Effect of Tiotropium on eye findings in the treatment of chronic obstructive pulmonary disease

Abstract

Background

Chronic obstructive pulmonary disease (COPD) is a persistent, chronic inflammatory disease of the lungs. Tiotropium, used in the treatment of COPD, is a muscarinic receptor antagonist that provides long-acting bronchodilation. Our study aimed to investigate the effects of Tiotropium on anterior chamber parameters.

Methods

The study was conducted as an observational cross-sectional and prospectively between October 2023 and April 2024. Patients were examined in three groups: Group 1 consisted of untreated COPD patients; Group 2 consisted of healthy volunteers similar age and gender, and Group 3 included COPD patients receiving Tiotropium 18 mcg via HandiHaler. Anterior chamber parameters, intraocular pressure values, and photopic-mesopic pupil diameters were measured at the initial visit for Group 1 and Group 2 patients, and at the third month of treatment for Group 3 patients.

Results

Thirty-six patients were included in each group in the study. No significant differences were observed in ocular findings between the patient and control groups. In COPD patients receiving Tiotropium, narrowing of angle parameters, an increase in photopic-mesopic pupil diameters, and intraocular pressure were observed at the third month of treatment.

Conclusion

This study is the first research that investigate the effects of Tiotropium on anterior chamber parameters, pupil diameters, and intraocular pressure in COPD treatment. In conclusion, patients with COPD receiving Tiotropium therapy for three months showed narrowing in angle parameters, an increase in intraocular pressure, and photopic-mesopic pupil diameter; however, no patients developed drug-induced acute angle closure glaucoma.

Trial registration

An independent ethics committee approved the study (Giresun EAH KEAK 2023/180 and 9.10.2023/02) which was performed in accordance with the Declaration of Helsinki, Guidelines for Good Clinical Practice. The study was conducted as prospectively, observational case–control. The Clinical Trial Number obtained for the study is NCT06525051 and was taken on 2024–07-29.

Introduction

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by persistent obstruction of the airways and chronic respiratory symptoms, often with progressive features [1]. The basic pathophysiological events in the course of COPD can be defined as airflow limitation, air trapping, changes in lung parenchyma, gas exchange abnormalities, excessive mucus secretion, and vascular changes [2].

There are five types of muscarinic receptors in the airways (M1-M5). M3 receptors mediate the bronchoconstrictor effect of acetylcholine in the airways. Therefore, antimuscarinic drugs that selectively block M3 receptors are considered ideal agents in the treatment of chronic airway disorders [3].

Bronchodilator drugs are used initially for pharmacotherapy in COPD. Short-acting bronchodilators are used for rapid symptom relief, while long-acting bronchodilators provide more prolonged symptom control. One of the long-acting bronchodilator drugs is inhaled antimuscarinics and the first member of this drug class is Tiotropium. Inhaled antimuscarinic drugs have been used in the treatment of COPD for many years and have a bronchodilator effect lasting more than 24 h [4]. Tiotropium reduces exacerbations of the disease and related hospitalizations and improves quality of life by providing effective symptom control.

Inhaled antimuscarinic agents have a broad therapeutic range and are well tolerated [5]. The most common side effects of Tiotropium include dry mouth, metallic taste in the mouth, and ocular side effects such as visual disturbances, mydriasis, increased intraocular pressure, narrow-angle glaucoma, and cataracts [6].

This study aims to investigate the effects of Tiotropium, a long-acting bronchodilator used in the treatment of COPD, on anterior chamber parameters.

Materials and methods

The study was conducted as prospectively, observational case–control at the Chest Diseases and Ophthalmology Clinic of Giresun Training and Research Hospital between October 2023 and April 2024 after obtaining local Ethics Committee approval (Giresun EAH KEAK 2023/180 and 9.10.2023/02). The Clinical Trial Number obtained for the study is NCT06525051 and was taken on 2024–07-29. Patients diagnosed with COPD and included in Group A according to the GOLD 2024 guidelines, along with healthy volunteers, were enrolled. Patients diagnosed with COPD, with mMRC scale 0–1, CAT score < 10, who had never experienced an exacerbation before or had a mild severity exacerbation once that not required hospitalization were considered as Group A [1].

Three groups were formed for the study. Group 1 consisted of COPD patients not receiving treatment, Group 2 consisted of healthy volunteers for similar age and gender, and Group 3 consisted of COPD patients of the same age and gender with receiving Tiotropium 18 mcg Handihaler. Anterior chamber parameters, intraocular pressure values and photopic-mesopic pupil diameters were measured at the initial visit for Group 1 and Group 2 patients, and at the third month of treatment for Group 3 patients.

Patients under 18 years of age, pregnant women, those who did not provide written consent, patients diagnosed with COPD who were using inhaled and/or systemic steroids, those using long-acting inhaled beta-2 agonists alone, and those using combined long-acting beta-2 agonists and long-acting anticholinergics, patients with comorbidities receiving medication (e.g., diabetes mellitus, hypertension), those diagnosed with or suspected of glaucoma, those using topical medication, those with shallow anterior chambers, those had previously undergone eyelid, refractive, or intraocular surgery, those with corneal diseases altering the corneal surface, those using contact lenses, and those with chronic eye diseases were excluded from the study.

Anterior segment optical coherence tomography (AS-OCT) was used to measure anterior chamber and angle parameters, corneal topography was utilized to assess anterior chamber depth, pupil diameter measurements in mesopic and photopic conditions, and intraocular pressure (IOP) was calculated using Goldmann applanation tonometry. Each patient underwent a comprehensive ophthalmic evaluation, including testing of best-corrected visual acuity, slit-lamp biomicroscopy, and fundoscopic examination.

Anterior segment optical coherence tomography (AS-OCT)

Ocular measurements were performed using the AS-OCT device (NIDEK RS-3000, NIDEK Co. Ltd, Japan). All measurements were conducted by the same AS-OCT operator, who was blinded to the treatment. Measurements were obtained for nasal and temporal quadrants (180° and 0° meridians) using the ACA line until adequate centering and quality were achieved.

The width of anterior chamber angle (ACA) was measured by calculating the angle between the posterior corneal angle and the tangent iris line. After manually identifying the apex of the iris recess and scleral protrusion, the width of ACA was analyzed using standard parameters. Angle opening distances (AOD), measured at 750 mm (AOD 750) and 500 mm (AOD 500), were measured as the perpendicular distances from the anterior surface of the iris to the scleral spur at 750 mm and 500 mm, respectively. Trabecular iris space area (TISA) was defined as the trapezoidal area (TISA 750 or 500) limited by the vertical distance between the anterior iris surface, the inner corneo-scleral wall, and the scleral spur, for either AOD 750 or 500 (Fig. 1). Intraocular pressure measurements were performed around 10:00 a.m. by the same researcher using the same Goldmann applanation tonometer, without any manipulation of the eyelids or with negligible manipulation. Angle parameters measured with anterior segment OCT were obtained by the same researcher, using the same device, at the same times of day and under similar lighting conditions.

Fig. 1

Anterior segment OCT image of angle parameters. ACA Anterior Chamber Angle, TISA Trabecular Iris Space Area, AOD Angle Opening Distance

Corneal topography

Corneal topography (Topcon Aladdin Corneal Topography, Japan) was used to evaluate anterior chamber depth and pupil diameter in mesopic and photopic conditions. Pupil diameters measured with corneal topography were obtained by the same researcher, using the same device, at the same times of day and under similar lighting conditions.

Goldmann applanation tonometry

In addition, intraocular pressure was measured using Goldman Applanation tonometry. All measurements were conducted by the same researcher around 10 a.m., using the same tonometer device, without any manipulation or negligible manipulation of the eyelids. Applanation was performed by rotating the dial on the Goldman tonometer previously set to 10 mm Hg. The procedure was repeated after one minute. If the difference between the first and second readings was greater than 2 mm Hg, a third reading was performed. The average of the data obtained from two readings was taken, and if a third reading was needed, the median was used instead.

Statistical analysis

Statistical analysis was performed using IBM SPSS v23. The normality distribution of quantitative data was assessed using the Shapiro–Wilk test. Independent samples t-test was used for normally distributed quantitative data comparison. The Pearson Chi-square test was used for qualitative data comparison. Data were presented as mean ± SD, minimum—maximum, and n (%). A p-value of < 0.05 was considered statistically significant.

Results

Thirty-six patients were included in each group in the study. Healthy volunteers matched for similar age and gender were included as the control group. There were no significant differences in age and gender between all three groups. The demographic characteristics, smoking status, mMRC score, CAT score, exacerbation history in the last year and spirometry results of COPD patients not using any bronchodilator (Group 1) and those using only Tiotropium (Group 3) are presented in Table 1. Group 1 consisted of 58.3% (n = 21) active smokers, while 52.8% (n = 19) of group 3 were ex-smokers. All patients in group 3 had an mMRC score of 1. %47.2 (n = 17) of group 1 did not experience any exacerbations of COPD in the last year, whereas all of group 3 experienced one exacerbation in the last year. There were no statistically significant differences observed between group 1 and group 3 in terms of smoking status, CAT score and spirometry findings. In group 3, parameters of mMRC score and COPD exacerbation in the last year were found to be statistically significant (p < 0.001).

Table 1 Demographics characteristics of groups

No significant differences were observed in ocular findings between COPD patient group and healthy volunteers matched for age and gender (Table 2). According to the ocular measurements at the third month, a decrease was observed in ACD, ACA T, ACA N, AOD 500 T, AOD 500 N, AOD 750 T, AOD 750 N, TISA 500 T, TISA 500 N, TISA 750 T and TISA 750 N values, while an increase was observed in photopic diameter, mesopic diameter, and IOP values. Statistically significant differences were observed in ocular measurements between patients receiving Tiotropium therapy (Group-3) and those not receiving any bronchodilator therapy (Group-1) (Table 2).

Table 2 Comparison of anterior chamber and angle parameters between groups

After three months of Tiotropium therapy in patients diagnosed with COPD; narrowing in angle parameters, an increase in photopic-mesopic pupil diameters and intraocular pressure were observed.

Discussion

Chronic inflammation and hypoxia seen in COPD can lead to ocular changes such as choroidal thinning, thinning of the retinal nerve fiber layer, retinal arterial hypoxia, increased retinal vein diameter, and subfoveal choroidal thickening [7].

In a study evaluating the effects of anticholinergic drugs in stable COPD, it was reported that accidental application of any anticholinergic drug directly to the eye during inhalation could cause pupil dilation and blurred vision, potentially exacerbating acute glaucoma [8]. These effects may occur when the drug is administered using a metered-dose inhaler (MDI) with eyes open, a poorly fitting mask with a nebulizer inhaler, or when inhaled in HandiHaler form [8]. Francis et al. reported a statistically significant increase in intraocular pressure in COPD patients following inhaler Tiotropium therapy [9]. Similarly, Verma et al. reported an increase in intraocular pressure after inhaled Tiotropium therapy [10]. In our study, we included healthy volunteers to investigate if HandiHaler Tiotropium has a more pronounced effect on the anterior chamber without influencing anterior chamber parameters, pupil diameter, and IOP in COPD. Tasli et al. reported no statistically significant difference in anterior chamber depth between COPD patients and healthy volunteers in their study comparing anterior segment parameters between the two groups [11]. In this study, we evaluated not only anterior chamber depth but also all angle parameters (AOD500, AOD750, TISA500, TISA750), anterior chamber angle (ACA N, ACA T), pupil diameters (mesopic, photopic), and intraocular pressure (IOP) between COPD patients not using any bronchodilator (Group 1) and healthy volunteers (Group 2). We found no statistically significant differences in any of these parameters between the two groups. The lack of significant differences in anterior chamber and angle parameters between Group 1 and Group 2 may be attributed to several factors. Patients in Group 1 did not use medications (such as steroids) that could potentially affect eye parameters. Additionally, both groups of patients did not have comorbidities (such as hypertension, diabetes mellitus, or glaucoma) that could lead to pathological findings in the eyes, as per exclusion criteria. These factors likely contributed to the absence of significant differences observed in the eye parameters between the two groups.

A case of unilateral angle closure glaucoma in the right eye of a patient using Tiotropium for COPD was reported by Oksuz et al. They speculated that the shorter axial length and narrower anterior chamber angle in the patient's right eye, as well as the dilation of the pupil caused by the Tiotropium treatment, contributed to the development of angle closure glaucoma. They hypothesized that the reason for the absence of angle closure glaucoma in the left eye was likely due to the wider anterior chamber angle resulting from the patient's previous cataract surgery in the left eye. They also suggested that patients receiving Tiotropium therapy should be warned about the inadvertent exposure of the eyes to Tiotropium dry powder with compromised capsule integrity, which could potentially lead to acute angle closure glaucoma, especially in high-risk individuals [12].

An analysis of Tiotropium found that neither the HandiHaler nor nebulized forms caused glaucoma development or worsening of preexisting glaucoma when compared to the placebo group [13]. Another study found that short- and long-acting antimuscarinic drugs (Ipratropium and Tiotropium) in MDI form did not cause a significant increase in intraocular pressure in COPD patients [14].

In our study, although narrowing in angle parameters, an increase in photopic-mesopic pupil diameter, and intraocular pressure values were observed in COPD patients receiving Tiotropium therapy via HandiHaler, none of the patients developed acute angle closure glaucoma due to the treatment. There were no ocular or systemic side effects potentially leading to discontinuation of the medication were observed in patients receiving Tiotropium therapy. We hypothesize that the increase in both mesopic and photopic pupil diameters could be attributed to anticholinergic effects of Tiotropium. The resulting partial mydriasis may cause peripheral iris crowding into the iridocorneal angle. This tissue crowding could partially obstruct aqueous humor outflow through the trabecular meshwork, leading to angle narrowing and a potential increase in intraocular pressure.

Since patients identified with narrow angles during anterior segment examinations were excluded from our study, the results allow for certain conjectures to be made regarding individuals with narrow angles. The findings suggest that reductions in angle parameters observed in patients using HandiHaler Tiotropium could be particularly clinically significant for those with narrow angles. In patients with narrow angles, HandiHaler Tiotropium may potentially lead to angle closure glaucoma. In patients with glaucoma, HandiHaler Tiotropium should be used cautiously due to its potential to increase intraocular pressure by causing pupil dilation, which can reduce the passage of aqueous humor through the iridocorneal angle. Similarly, when planning intraocular anterior segment surgery, potential changes in angle parameters, intraocular pressure, and pupil diameter due to HandiHaler Tiotropium should be considered.

This study is the first research that investigate the effects of HandiHaler Tiotropium on anterior chamber parameters, pupil diameters, and intraocular pressure in the treatment of COPD. It suggests that prior to commencing Tiotropium treatment for stable COPD, patients should undergo a detailed ophthalmological examination, and particular caution should be exercised in receiving of Tiotropium therapy in patients with narrow anterior chamber angles. Furthermore, due to the risk of exposure to the powdered form of Tiotropium when the capsule integrity is compromised, it should be specifically emphasized to patients that the medication should be used without compromising the capsule integrity.

Limitations of our study include the relatively small sample size, short-term follow-up, and the use of only the HandiHaler form of the drug.

Conclusion

In conclusion, patients receiving Tiotropium therapy via HandiHaler for three months showed narrowing in angle parameters, an increase in intraocular pressure, and photopic-mesopic pupil diameter; however, no patients developed drug-induced acute angle closure glaucoma.

Although acute angle closure glaucoma was not observed in patients using Tiotropium for three months, the changes in angle parameters raise concerns about the careful use of Tiotropium therapy, especially in patients with narrow angles. The reliability of our study could be further supported by larger patient cohorts and more comprehensive studies with longer follow-up periods.