|Year : 2017 | Volume
| Issue : 1 | Page : 44-49
Clinical effectiveness of anticholinergic tiotropium bromide as an add-on therapy in patients with severe bronchial asthma: A randomized controlled trial
VG Santhosh, Gajanan S Gaude, Jyothi Hattiholi
Department of Pulmonary Medicine, Jawaharlal Nehru Medical College, Belagavi, Karnataka, India
|Date of Web Publication||18-Jan-2017|
Dr. V G Santhosh
Department of Pulmonary Medicine, Jawaharlal Nehru Medical College, KLE University, Belagavi, Karnataka
Source of Support: None, Conflict of Interest: None
Background and Objectives: Severe asthma seen in substantial proportion of patients has been a poorly controlled disease, with recurring symptoms and exacerbations despite the use of inhaled glucocorticoids (ICS), long-acting beta-agonists (LABAs-2), leukotriene receptor antagonist (LTRA), and theophyllines. A potential alternative approach is addition of a second bronchodilator with an alternative mode of action, the anticholinergic tiotropium bromide. Hence, the present study was undertaken to evaluate clinical effectiveness of tiotropium bromide 18 mcg as add-on therapy in severe asthma patients.
Methodology: A single-blinded randomized study was carried in patients with severe asthma. The patients were randomized into two groups. The study group received an addition of 18 mcg of tiotropium while both groups were continued on LABA and high dose ICS combination, theophyllines, and LTRA. Improvement in lung function (forced expiratory volume in 1 s [FEV1], forced vital capacity [FVC], and peak expiratory flow rate [PEFR]), clinical symptoms, and quality of life were assessed by mini asthma quality of life questionnaire (mini-AQLQ) at 4, 8, and 12 weeks.
Results: Seventy patients were included in the study, of which 63 completed the study period. Baseline characteristics were well matched between the groups. At the end of 12 weeks, the tiotropium group showed a mean improvement in FEV1 and FVC of 450 ml and 560 ml, respectively, as compared to the control group (P < 0.0001). PEFR showed mean difference of 16.8 L/min in the study group at the end of 12 weeks as compared to the control group and it was statistically significant (P < 0.0001). Quality of life as assessed by mini-AQLQ was statistically significant in study group as compared to control group (3.42 vs. 3.07; P < 0.0001). In study group, about 21 patients (65.62%) had no exacerbations compared to eight patients (25.8%) in the control group (P = 0.045).
Conclusions: The addition of once-daily tiotropium to severe asthma treatment regimen including high-dose ICS plus LABA, theophyllines, and LTRA significantly improves lung functions and quality of life over 12 weeks of therapy.
Keywords: Forced expiratory volume in 1 s, lung functions, mini asthma quality of life questionnaire, severe asthma, tiotropium bromide
|How to cite this article:|
Santhosh V G, Gaude GS, Hattiholi J. Clinical effectiveness of anticholinergic tiotropium bromide as an add-on therapy in patients with severe bronchial asthma: A randomized controlled trial. Indian J Health Sci Biomed Res 2017;10:44-9
|How to cite this URL:|
Santhosh V G, Gaude GS, Hattiholi J. Clinical effectiveness of anticholinergic tiotropium bromide as an add-on therapy in patients with severe bronchial asthma: A randomized controlled trial. Indian J Health Sci Biomed Res [serial online] 2017 [cited 2019 Oct 20];10:44-9. Available from: http://www.ijournalhs.org/text.asp?2017/10/1/44/198588
| Introduction|| |
Asthma is one of the most common chronic diseases in the world. It is estimated that around 300 million people in the world currently have asthma. The rate of asthma increases as communities adopt western lifestyles and become urbanized. Worldwide, asthma accounts for around 1% of all disability adjusted life years lost, which reflects the high prevalence and severity of asthma.
The overall burden of bronchial asthma in India is estimated to be more than 15 million. In a study conducted in India, the prevalence of asthma is found to be 2.05%; rural - 2.28% and urban - 1.64%. Aggrawal et al. reported that the overall prevalence of asthma in the various populations (Delhi, Bengaluru, Kanpur) studied was 2.38%.
Severe asthma which is seen in substantial proportion of patients, has been a poorly controlled disease, with recurring symptoms and exacerbations despite the use of inhaled glucocorticoids (ICS), long-acting beta-agonists (LABAs), and the last recommended step in global initiative for asthma (GINA) such as leukotriene receptor antagonist (LTRA), theophylline derivatives, and anti-IgE antibody.
A potential alternative approach is the addition of a second bronchodilator with an alternative mode of action, the anticholinergic tiotropium bromide, which has been shown to be effective in patients with chronic obstructive pulmonary disease (COPD), where it has been widely used. Beneficial effects of tiotropium maintenance dosing in patients with bronchial asthma have been reported in few studies.,,
Since there are few studies in literature which have proved the efficacy of long-acting muscarinic anticholinergics in the management of severe asthma, the current study was undertaken to evaluate the clinical efficacy of tiotropium bromide in severe bronchial asthma.
| Methodology|| |
Source of data
The present prospective study was conducted in the Department of Pulmonary Medicine, KLE's Dr. Prabhakar Kore Hospital and Medical Research Centre, Belagavi, in bronchial asthma patients during January 2014-December 2014.
Institution-based single-blinded, randomized controlled trial.
A total of 63 diagnosed cases of severe bronchial asthma were analyzed in the study.
Patients diagnosed with severe bronchial asthma between the age group of 18 and 75 years will be included in the study.
Severe bronchial asthma is defined as:
- Poor symptom control: Mini asthma quality of life questionnaire (mini-AQLQ) ≥1.5
- Patient requiring high-dose ICS therapy: Patient on high-dose inhaled corticosteroids (ICS) and long-acting beta-agonist or systemic corticosteroid (high dose ICS is budesonide ≥800 and its equivalent )
- Frequent or severe exacerbations: Two or more times systemic corticosteroid requirements, including those requiring emergency visits or hospitalization.
- Lifetime smoking history >10 pack years
- Diagnosis of COPD
- Concurrent use of anticholinergic bronchodilators
- Serious coexisting illness.
The study was approved by the ethical and research committee of Jawaharlal Nehru Medical College, Belagavi. Selected patients were briefed about the study and written informed consent was obtained.
Lung function tests were done at the baseline of study using spirometer. The parameters that were recorded include forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and peak expiratory flow rate (PEFR). Moreover, all the patients were requested to complete mini-AQLQ, which consist of total 15 questions; first 11 questions are based on patient's symptoms and remaining four questions are based on daily activities with score ranging from 1 to 7 to assess the quality of life. After initial assessment, all the patients were then randomized on block randomization in 1:1 ratio in either study or control groups. Patients in study group received 18 mcg of tiotropium bromide once daily by dry powder inhaler/metered dose inhaler (DPI/MDI). Whereas both groups were continued on standard therapy as per GINA guidelines which consist of LABA and ICS combination, theophylline's and leukotriene's receptor antagonist.
All the patients will be followed up for total period of 12 weeks. At the end of each 4 weeks, interval clinical symptom, lung function, and mini-AQLQ were assessed.
This is a randomized controlled study in which spirometric values, mini-AQLQ score were assessed and recorded till 12 weeks of follow-up. Comparison of age, body mass index, and duration of the illness between the groups was done using student unpaired t-test. The presence of comorbidities and presentation of symptoms on admission were compared using Mann-Whitney U-test. Spirometric values such as FEV1, FVC, FEV1/FVC, and PEFR and mini-AQLQ recorded at different points of time during the study were compared between the study and control groups using student unpaired t-tests. A P < 0.05 was considered statistically significant.
| Results|| |
A total of seventy patients were included in the study [Figure 1]. Seven patients were lost for follow-up, three in the study group and four in control group. Final analysis was done on 63 patients.
Both the groups are well matched [Table 1]. Mean age of the patients in the study group is 48.0 ± 12.0 years and in the control group is 45.2 ± 11.8 years (P = 0.357). There were 17 males (53.1%) and 15 female patients (46.8%) in the study group, whereas in the control group, 14 were males (45.1%) and 17 were female patients (54.8%) [Table 1]. Mean duration of asthma was higher in the study group compared to the control group (7.6 ± 2.7 year vs. 7.3 ± 1.9 year) although it was not statistically significant (P = 0.6196) [Table 1]. A number of smokers were relatively higher in study group (21.8% vs. 15.8%) compared to control, but it was not statistically significant (P = 0.806). There were relatively more number of admissions due to exacerbation in study group in previous year [Table 1].
|Table 1: Baseline demographic characteristics of patients at enrollment to study |
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We observed that improvement in FEV1 till 4th week of therapy was almost similar in both the groups while at 8th and 12th weeks, there was statistically significant improvement in FEV1 in the study group as compared to the control group (P < 0.0001). Moreover, there was gradual improvement in FVC over a period of 12 weeks in tiotropium group as compared to control group (without tiotropium) and it was statistically significant (P < 0.0001) [Table 2].
|Table 2: Spirometric value at variable intervals during the study period |
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We observed that there was no significant improvement in PEFR at 4 and 8 weeks of treatment between group while at the end of 12 weeks, there was minimal improvement in the study group (tiotropium group) as compared to the control group and it was statistically significant (2.49 ± 0.44 L/S vs. 2.19 ± 0.27 L/S, P < 0.0020) [Table 2].
For assessment of clinical symptom and quality of life, we used mini-AQLQ questionnaire and it was observed that after 4 and 8 weeks of therapy, there was minimal difference between groups and statistically not significant. While at the end of 12 weeks of therapy, there was significant improvement in mini-AQLQ score and statistically significant in tiotropium group compared to control group (P < 0.0001) [Table 3].
|Table 3: Mini asthma quality of life questionnaire score at variable intervals during the study period |
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We observed significant mean change in FEV1 from baseline to 12 weeks between study group and control group (710 + 360 ml vs. 260 + 190 ml), with difference of 450 + 170 ml and it was statistically significant (P < 0.001) [Table 4]. And also, there was significant mean change in PEFR from baseline to 12 weeks between tiotropium and without tiotropium group (38.4 + 27 L/m vs. 21 + 19.2 L/m), with statistically difference of 16.8 + 7.8 L/m [Table 4].
|Table 4: Mean change of spirometric variables from baseline to 12 weeks |
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In our study, we observed that 65.6% (n = 21) of patients in tiotropium group had no exacerbations during the study period compared to control group (25.85%, n = 8) and it was statistically significant (P < 0.045). 34.37% (n = 11); patients in study group had 1-2 exacerbations while in control group, 64.51% (n = 20) had 1-2 exacerbations and 9.67% (n = 3) had more than two exacerbations [Table 5].
|Table 5: Number of exacerbations in the study and control groups during the study period |
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About 13 patients (40.6%) in the study group and nine patients (29.o %) in the control group had developed minor adverse effects. These were mild and transient in nature and included dry mouth, headache, increased cough, sinusitis, and upper respiratory tract infection. There was no statistical difference between the two groups (P < 0.6822) [Table 6].
| Discussion|| |
Severe bronchial asthma seen in substantial proportion of patients is poorly controlled disease with recurring symptoms and exacerbations. Treatment of these individual patients is always challenging as they remain symptomatic despite treatment with high-dose ICS and LABA combination with addition of second controller medications such as theophyllines and/or LTRA. A potential alternative approach is the addition of a second bronchodilator with an alternative mode of action, the anticholinergic tiotropium bromide, which has been shown to be effective in patients with COPD, where it has been widely used.
In our study, there was significant mean improvement in FEV1 values in the study group from enrollment to 8 weeks and to 12 weeks compared to the control group and this was statistically significant (P < 0.035 and P < 0.001, respectively) [Table 2]. The mean difference in FEV1 from baseline was observed to be 210 ml and 450 ml at 8 weeks and 12 weeks, respectively. Peters et al. study showed mean improvement of 100 ml in FEV1 in tiotropium group at the end of 4 weeks as compared with doubling the dose of ICS. Kerstjens et al. did another two replicate studies involving 912 patients. At the end of 24 weeks, the mean (± standard error) change in the peak FEV1 from baseline was greater with tiotropium than with placebo in two trials: a difference of 86 ± 34 ml in trial 1 (P = 0.01) and 154 ± 32 ml in trial 2 (P < 0.001). In another study by Park et al., only about 46 of the 138 asthmatics (33.3%) responded to tiotropium treatment.
We observed in our study, there was a gradual increase in FVC over a period of 12 weeks in tiotropium group and it was statistically significant as compared to control group (P < 0.0001) [Table 2]. The mean improvement from baseline to 4 weeks, 8 weeks, and 12 weeks was 150 ml, 280 ml, and 560 ml, respectively, in tiotropium group and it was statistically significant as compared to control group. Kerstjens et al. observed trough FVC improvement of 127 ml in 5 mcg and 119 ml in 10 mcg of tiotropium group and it was statistically significant as compared to placebo (P < 0.001).
In another trial by Kerstjens et al. involving 912 patients, they were observed that peak FVC improvement was 89 ml at the end of 24 weeks and 125 ml at the end of 48 weeks in trial 1 in tiotropium group as compared to placebo, and trial 2 also showed similar improvement of 94 ml and 114 ml at the end 24 weeks and 48 weeks, respectively.
PEFR is the maximal flow achieved during maximally forced expiration initiated at full inspiration which is measured in L/S or L/min. Peak flow rate primarily reflects large airway flow and depends on the voluntary effort and muscular strength of the patient. In our study, we observed that PEFR at the end of 4 weeks and 8 weeks was almost similar in tiotropium and control group. However, at the end of 12 weeks, there was statistically significant improvement in PEFR in patients who received 18 mcg tiotropium DPI/MDI once daily as compared to the control group (2.4 + 0.4 L/S vs. 2.1 + 0.2 L/S; P < 0.002). Mean improvement of PEFR from baseline showed no significant difference at the end of 4 weeks and 8 weeks between the two groups. However, at the end of 12 weeks, there was 16.8 L/min mean improvement in PEFR from baseline with once-daily tiotropium group as compared to control group and it was statistically significant (P < 0.006) [Table 4].
Peters et al. observed that patients who were receiving tiotropium had a morning PEF that of 25.8 L/min higher than the patients who received double dose of glucocorticoids (P < 0.001). Fardon et al. observed that addition of 18 mcg of tiotropium to half the dose of ICS and LABA, when compared to double the dose of ICS and LABA combination, was superior with mean improvement in morning PEFR of 55.3 L/min versus 41.5 L/min (P < 0.01).
The mini-AQLQ is a shorter and simpler questionnaire. It has only 15 items with a 2-week recall, and weighting, scoring, and analysis of mini-AQLQ are similar to AQLQ in all respects. A higher score indicates better health-related quality of life. In our study, we found that there was clinically significant improvement in quality of life as assessed by mini-AQLQ at the end of 12 weeks with 0.4 score (3.4 ± 0.3 score vs. 3.0 ± 0.3 score) improvement from enrollment in patients who were on 18 mcg of tiotropium once daily as compared with control group (P < 0.0001). At the end of 4 weeks (3.08 ± 0.3 score vs. 3.07 ± 0.3 score) and 8 weeks (3.2 ± 0.4 score vs. 3.0 ± 0.2 score), there was no significant difference observed in mini-AQLQ [Table 3]. Mean improvement in mini-AQLQ score of 0.19 and 0.44 from baseline to 8 weeks and to 12 weeks, respectively, was observed in tiotropium group compared to control group and it was statistically significant (P < 0.048 and P < 0.001, respectively).
Kerstjens et al. did a two replicate trials and they observed significant differences in the AQLQ score between the tiotropium and the placebo groups at the end of 24 weeks. In trial 2, there was a significant improvement in AQLQ (0.18 units, P = 0.02); however, in trial 1, the difference (0.04 units) was not significant.
Fardon et al. observed no significant improvement in mini-AQLQ score in any of the three groups, first group who were on high-dose ICS alone (5.0 score), second on half the dose of ICS and LABA combination (5.3 score), and third group on ICS plus LABA and tiotropium (5.3 score).
In our study, they were significantly less exacerbations. A total of 65.6% of patients had no exacerbations during treatment period of 12 weeks who were using tiotropium as compared to control group (25.8%) and it was statistically significant (P < 0.045) [Table 5]. Peters et al. observed no significant difference in exacerbations between tiotropium and double ICS or with salmeterol group. Kerstjens et al. observed that in tiotropium group, 122 of 453 patients (26.9%) had at least one severe exacerbation as compared with 149 of 454 patients (32.8%) in the placebo group.
| Conclusions|| |
In the present study, it was observed that after addition of 18 mcg tiotropium bromide, there was improvement in FEV1 at 8 weeks and 12 weeks, FVC improved at 4 weeks, 8 weeks, and 12 weeks, and PEFR improved at 12 weeks and these spirometric changes were well correlated with improvement in quality of life with a significant decrease in number of exacerbations and increase in mini-AQLQ score over 12 weeks of therapy and this can be translated into clinical practice.
Recently, in 2015, Food and Drug Administration (USA) has approved tiotropium as an add-on therapy in uncontrolled bronchial asthma.
The study has some limitations. First, the sample size is relatively small. Second, mini-AQLQ questionnaire is not validated for regional local language of Kannada and Marathi, so the questionnaire was given in English and translated orally. Many patients found difficulty in completing the questionnaire and most of them required the help of health educators for completing questions. Finally, this was a single-center and a single-blinded study. Hence, the results cannot be generalized to the general population.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]