Efficacy of Single Glaucoma Medication in Combined Latanoprost and Timolol XE Therapy in Patients with Open-Angle Glaucoma and Ocular Hypertension: A Discontinuation Study

Abstract

Purpose:

To study the effect of single drug discontinuation in combined timolol XE 0.5% and latanoprost 0.005% treatment.

Methods:

Fifty patients with open-angle glaucoma or ocular hypertension who had received both latanoprost and timolol XE for at least 6 months were enrolled in this study. Timolol XE and latanoprost were administered once daily, timolol XE in the morning and latanoprost in the evening. Twenty-five patients discontinued timolol XE and the remaining 25 patients discontinued latanoprost. Either latanoprost or timolol XE was discontinued and 8 weeks later it was resumed. A change in intraocular pressure (IOP) was studied.

Results:

All patients had complete follow-up visits. A significant increase in mean IOP was found following drug discontinuation in the 2 groups. Mean change in IOP 8 weeks after discontinuation of the drug was +1.6±1.2 mmHg (10.3%±8.0%) in the timolol XE group and +4.3±1.6 mmHg (+27.2%±11.8%) in the latanoprost group. The change in the latanoprost group was significantly greater compared with that in the timolol XE group (P<0.0001). There was no significant difference in mean IOP between before drug discontinuation and at 8 weeks after drug resumption in any group.

Conclusions:

There was a significant increase in IOP from discontinuation of timolol XE and latanoprost. The hypotensive effect of latanoprost in the combined drug therapy is significantly greater compared with timolol XE.

Introduction

Multiple drug therapy is used to treat glaucoma when monotherapy is not effective or sufficient. A combination of several drugs, including prostaglandin analogues, β-blockers, cholinergic agonists, adrenergic agonists, α₂-stimulants, α₁-blockers, and carbonic anhydrase inhibitors, have been reported to be effective.^1–6 These studies were carried out at the time when additional drugs were first administered in patients already receiving 1 drug. Several investigators demonstrated that patients with less dosing showed better adherence and higher persistency.^7–9 When a patient with 2 or 3 antiglaucomatous drugs has an intraocular pressure (IOP) low enough to approach the target pressure, ophthalmologists are concerned with whether one of the drugs can be discontinued. However, the efficacy of each drug in the patients who continue to administer 2 or more drugs is not available. In this study, we studied the efficacy of each drug in patients receiving timolol XE 0.5% and latanoprost 0.005% for at least 6 months with its discontinuation.

Methods

Patients

Fifty patients with open-angle glaucoma and ocular hypertension who had received timolol XE and latanoprost for at least 6 months were enrolled in this study. A diagnosis of glaucoma was based on the appearance of the optic nerve head cupping and visual field alteration according to the guideline of the Japanese Glaucoma Society.¹⁰ Patients with angle closure glaucoma or posttraumatic, uveitic, neovascular or dysgenetic glaucoma were excluded, as well as patients with a known life-threatening disease. Patients with systemic β-blockers were also excluded. The study protocol and consent forms were approved by the Human Subjects Committee.

The patients were prospectively randomized to discontinue timolol XE or latanoprost, with only 1 eye of a patient to be randomized. Timolol XE and latanoprost were administered once daily, timolol XE in the morning and latanoprost in the evening. When both eyes were eligible, the right eye became the study eye. Within 24 h after enrollment, the patients were randomized using an envelope method. In brief, we prepared each 25 envelopes that contained a card that showed either timolol XE group or latanoprost group. Within 24 h after enrollment, an envelope was picked up and the inside card showed the way to discontinue timolol XE or latanoprost. Twenty-five patients discontinued timolol XE and the remaining 25 patients discontinued latanoprost. Treatment began within a week after these random assignments. In consideration of crossover effect of β-blocker, the administration of the β-blocker or latanoprost was discontinued in both eyes if patients were taking 2 drugs in both eyes.

Evaluation of outcomes

Patients read and signed an Institutional Review Board–approved informed consent form before any procedures were performed in this study. Patients had ocular and systemic histories taken and underwent slit-lamp biomicroscopy, visual acuity testing, a physical examination, and dilated funduscopy. Goldmann applanation tonometry was carried out at the same time (±1:00) between 9:00 am and 12:30 pm at 3 visits with a 2-week interval and the mean of the 3 values was calculated to determine the baseline IOP. Three measurements per visit were recorded in each eye and the mean of these was used in the calculations. The optic nerve was examined with a Goldman 3-mirror lens and measurements were taken of the size of the disc, the vertical and horizontal cup/disc ratios, the presence of rim notching or splinter hemorrhage, and the presence of peripapillary atrophy. Visual field testing with a Humphrey visual field analyzer (Humphrey-Zeiss, Dublin, CA) and Program 30-2 SITA STANDARD™ testing were carried out before and 16 weeks after discontinuation of drugs.

Patients who qualified for the study were instructed to discontinue timolol XE or latanoprost for 8 weeks and then resume taking the discontinued drug. We asked the patients questions concerning their compliance with treatment and discontinuation more than once per visit to increase the accuracy of the compliance rate.^7,9 The patients were reviewed at the interval of 2 weeks for 16 weeks. IOP was measured at the same time (±1:00) as at baseline and its change was studied. A single observer (H.K.) took IOP measurements in all the eyes.

Study end

All patients were meant to reach a 16-week follow-up, but the following were considered as endpoints: (1) the need for any further medical or surgical treatment and (2) failure to attend scheduled visits, allowing for a margin of tolerance.

Statistical analysis

The sample size was chosen to assure a power of at least 90% in detecting at least a 3 mmHg difference between groups with a standard deviation of 3 mmHg with a 2-sided α error of 5%.

Continuous variables were shown in mean±standard deviation as well as range. Evaluation of continuous variables was achieved using the Student's t-test. To evaluate the difference in IOP between follow-up intervals, the paired t-test was implemented. All t-tests were 2-tailed. Categoric variables were evaluated with chi-squared test, the Fisher exact test, or the Spearman rank correlation, when appropriate. A level of P<0.05 was accepted as statistically significant.

Results

Baseline

Baseline data are summarized in Table 1. Fifty patients were enrolled in this study. There were 43 patients with primary open-angle glaucoma and 7 patients with ocular hypertension. Mean age was 62.1±9.1 years in the timolol XE group and 62.5±12.2 years in the latanoprost group. No significant difference was found between the 2 groups in age, gender, best-corrected visual acuity, the time at which IOP was measured, and duration of administration of timolol XE and latanoprost. All patients had complete follow-up visits and reported to be compliant.

Table 1.

Demographics of Patients

	Timolol XE group	Latanoprost group	P
No. of patients	25	25	—
Age (years)	62.1±9.1 (42–76)	62.5±12.2 (44–75)	0.9
Gender	16 women, 9 men	12 women, 13 men	0.6
Type
POAG	21 (84%)	22 (88%)	0.8
Ocular hypertension	4 (16%)	3 (12%)
Time at IOP measurement	10:21±1:01 (9:00–12:30)	10:32±0:58 (9:00–12:30)	0.9
IOP before glaucoma medication	22.9±1.7 (21–27)	22.8±1.5 (21–26)	0.8
IOP before discontinuation of timolol XE or latanoprost	16.2±1.7 (14–20)	15.9±1.5 (15–19)	0.5
Best-corrected visual acuity	1.0 (20/20)	1.0 (20/20)	1.0
Humphrey visual analyzer 30-2 mean deviation (dB)	−1.80±1.45 (−4.20 – +1.22)	−1.83±1.32 (−4.09 – +1.25)	0.5
No. of patients receiving both drugs in both eyes	24 (96%)	23 (92%)	0.6
Duration of administration of 2 drugs (months)	18.3±6.2 (9–34)	17.8±7.3 (9–36)	0.8

Mean±SD shows mean±standard deviation, and parenthesis indicates range.

POAG, primary open-angle glaucoma; IOP, intraocular pressure.

The change in IOP

Mean IOP before and 8 weeks after discontinuation of timolol XE or latanoprost was 16.2±1.7 and 17.8±1.9 mmHg in the timolol XE group and 15.9±0.9 and 20.1±1.6 mmHg in the latanoprost group; there was no significant difference in baseline IOP among the groups (Fig. 1). A significant increase was found in the 2 groups at any visit after discontinuation of the drugs (timolol XE: P=0.0266; latanoprost: P<0.0001) (Fig. 1). Mean change in IOP by discontinuation of the drug was +1.6±1.2 mmHg (10.3%±8.0%) in the timolol XE group and +4.3±1.6 mmHg (+27.2%±11.8%) in the latanoprost group. The change in the latanoprost group was significantly greater compared with that in the timolol XE group (P<0.0001) (Table 2). Mean IOP 8 weeks after resumption was 15.9±1.9 mmHg in the timolol XE group and 16.0±0.8 mmHg in the latanoprost group; there was no significant difference between before discontinuation and 8 weeks after resumption in any group (Fig. 1, Table 2). No adverse events were reported during the discontinuation period.

FIG. 1.

A change of intraocular pressure (IOP) after discontinuation of drugs. IOP (A) and IOP change (B). The solid squares and solid line indicate the timolol XE group and the open squares and broken line indicate the latanoprost group.

Table 2.

Intraocular Pressure Change

	Timolol XE group	Latanoprost group	P
IOP (mmHg)
Baseline	16.2±1.7	15.9±0.9	0.4
2 weeks	17.8±2.0	19.5±1.6	0.0017
4 weeks	17.8±2.1	20.2±1.6	<0.0001
6 weeks	17.9±2.2	20.2±1.6	<0.0001
8 weeks	17.8±1.9	20.1±1.6	<0.0001
10 weeks	16.1±1.8	16.4±1.5	0.5
12 weeks	16.0±2.0	16.1±0.8	0.8
14 weeks	16.0±2.1	16.0±0.9	1.0
16 weeks	15.9±1.9	16.0±0.8	0.8
IOP change (mmHg/%)
2 weeks	+1.6±1.0 (+9.9%±6.3%)	+3.6±1.7 (+22.9%±12.1%)	<0.0001 (<0.0001)
4 weeks	+1.6±1.2 (+10.1%±8.0%)	+4.3±1.8 (+27.4%±12.7%)	<0.0001 (<0.0001)
6 weeks	+1.7±1.2 (+10.3%±8.0%)	+4.3±1.8 (+27.4%±12.7%)	<0.0001 (<0.0001)
8 weeks	+1.6±1.2 (+10.3%±8.3%)	+4.3±1.6 (+27.2%±11.8%)	<0.0001 (<0.0001)
10 weeks	−0.1±0.9 (−0.7%±5.3%)	+0.5±1.4 (+3.5%±9.6%)	0.1 (0.1)
12 weeks	−0.3±1.1 (−1.4%±7.1%)	+0.2±0.9 (+1.5%±6.0%)	0.1 (0.1)
14 weeks	−0.2±1.2 (−1.0%±7.5%)	+0.1±1.0 (+1.0%±6.4%)	0.3 (0.3)
16 weeks	−0.3±1.2 (−1.6%±7.8%)	+0.2±0.9 (+1.2%±5.7%)	0.1 (0.2)

P indicates probability in mmHg. Values in parenthesis indicate probability in percentages.

Discussion

In the current study, we demonstrated that the discontinuation of timolol XE 0.5% and latanoprost 0.005% provided a significant increase in IOP in patients with primary open-angle glaucoma or ocular hypertension. The discontinuation of latanoprost produced a significantly greater increase compared with timolol XE.

In previous studies, although a wide variation existed in washout times among individuals, the mean washout periods of latanoprost and timolol XE have been reported to be less than 6 weeks and the majority of the patients reached baseline by 8 weeks after the discontinuation of each drug.^11–14 In this study, we assumed that 8 weeks may be sufficient to eliminate the effect of the drugs. Although mean IOP at 2 weeks after discontinuation of latanoprost increased to 84% of the increment shown at 8 weeks, there were 7 patients (28%) showing the IOP increase at 2 weeks less than half of that at 8 weeks. Schuman et al. demonstrated that the use of systemic β-blocker reduced the IOP lowering efficacy of topical β-blockers.¹⁵ In this study, no patient used systemic β-blockers. Since latanoprost has been reported to decrease the IOP up to 6 months,¹⁶ we enrolled patients who had administered the drug for at least 6 months.

Previous studies showed that β-blockers are additive to latanoprost therapy as well as latanoprost to β-blockers.¹⁷ Adding latanoprost to the eyes treated with timolol provides a reduction of 2.6±1.1 mmHg (13%), whereas timolol to the eyes receiving latanoprost gave a reduction of 2.6±2.2 mmHg (14%).¹⁷ Interestingly, in this study, timolol and latanoprost appeared to have a similar IOP-lowering effect in the combined treatment, although there was a significant difference found in the current study.

In spite of the long-term efficacy of timolol therapy, investigators have noted that the IOPs initially well controlled in some patients slowly increased after several months.^11,12 Stewart et al. evaluated the efficacy of the monotherapy of currently available ocular hypotensive medicines, including β-blocker, derived from 24-h studies in a meta-analysis.¹⁸ An IOP change after the discontinuation of timolol XE lasting for 6 months or longer in the current study appeared to be significantly less compared with after the initial addition of timolol. Brubaker et al. also demonstrated fluorophotometrically that the timolol-induced reduction of aqueous flow is less pronounced at 1 year compared with 1 week after beginning treatment.¹⁹ Long-term drift maybe related to partial adaptation of the ciliary body to chronic administration of timolol.²⁰ However, in this study, we enrolled patients who had administered timolol XE for various time, 9–36 months. Shorter duration of treatment with β-blocker may not produce tachyphylaxis from β-receptor downregulation.

This study has important limitations. The sample size of this study was small, therefore not powered to detect small differences. Small sample size also precluded assessment of safety. Furthermore, a masked study design could have reduced observer bias.

Although the sample size in each group was small, the current study demonstrated that (1) there was a significant increase in IOP from discontinuation of timolol XE and latanoprost in the concomittant drug treatment, and (2) the hypotensive effect of latanoprost in the combined drug therapy is significantly greater than that of timolol XE. Future study of a large population is needed to verify these observations. However, this information may be clinically valuable when treating patients with primary open-angle glaucoma and ocular hypertension.

Footnotes

Acknowledgment

There was no commercial sponsorship or support for this study.

Author Disclosure Statement

No competing financial interests exist.

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