Introduction

Topical medication remains the most commonly applied treatment option in glaucoma [1]. In the long run, many glaucoma patients require more than one active intraocular pressure (IOP)-lowering molecule to reach the target IOP and prevent glaucomatous progression, and a considerable subset of the patients requires complex medication comprising more than two active IOP-lowering molecules [1,2,3,4]. Use of topical fixed dose combinations (FCs) reduces the number of daily eye drop instillations and therefore supports adherence [1, 5, 6]. However, in almost all IOP-lowering FCs, one of the active ingredients is a beta receptor blocker (timolol), which makes it impossible to combine the timolol-containing FCs. The FC of brinzolamide 1% and brimonidine 0.2% (BBFC), manufactured in suspension formulation, is the first IOP-lowering FC without a beta receptor blocker. This characteristics allow BBFC to be used not only as a stand-alone therapy but also as part of complex medication involving timolol, prostaglandin analogues (PGs) and their combinations.

In the randomized prospective parallel group studies, the IOP-lowering efficacy of stand-alone BBFC ranged between 5.4 and 9.3 mmHg in open-angle glaucoma and ocular hypertension [7,8,9,10,11,12,13,14,15]. The relative IOP reduction ranged between approximately 25% (trough efficacy) and 35% (peak efficacy). BBFC is additive to PG monotherapy. When added to a PG monotherapy, the additional IOP reduction was 3.0 to 5.6 mmHg (13.0 to 16.5%) greater than that found when vehicle alone was added to the same PG monotherapy [16,17,18].

While short-term prospective studies are relatively numerous, there have been few long-term real-life clinical investigations, which can inform clinicians about IOP reduction and tolerance of BBFC in cases not eligible for inclusion in prospective randomized studies. In a recent investigation, it was shown that BBCF is effective both in treatment naive and under topical treatment of normal tension glaucoma eyes during a 18-month period [19]. In another retrospective investigation, IOP reduction 2 to 17.5 month after the introduction of BBFC was evaluated on 76 under treatment open-angle glaucoma patients [20]. The mean IOP reduction was 2.76 mmHg, but the authors provided no information on the previous therapies and the treatment changes made at the time of the introduction of BBFC in the treatment. To our knowledge, no long-term real-life investigation has been published on the use of BBFC in difficult to control high-pressure open-angle glaucoma. Therefore, in our current investigation, we retrospectively analysed the data of all open-angle glaucoma and ocular hypertensive patients treated with BBFC between February 2016 and June 2018 in our clinical unit, a European tertiary glaucoma centre.

Materials and methods

A retrospective analysis of the electronic records was conducted. All open-angle glaucoma and ocular hypertensive patients treated with at least one drop of BBFC in the Glaucoma Centre of Semmelweis University between February 2016 (when BBCF became available in Hungary) and June 2018 were included in the analysis. The research protocol was approved by the Institutional Review Board for Human Research of Semmelweis University, Budapest. All applicable institutional and governmental regulations concerning the ethical use of patients’ data were followed.

All patients used BBFC twice daily at intervals of approximately 12 h. Data of one eye per person were analysed. When both eyes of a patient were treated with BBFC, the eye with the higher IOP prior to the introduction of BBFC was selected for the study. The analysed parameters comprised the clinical diagnosis, age, sex, best corrected visual acuity, refractive error (spherical equivalent), central corneal thickness, Octopus perimetry mean defect, vertical cup/disc ratio, treatment prior to the introduction of BBFC, treatment containing BBFC, IOP on medication prior to the introduction of BBFC, IOP at 1, 3, 6 and 12 months and in the last visit on topical medication containing BBFC, adverse events related to BBFC, duration of BBFC therapy before the adverse events appeared and reasons for BBFC termination. The IOP measurements were all made between 8 a.m. and 12 noon. When IOP phasing was done, the morning IOP values were averaged for the between-visit comparisons.

Statistics

The baseline demographics data are presented as mean and SD. Due to the considerable differences in the number of eyes between the various follow-up time points, the paired t test with Bonferroni correction was used for the comparison of the IOP values between the various follow-up time points. Bonferroni corrected p values less than 0.05 were considered as statistically significant.

Results

Fifty-two patients were identified. Precise IOP measurement was not possible in two patients due to poor cooperation. These eyes were not included in the efficacy analysis. The length of the follow-up period on therapy containing BBFC was 12.8 ± 9.7 months. The maximal follow-up was 28 months. The age of the patients was 69.3 ± 10.2 years. Twenty-five patients were females and 27 were males. The best corrected visual acuity was 0.8 ± 0.3; the refractive error − 0.7 ± 2.4 dioptres; and the central corneal thickness 538.5 ± 29.8 µm. Thirty-nine patients had primary open-angle, 6 exfoliative, 2 pigment, 1 normal tension and 1 juvenile open-angle glaucoma, and 3 patients had ocular hypertension on the study eye. The Octopus perimetry visual field mean defect was 12.8 ± 7.7 dB, and the vertical cup/disc ratio was 0.9 ± 0.16 (Table 1).

Table 1 Baseline demographics of the patients and study eyes
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The therapy prior to the introduction of BBFC was a PG on 4 eyes, a PG/timolol FC on 20 eyes, a PG/timolol FC and a topical carbonic anhydrase inhibitor (CAI) on 19 eyes, a timolol/CAI FC on 1 eye, a PG and a CAI on 4 eyes, a timolol/pilocarpine FC and a PG on 1 eye, a timolol/brimonidine FC and a PG on 1 eye, and a timolol/brimonidine FC, a PG and a CAI on 2 eyes (Table 2). At the time of the introduction of BBFC, the therapy was modified to a PG/timolol FC and BBFC on 41 eyes, a PG and BBFC on 9 eyes, timolol and BBFC on 1 eye, and timolol/pilocarpine FC, a PG and BBFC on 1 eye (Table 2). The therapy modification (simplification) at the time of the introduction of BBCF made it possible for 50 of the 52 patients to have only three eye drop instillations per day despite the fact that 9 patients used 3 and 41 patients used 4 IOP-lowering molecules. The IOP was 21.2 ± 3.7 mmHg before, and 16.9 ± 2.6 mmHg, 16.0 ± 2.2 mmHg, 17.6 ± 3.1 mmHg and 18.0 ± 3.1 mmHg after the introduction of BBFC at month 1, 3, 6 and 12, respectively (Table 3; p < 0.0003 for all time points compared to baseline, p = 1.0 for all other comparisons). In the last visit, the IOP was 18.5 ± 5.0 mmHg (p < 0.0001 compared to baseline).

Table 2 Comparison of the number of daily instillations and the intraocular pressure-lowering ingredients before and after therapy change
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Table 3 Comparison of under treatment intraocular pressure before and after introduction of the brinzolamide/brimonidine fixed combination (BBFC)
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Thirty-one patients (59.6%) experienced no adverse event under BBFC treatment. Seventeen patients (32.7%) had ocular and 6 patients (11.5%) systemic adverse events (Table 4). None of the adverse events was classified as a serious adverse event. All ocular adverse events were similar: the patients complained about moderate or severe ocular discomfort and some ocular redness; the conjunctiva hyperaemia or conjunctiva and lid hyperaemia was visible on slit lamp examination, but its degree was mild in all cases. The onset of the adverse events ranged between 1 day and 16 months for ocular and 3 days and 11 months for systemic adverse events after the introduction of BBFC. BBFC therapy was terminated on 27 patients (51.9%). On 19 patients (36.5%), it was terminated due to adverse events. The BBFC therapy was terminated in all 6 patients (11.5%) experiencing a systemic adverse event. The ocular adverse events led to termination in 13 patients (25.0%). In 8 patients (15.4%), BBFC therapy was terminated due to insufficient IOP reduction. In these cases, glaucoma surgery was performed.

Table 4 Summary of adverse events related to the brinzolamide/brimonidine fixed combination
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Discussion

In the current investigation, we evaluated the IOP-lowering efficacy and tolerance of BBFC on open-angle glaucoma and ocular hypertension eyes which required complex glaucoma medication. The study population comprised all our patients who received at least one instillation of BBFC during the first 28 months after BBFC was introduced in Hungary. In contrast to the previous studies in which BBFC was used as a stand-alone medication [7,8,9,10,11,12,13,14,15] or an adjunctive medication to PGs [16,17,18], our investigation reflects real-life clinical experience. Almost all our patients were difficult to control open-angle glaucoma cases on different complex topical medications with advanced disc damage and poor IOP control. In clinical practice, such cases represent a real challenge for the ophthalmologists, and the existing literature on BBFC provides minimal information on the usefulness of BBFC on such eyes. Despite the inhomogeneity of the topical treatment used before BBFC was introduced, we were able to draw useful conclusions from our results.

First, when BBFC was introduced, a major change in the complex topical therapy was also performed. This made it possible to introduce BBFC but at the same time not to increase the number of the daily eye drop instillations to a level that would negatively influence the adherence. In fact, it was possible to apply 3 or 4 IOP-lowering molecules via 3 drop instillations day per in 50 of the 52 patients while the number of daily instillations ranged between 1 and 5 before the therapy change.

Second, we experienced a favourable IOP reduction in the modified therapy containing BBFC. Compared to the baseline IOP on medication (21.2 ± 3.7 mmHg), the new therapy provided a mean IOP reduction of approximately 3.2 to 5.2 mmHg (15.1 to 24.5%) during the study period, which is clinically meaningful. The IOP early after treatment modification (at month 1) was 16.9 ± 2.6 mmHg, and at month 12 it was 18.0 ± 3.1 mmHg. When the treatment effect was evaluated for the individual patients considering their individual target IOP values, the favourable effect was confirmed: the target IOP was not reached in only 8 patients (15.4%). We think that the favourable IOP reduction was caused both by the rationalization of treatment and by the additional IOP reduction induced by BBFC.

Third, our experience with the BBFC-related adverse events is somewhat different compared to the data published in short-term studies in which BBFC was a stand-alone medication or was added to a PG therapy [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22]. In our investigation, 40.3% of the patients experienced at least one adverse event. Most of these patients experienced ocular adverse events (32.7% of the total population), which in all cases comprised moderate or severe ocular discomfort, and redness reported by the patients, though only mild ocular hyperaemia was revealed by slit lamp examination. No corneal adverse event was seen. Interestingly, in the published studies, the adverse event frequencies are given in detail for several adverse event categories, separately, but no global adverse event frequency is provided for all ocular adverse events. Therefore, no direct comparison of our current results with the published data is possible. However, if the published adverse event frequencies given for all ocular adverse event categories are summed, the total figure is rather similar to that of the current study. Though this calculation is not scientifically correct (one patient can experience more than one adverse event), one may speculate that the high frequency of BBFC-related adverse events in the current investigation is not extraordinary. The clinically important question raised by the relatively high adverse event frequency in our study is whether eyes on complex topical medication are more prone to topical adverse events caused by BBFC than the treatment naive or after washout eyes. This question, however, cannot be answered without further investigations. The length of the period investigated in the current study (mean treatment period 12.8 month) is greater than that in the prospective BBFC studies. This may also play a role in the relatively high frequency of adverse events. Systemic adverse events appeared in 11.5% of the patients and comprised well-known systemic adverse events associated with brimonidine: systemic arterial hypotension, tachycardia, dry mouth and sleep disorder. Termination of BBFC therapy due to adverse events occurred in 36.5% of the patients, which underlines the importance of adverse events in BBFC users.

Our study has limitations due to its retrospective and single-centre nature and the lack of a standardized measure for ocular adverse event severity. All IOP measurements were made in the morning hours. Therefore, the 24-h IOP-lowering effect of BBFC was not investigated.

In conclusion, our results show that BBFC can be usefully applied on difficult to control open-angle glaucoma and ocular hypertension eyes that require complex topical medication. A clinically meaningful IOP reduction was reached on the majority of the eyes. However, we also found that BBFC-related adverse events are common. In our study, they led to termination of BBFC therapy in more than one third of the patients. This suggests that in routine clinical practice, clinicians need to count with a considerable percentage of BBFC treatment terminations.