inc.
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