Introduction

Long-term management of asthma aims to provide symptom control and reduce future risks including exacerbations, persistent airway limitation, and side effects of treatments in particular. In this respect, a stepwise approach based on the dosage of inhaled corticosteroids (ICS) is recommended. If disease control is not achieved despite a moderate-high dose of ICS and long-acting beta-agonist (LABA) therapy in Steps 4 and 5, add-on therapies are considered following the elimination of modifiable risk factors.¹

Long-acting muscarinic antagonists (LAMAs) antagonize the action of acetylcholine by inhibiting muscarinic M1 and M3 receptors in the airways, resulting in smooth muscle relaxation and reduction in airway inflammation, mucus secretion, and asthma-related airway remodeling.^2,3 In clinical studies, the addition of tiotropium, which is one of the LAMAs and acts mainly on M₃ muscarinic receptors located on smooth muscle cells and submucosal glands, to a medium or high dose of ICS and a second controller therapy, was shown to increase peak and trough forced expiratory volume in 1 s (FEV1) values and delay the time of next asthma exacerbation.^4,5 In 2015, the United States Food and Drug Administration (FDA) approved tiotropium for the maintenance treatment of asthma in patients aged ≥ 12 years.⁶ Based on clinical studies, the Global Initiative for Asthma (GINA) 2015 recommended adding tiotropium to the treatment of patients who were not under control with medium-dose ICS and LABA in Step 4, and in patients whose asthma was not controlled with high-dose ICS and LABA in Step 5.⁷ In real-life studies, the administration of tiotropium as add-on therapy in patients with severe asthma was associated with improved asthma control and lung function. It was shown to significantly reduce the number of emergency room visits and hospitalizations.^8,9 Recently, the effectiveness of fixed-dose combinations of mometasone furoate/indacaterol/glycopyrronium, beclometasone dipropionate/formoterol fumarate/glycopyrronium, and fluticasone furoate/vilanterol/umeclidinium was demonstrated in severe asthma.^10–13 Regarding the clinical trials, the triple combination of ICS/LABA/LAMA was added in Step 5 to the previous recommendations in GINA 2021.¹⁴ Add-on LAMA therapy has been recommended irrespective of the basal asthma phenotype. There is no specific recommendation for which patient group LAMA should be added.¹⁴ Besides that, there is scant data in the literature on the frequency and characteristics of patients with asthma using LAMA.

In this context, the objectives of this study were to determine the frequency of patients using LAMA and to define the sociodemographic and clinical characteristics of these patients in our asthma follow-up center specialized in the management of severe asthma, which has a large and diverse patient population. We also aimed to examine the features that distinguished patients who used LAMA, if any, from patients who were followed up with Steps 4 and 5 medication but did not use LAMA. Thus, additional data will be obtained on the indications of LAMA in the treatment of patients constituting the severe asthma group.

Materials and Methods

Study design and study population

The study was planned as an observational, descriptive, cross-sectional study in accordance with the Declaration of Helsinki. The study protocol was approved by the Local Ethics Committee (Cod: 2023/137).

Data were collected from file records of all patients with asthma who had been on follow-up in our asthma clinic. Our center is experienced in the field of asthma diagnosis and management and is one of the leading referral centers in our country. Patients are examined every day of the week, and the total number of registered patients is over 700 with about 100 new registries annually. A physician and a nurse are assigned to the asthma outpatient clinic in which four professors provide supervision and consultation. Patients with asthma on the treatments of GINA Steps 4 and 5 with at least 1 year follow-up in our center were included after obtaining written permission. It was also noted whether the patients were using LAMA or not. In order to consider patients as “using LAMA,” they should have been on LAMA for at least 6 months.

The LAMA used by the study group was tiotropium because it was the only one approved for asthma and the only LAMA available in our country before 2021.

Clinical data collection

The file review phase of the study was conducted between April 2023 and May 2023. During these dates, the records of patients who had followed up at our center for at least 1 year were reviewed. The data collected included the sociodemographic features of the patients, phenotypic features and clinical presentations of asthma, the presence of allergic and systemic comorbidities, and asthma treatment steps. Clinical follow-up parameters including asthma control test (ACT) scores, asthma exacerbations and hospitalizations in the previous year, and pulmonary function test results were also included. The use of tiotropium as add-on therapy, the treatment step at which tiotropium was initiated, and the current treatment to which tiotropium was added were evaluated. Following data evaluation, the characteristics of the patients using add-on tiotropium were documented as well as their disease features. The outcomes of the patients who did and did not receive tiotropium at Steps 4 and 5 were compared within steps for each step.

Definitions

Phenotypic evaluation

Allergic: Patients who were sensitive to at least one inhalant allergen consistent with their history and clinical features in a skin prick test and/or sp IgE measurement.

Eosinophilic: Patients who had a blood eosinophil count of 300/μL or higher in the oral corticosteroid (OCS)-free period or 150/μL or higher under OCS at least twice during the follow-up period.

Non-eosinophilic: Patients who did not fulfil the eosinophilic requirements were considered non-eosinophilic.

Phenotypic groups: Formed according to eosinophilic/non-eosinophilic and allergic/nonallergic status as follows: allergic eosinophilic (AE), nonallergic eosinophilic (NAE), allergic non-eosinophilic (ANE), nonallergic non-eosinophilic (NANE).

Based on age at asthma onset

Early-onset asthma: Diagnosed before the age of 18 years; Adult-onset: Asthma diagnosed between the age of 18 and 40 years.

Late-onset: After the age of 40 years.

Asthma control status at the last visit

Patients were checked in terms of control status according to the following criteria:

1. Having an ACT score of ≥ 20 at the last visit

2. FEV1 variability of less than 12% between visits in the past year

3. Having no history of asthma exacerbation in the previous year.

Well-controlled patients had to meet all three criteria. Partial-controlled patients did not meet one or two of the criteria. Uncontrolled patients met none of the criteria.

Asthma exacerbation

It is defined as the worsening of asthma symptoms, which requires systemic steroid use for at least 3 days.

Pulmonary function test

Minimum forced expiratory volume in 1 s (FEV1min): lowest FEV1 value during follow-up.

Maximum forced expiratory volume in 1 s (FEV1max): highest FEV1 value during follow-up.

Measurements

Skin prick test

Skin prick tests were performed using common aeroallergen extracts (Dermatophagoides pteronyssinus; Dermatophagoides farinae; mixtures of grass pollens [Dactylis, Festuca, Lolium, Phleum, Poa], tree pollens [Alnus, Betula, Corylus], and cereal pollens [Avena, Triticum, Hordeum, Secale]; weed pollens [Artemisia vulgaris; Parietaria judaica]; molds [Aspergillus fumigatus; Cladosporium; Alternaria alternata]; and cat and dog epithelia) (ALK, Abello, Spain).

Prick tests were considered positive if at least 3 mm or more edema accompanied by erythema occurred in early readings at the 15th minute with validation by positive (histamine 10 mg/mL) and negative controls (saline).

Specific IgE

The ImmunoCAP fluoroenzyme immunoassay system (Phadia, Uppsala, Sweden) was used for specific IgE testing. Values equal to or higher than 0.35 kU/L were defined as positive.

Pulmonary function test

FEV1, forced vital capacity (FVC), peak expiratory flow (PEF), and maximum mid-expiratory flow (MMF) were measured using a spirometry device (ZAN 100, Germany) and evaluated according to the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines.

Statistical analysis

Statistical analyses were performed using the SPSS version 23 software (SPSS, Chicago, III, USA).

The normality of distribution was assessed using the Kolmogrov–Smirnov method. Frequency of distribution was analyzed, and descriptive statistics was calculated using mean and standard deviation for normally distributed variables, and median and interquartile range for non-normally distributed variables. Classified categoric variables were compared using Fisher’s exact test or Pearson’s chi-square (χ²) test, as appropriate. Comparisons of variables between groups were performed using Student’s t-test/Mann–Whitney U test, and one-way analysis of variance (ANOVA). P-values less than 0.05 were considered statistically significant.

Results

In total, 279 patients with asthma received Step 4 (26.5%, n = 74) and Step 5 (73.5%, n = 205) treatment with at least 1-year of follow-up in our clinic. The mean age was 50.84 ± 12.42 years, and 77.1% (n = 215) were females. A total of 79 (28.3%) patients (female/male: 60/19) with a mean age of 52.45 ± 11.61 years used tiotropium as add-on therapy (Figure 1). All patients had regular follow-ups with a median visit number of five per year.^1–15 The median follow-up period of the patients in our center was 7 (min–max: 1–34) years. Most patients were overweight (39.2%, n = 31) or obese (43.0%, n = 34) and had adult (53.2%, n = 42) or late-onset (38.0%, n = 30) asthma. More than half were nonallergic (64.6%, n = 51) and eosinophilic (70.9%, n = 56). The mean ACT score was 20.88 ± 4.70 at the last visit, and more than half of the patients were well-controlled or partially controlled (34.2%, n = 27 and 36.7%, n = 27 respectively) in the previous year (Table 1). The most common allergic comorbidities were allergic rhinitis (30.7%, n = 24), nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) (16.5%, n = 13), venom allergy (5.1%, n = 4), and urticaria (5.1%, n = 4). Chronic rhinosinusitis (34.2%, n = 27), nasal polyposis (25.3%, n = 20), gastroesophageal reflux (19.0%, n = 15), hypertension (13.9%, n = 11), and diabetes mellitus (8.9%, n = 7) were mostly seen as systemic comorbidities.

Figure 1 Flow chart of the study.

Tiotropium initiation was higher in patients using Step 4 medication compared to those using Step 5 medication (n = 28, 37.8% vs n = 51, 24.8%) (P = 0.034).

Tiotropium was used as add-on therapy at Step 4 in 28 patients, constituting 37.8% of the patients who received Step 4 treatment and 35.4% of the patients with add-on tiotropium (Figure 1). The mean age was 54.05 ± 10.45, and 89.3% (n = 25) were females. More than half of the patients were eosinophilic (57.1%, n = 16) and most were nonallergic (71.4%, n = 20). The nonallergic eosinophilic group was the most (39.3%, n = 11), followed by the nonallergic non-eosinophilic group (35.7%, n = 10). When the patients who did (n = 28) and did not (n = 46) receive tiotropium at Step 4 were compared, there was no difference between the two groups in terms of age, sex, being eosinophilic or allergic, BMI, asthma onset, history of smoking, and number of asthma exacerbations in the previous year (Table 2). Although the patients with add-on tiotropium were mostly in the NAE and NANE groups, the distribution of patients in phenotypic groups was more homogeneous than those who did not receive tiotropium; however, there was no statistical difference between the two groups in terms of phenotypes (P = 0.082). Asthma control scores at the last visits were similar in both groups (P = 0.088), but when we looked at the control status in the previous year, patients who received tiotropium were more controlled than those who did not (P = 0.001). The patients who received tiotropium had lower minimum FEV1 scores during the follow-up period (P = 0.030) (Table 2).

Fifty-one patients received tiotropium at Step 5; 24.8% of the patients received Step 5 treatment, and 64.6% of the patients received add-on tiotropium. In 16 patients, tiotropium was added to high-dose ICS-LABA; and in 23 patients, tiotropium was added to high-dose ICS-LABA ± OCS, but these patients eventually switched to biologic therapy. The remaining 12 patients with add-on tiotropium were on biologic therapy in addition to high-dose ICS-LABA ± OCS (Figure 1). Among the patients who followed up with Step 5 treatment in our clinic, compared with the patients with and without add-on tiotropium (n = 51 and n = 154, respectively), there was no difference between the two groups in terms of age, sex, blood eosinophil count, atopy, asthma phenotypes, BMI, age of asthma onset, and smoking history (Table 3). ACT scores of the patients with and without add-on tiotropium were similar (P = 0.362). Patients with add-on tiotropium at Step 5 experienced more frequent asthma exacerbations than those without tiotropium (P < 0.001), and therefore being well-controlled was more common in patients without add-on tiotropium. The rate of being partially controlled was higher in the group with add-on tiotropium (P < 0.001). The patients with add-on tiotropium had lower pulmonary function test values than those without add-on tiotropium (P < 0.001). The mean minimum FEV1 of patients with add-on tiotropium was 1.38 ± 0.55 L (56.49 ± 20.52%), whereas it was 1.99 ± 0.75 L (75.69 ± 18.31%) for patients without tiotropium. The mean maximum FEV1 value of patients with add-on tiotropium was 1.85 ± 0.67 L (72.55 ± 25.52%), and it was 2.48 ± 0.86 L (93.81 ± 18.40%) in the patients without add-on tiotropium (Table 3).

The patients were divided into three groups, Groups 1–3, according to the treatment stage in which tiotropium was added at Step 5. In Group 1 (n = 16), tiotropium was added to high-dose ICS-LABA. In Group 2 (n = 23), which included patients who had tiotropium added to high-dose ICS-LABA and/or low-dose OCS; 4 patients received omalizumab and 19 patients received mepolizumab as biological treatments during follow-up. In Group 3 (n = 12), tiotropium was added to high-dose ICS-LABA and with biologic treatment already being received and/or low-dose OCS. In Group 3 (n = 12), which consisted of patients already receiving biologic therapy, six patients each were on omalizumab and mepolizumab. The proportion of eosinophilia was higher in Groups 2 and 3 than in Group 1 (P = 0.003). Although NAE was higher in Groups 2 and 3 (n = 14, 60.9% and n = 7, 58.3%, respectively), almost half of Group 1 was NANE (n = 7, 43.8%) (P = 0.002). Group 2 had the highest number of asthma exacerbations (P = 0.041). Minimum FEV1 was lower in Group 3 than in Groups 1 and 2 (1.04 ± 0.34 L vs 1.32 ± 0.50 L and 1.58 ± 0.59 L, respectively) (P = 0.018). Similarly, the maximum FEV1 measurement was lowest in Group 3 compared to Groups 1 and 2 (1.56 ± 0.59 L vs 1.64 ± 0.53 L and 2.14 ± 0.69 L, respectively) (P = 0.014). Refer Table 4.

Finally, biologic treatment began before tiotropium in 12 (23.4%) patients with add-on tiotropium in Step 5 treatment (group 3); 117 (76.0%) patients using Step 5 medication without tiotropium were receiving biologic treatment (P < 0.001). As stated before, patients in Group 2 (n = 23) at Step 5 were those who were started on biologic treatment after tiotropium due to asthma exacerbations.

Discussion

The results of our study indicate that tiotropium was initiated as an add-on therapy independent of demographic characteristics and asthma phenotype at both Steps 4 and 5 in our center. However, we tended to initiate tiotropium for patients with low pulmonary functions. Asthma control seemed to increase with the addition of tiotropium in patients using Step 4 medication. In Step 5 treatment, regardless of the stage at which tiotropium was started, asthma control was worse, and asthma exacerbations were more frequent in patients with add-on tiotropium than in those without.

The fact that there was no difference in terms of demographic and clinical characteristics of the patients between the groups using and not using tiotropium in our study suggested that it is not crucial to consider age, sex, asthma phenotype, existence of obesity, asthma onset, and smoking status when starting tiotropium. This finding is also compatible with the recommendations of existing guidelines.¹ Consequently, no certain phenotypic or endotypic feature related to the effectiveness of add-on LAMA was detected in the studies that provided the rationale for this recommendation.^5,11,13,15

Since the first studies investigating the place of LAMAs in asthma treatment, many studies have shown that add-on LAMA increased peak and trough FEV1 values.^4,5,13,16,17 Therefore, although add-on LAMA is recommended in the treatment of asthma regardless of the basal FEV1 value, as well as the baseline inflammatory phenotype,^17,18 it has been preferred in our patients with asthma with low FEV1 in both Steps 4 and 5.

In our study, add-on tiotropium seemed to facilitate achieving overall asthma control in Step 4 according to our composite control assessment including symptom control, exacerbations, and FEV1. In the randomized-control trial evaluating the efficacy of single-inhaler triple therapy in asthma, in one of the two parallel groups including adult patients with uncontrolled asthma previously treated with medium-dose ICS and LABA, the rate of moderate and severe exacerbations decreased significantly accompanied by an increased FEV1 with the addition of LAMA.¹² In the study assessing the efficacy of add-on LAMA (glycopyrronium) to medium-dose ICS and LABA in Step 4, medium-dose ICS/LABA/LAMA increased lung function and reduced asthma exacerbations more than high-dose ICS/LABA.¹⁹ These studies suggest that adding LAMA may be a better option in Step 4 rather than increasing the ICS dose. The finding that tiotropium was started in Step 4 at a significantly higher rate in our clinic and that control was better in patients with add-on tiotropium was compatible with this result.

In contrast to the current GINA recommendation related to adding LAMA before biologic treatment in Step 5, the rate of receiving biologic treatment without tiotropium in Step 5 was higher in our study population. We believe that this is because our center is an allergy–immunology clinic with a high number of patients referred to biologic therapy, and has a high number of patients included in clinical phase trials^20–23 and real-life studies.^24–27 In parallel to our result, in a study with a large population of moderate-to-severe asthmatics assessing the use of LAMA or biologic treatment as an add-on treatment, pulmonologists were more likely to initiate LAMA, whereas allergists tended to initiate biologic treatments.²⁸ The other explanation for the imbalance of initial rates could be that our patients were being followed for a long time and only recently was add-on LAMA treatment placed before phenotyping for biologics in the guidelines. Therefore, although symptom control was similar in both groups, the control status in the previous year was worse in patients with tiotropium than in those without add-on tiotropium. In other words, poor control in patients with add-on tiotropium at Step 5 may be explained by the fact that they were not under biological treatment.

We believe that this study will make a valuable contribution to the data gap on the use of LAMA in patients with asthma because we know it is the first study from our country and one of the limited real-life studies in world literature. However, the study also has some limitations. First, because of being a cross-sectional study, no direct results demonstrating the effect of add-on tiotropium on asthma outcomes could be obtained. In addition, due to the nature of the study, data on follow-up could not be provided. Another limitation is that only the data of patients receiving tiotropium are presented in our study because the triple treatment option in a single device is very recent in our country and our patients have been followed for many years.

Conclusion

In the present study, individuals with asthma using Step 4 medication with add-on tiotropium showed improved asthma control compared with those without add-on tiotropium independent of baseline characteristics and asthma phenotype. Our results showed that we preferred biologic treatment before add-on tiotropium, especially in type-2 dominant individuals in Step 5. Taken together, these findings will help to encourage starting LAMA in patients using Steps 4 and 5 medication before biologics. Future follow-up real-life studies should focus on investigating the effectiveness of add-on LAMA in patients with various phenotypes and distinct features.