Efficacy of Anticholinergic Drugs in Asthma
Efficacy of Anticholinergic Drugs in Asthma
Tiotropium is the first long-acting anticholinergic drug that has been developed in the early 1990s and approved for the management of stable COPD. The efficacy and safety of tiotropium in all stages of COPD severity has been largely demonstrated by several studies, including the recent 4-year UPLIFT study. Despite the large amount of data available on tiotropium in COPD, it is only recently that studies have been conducted in asthma. The decision of not promoting tiotropium in asthma was derived from the opinion that in COPD, and not in asthma, the cholinergic tone played a more relevant role on the airway caliber than the β2-agonist relaxation.
In the last 5 years, several studies have been performed in order to assess whether tiotropium might have positive effects in asthma. The first trials have been conducted in special subgroups of asthmatic patients (patients with asthma and COPD, and those with asthma with persistent bronchoconstriction) but, more recently, some randomized controlled trials (RCTs) have been completed in unselected asthma populations.
Six RCTs and one longitudinal open study included almost 1500 patients with asthma and compared at least 4-week tiotropium treatment (range: 4–16 weeks) added to inhaled corticosteroids (ICS) alone or combined with long-acting β2-agonists (LABAs), with placebo or salmeterol. Apart from the study by Magnussen et al. that took into account patients affected by COPD and asthma, the other studies excluded COPD patients and evaluated persistent asthmatics needing daily therapy. Only two studies were conducted on severe asthmatics with persistent bronchoconstriction who remained, symptomatic despite therapy with a high-dose ICS and LABA. These studies are summarized in Table 2.
The efficacy of tiotropium has been assessed primarily through its impact on lung function evaluated by spirometry or PEF. Moreover, other important outcomes, including symptoms and quality of life, were taken into account.
In a first pilot study by Fardon et al., 26 nonsmoking patients with severe persistent asthma (FEV1: 51% of predicted) were treated with hydrofluoralkanes (HFA)–fluticasone propionate 250 µg/salmeterol 50 µg twice daily plus tiotropium bromide 18 µg once daily, or HFA–fluticasone propionate 250 µg/salmeterol 50 µg twice daily and placebo, for 4 weeks after a run-in period of 4 weeks with HFA~fluticasone 500 µg twice daily. Patients underwent spirometry and body plethysmography in order to evaluate the effect of halving the fluticasone dose with the addition of salmeterol alone or salmeterol plus tiotropium. Adding either salmeterol alone or salmeterol/tiotropium to half the dose of fluticasone led to an improvement versus baseline in morning PEF (+41.5 l/min [p < 0.01] and +55.3 l/min [p < 0.01] respectively) and airway resistance (Raw); moreover, salmeterol/tiotropium also improved FEV1 (+0.17 l [p < 0.05]) and forced vital capacity (FVC; +0.24 l [p < 0.05]). There were no significant changes in symptoms or quality of life compared with baseline in both treatments, which were not significantly different between them.
Recently, a large randomized, crossover, placebo-controlled study has compared the addition of tiotropium bromide to ICS versus the addition of LABA to ICS versus double-dose ICS for 14 weeks, in 210 asthmatics with FEV1of more than 40% of the predicted value (mean prebronchodilator FEV1: 71.5%). The addition of tiotropium to ICS showed a superiority to the double-dose ICS for the morning PEF (mean difference 25.8 l/min [p < 0.001]), which was the primary outcome; and for most secondary outcomes, including evening PEF (mean difference 35.3 l/min [p < 0.00]), pre- and post-bronchodilator FEV1 (mean difference 0.10 l [p = 0.004] and 0.04 l [p = 0.01] respectively), number of asthma-control days (with a difference of 0.079; p = 0.01), daily symptoms score and Asthma Control Questionnaire (with a difference of -0.18 points; p = 0.02) (Figure 2). Moreover, the addition of salmeterol to ICS, compared with double-dose ICS, showed an improvement in these outcomes, except for the pre- and post-bronchodilator FEV1(in particular, for the morning PEF, the mean difference was 19.4 l/min [p < 0.001], and for the evening PEF, the mean difference was 24.7 l/min [p< 0.001]). There were no significant differences between tiotropium and salmeterol treatments with respect to morning PEF (mean difference in change from baseline for tiotropium vs salmeterol: +6.4 l/min), evening PEF, number of asthma-control days, daily symptoms score and Asthma Control Questionnaire. The tiotropium treatment was superior to the salmeterol treatment with respect to the pre- and post-bronchodilator FEV1 measured in the morning (mean difference: 0.11 l [p = 0.003] and 0.07 l [p < 0.001], respectively).
(Enlarge Image)
Figure 2.
Effects of tiotropium and salmeterol, added to low-dose inhaled corticosteroids versus double-dose inhaled corticosteroids, in a short-term crossover study in unselected moderate asthmatics not controlled by low-dose inhaled corticosteroids. Similar effects of tiotropium in comparison with salmeterol were demonstrated for (A) morning and (B) evening PEF, and (D) the percentage of days with asthma control, while (C) a better effect of tiotropium was demonstrated for prebronchodilator FEV1.FEV1: Forced expired volume in 1 s; PEF: Peak expiratory flow.Data taken from [28].
Further studies have confirmed this improvement in pulmonary function, but not in control of symptoms and quality of life. Kerstjens et al. performed a randomized, double-blind, crossover study on 107 patients with uncontrolled severe asthma (mean prebronchodilator FEV1: 58%), despite maintenance treatment with high-dose ICS plus LABA, in order to compare (vs placebo) the efficacy and safety of the addition of two doses of tiotropium (5 and 10 µg daily), administered through the Respimat® inhaler for 8 weeks. The mean peak FEV1response in the first 3 h after dosing at the end of the 8-week treatment period (the primary outcome) was significantly superior to placebo with both tiotropium doses (5 µg: difference from placebo 139 ml [p < 0.001], 10 µg: difference from placebo 170 ml [p < 0.001]). Both doses of tiotropium were significantly superior compared with placebo in all other functional assessments: trough FEV1 (5 µg: difference from placebo 86 ml [p < 0.001]; 10 µg: difference from placebo 113 ml [p < 0.001]), mean peak FVC in the first 3 h after dosing, trough FVC and FVC area under the curve (AUC) 0–3 h, the weekly mean predose morning and evening PEF for weeks 4–8 (for morning PEF, difference from placebo: 7.9 l/min (p = 0.02) with 5 µg, and 15.3 l/min (p < 0.001) with 10 µg). Despite these good results on lung function, no significant effect on clinical parameters was demonstrated. In fact, there were no significant differences among the three treatments in the rescue medication use, the mini-Asthma Quality of Life Questionnaire score (change over the entire period treatment: placebo: 0.108, tiotropium 5 µg: 0.205 and tiotropium 10 µg: 0.206) and in the symptom scores measured with an electronic asthma diary (for asthma symptom days, change over the entire period treatment: placebo: -0.121, for tiotropium 5 µg: -0.140 and for tiotropium 10 µg: -0.152). The lack of efficacy in the patient-reported outcomes can be related to the size of the study and to the design of the study, without an appropriate washout period before the beginning of the tiotropium treatment.
A particular consideration about the use of tiotropium in asthma is the potential interaction between muscarinic and β2-agonist receptors. For example, polymorphisms of the β2-agonist receptor might reduce the responsiveness to β2-agonists and then favorably influence responsiveness to anticholinergics. The polymorphism of the β2-agonist receptor, in particular related to the Arg/Arg versus Gly/Gly polymorphism in the 16th position, has been considered to be associated with a lower response to stimulation by β2-agonists, such as salbutamol, salmeterol and formoterol. In these subjects, anticholinergic drugs may have a more favorable effect than β2-agonists. In this regard, Park et al. studied 138 severe asthmatics, adding tiotropium to their conventional medication, in order to identify prognostic factors of response to tiotropium using a pharmacogenetic approach. These authors defined responders as those patients with an improvement of ≥15% (or 200 ml) in FEV1 that was maintained for at least 8 successive weeks. They reported a higher response rate to tiotropium in asthmatics with the B16 Arg/Arg genotype.
Based on this preliminary result, a recent large placebo-controlled study has been performed only in Arg/Arg patients with asthma noncontrolled with ICS alone. In this study, 388 asthmatics, after a 4-week run-in period with 50 µg of twice-daily salmeterol, were randomized to 16 weeks of treatment with 5 µg Respimat tiotropium once daily, 50 µg salmeterol twice daily, or placebo. The primary end point was the change in the weekly PEF from the last week of the run-in period to the last week of active treatment. Mean weekly morning predose PEF was maintained during the treatment period with tiotropium and salmeterol, but decreased in patients switched to placebo (-3.9 l/min for tiotropium, -3.2 l/min for salmeterol and -24.6 l/min for placebo; p < 0.05). Tiotropium was noninferior to salmeterol (estimated difference: -0.78 l/min), and both tiotropium and salmeterol were superior to placebo. Similar results were obtained for mean weekly evening PEF, FEV1 and FVC (for mean weekly predose FEV1: +0.01 l for tiotropium, -0.01 l for salmeterol and -0.10 l for placebo). The aim of this study was to demonstrate the similar efficacy of tiotropium and salmeterol in a group of asthmatics considered at increased risk of adverse effects by use of β2-agonists and possibly better responders to anticholinergics (on the basis of the study by Park et al.). Before the publication of this study, large prospective studies have shown the safety of the use of β2-agonists in Arg/Arg asthmatics, but the demonstration of a similar efficacy of LABA and tiotropium is still important from a clinical point of view. It is important to note that a similar improvement in pulmonary function was observed in the study by Bateman et al. (mean difference from placebo in morning PEF: 20.7 l/min and in prebronchodilator FEV1: 0.113 l) in comparison with the study by Peters et al. (mean difference from doubling dose ICS in morning PEF: 25.8 l/min and in prebronchodilator FEV1: 0.100 l). However, also in this study, the results on patient-related outcomes were more disappointing, with no significant improvement of tiotropium versus placebo on daytime asthma symptoms (change from baseline: placebo: 0.015; salmeterol: -0.221; tiotropium: -0.088; significant difference between placebo vs salmeterol but not between placebo vs tiotropium), rescue medication use (change from baseline: placebo: 0.294; salmeterol: -0.273; tiotropium: -0.074; significant difference of placebo vs salmeterol but not of placebo vs tiotropium) and quality of life (evaluated by Mini-Asthma Quality of Life Questionnaire; change from baseline: placebo: 0.039; salmeterol: 0.280; tiotropium: 0.131; significant difference of placebo vs salmeterol but not of placebo vs tiotropium). There was no significant difference between the two active treatments on these outcomes.
Another study that deserves to be mentioned is that of Magnussen et al., conducted in a subgroup of patients with COPD and a history of asthma diagnosed before 40 years of age. In this randomized, placebo-controlled study, 472 patients with diagnosis of asthma and COPD were treated with tiotropium or placebo for 12 weeks in addition to the current therapy. Patients were allowed to continue treatments with ICS (inhaled steroid use was an inclusion criteria), LABA, theophyllines, leukotriene inhibitors and/or oral corticosteroids. Tiotropium led to a significant improvement not only in the primary end point, which was the change in FEV1 AUC over 6 h (AUC0–6 h) after 12 weeks of treatment, but also in all secondary outcomes: morning predose FEV1, FVC AUC0–6 h, morning predose FVC, morning and evening PEF, and the use of rescue medications (the mean weekly number of daily puffs of salbutamol was reduced by 0.05 ± 0.12 puffs/day in the placebo group and by 0.50 ± 0.12 puffs/day in the tiotropium group at week 12; p < 0.05).
Another small study conducted by Iwamoto and colleagues on 17 severe persistent asthmatics suggested an association between the responsiveness to tiotropium and the type of inflammatory cells in the induced sputum. This author observed a positive correlation between sputum neutrophils and FEV1 improvement after 4 weeks of therapy, and an inverse correlation between sputum eosinophils and improvement in FEV1 after 4 weeks of therapy, suggesting that tiotropium may be particularly effective in noneosinophilic asthma.
Important outcomes that are not evaluated in all studies published until now are the reduction of exacerbations and the anti-inflammatory effects of tiotropium. Only the studies by Peters et al. and Magnussen et al. reported data about exacerbations. In the study by Peters et al., an asthma exacerbation (for which oral or intravenous glucocorticoids were administered) occurred in seven patients receiving tiotropium, in 13 receiving double-dose corticosteroids and in five receiving salmeterol. In the study by Magnussen et al., an exacerbation of COPD and asthma occurred in 28 patients (11.5%) receiving placebo and in 15 patients (6.6%) receiving tiotropium. These data suggest a possible role of tiotropium in reducing the exacerbation rate, but the observational period of these studies is too short to correctly assess an effect on the frequency of exacerbations.
In terms of a possible impact on airway inflammation, there are only small observations in the studies by Fardon et al. and Peters et al.. In the study by Fardon et al., there was a little but significant reduction (2.86 ppb) in the fraction of exhaled nitric oxide during treatment with fluticasone propionate/salmeterol/tiotropium bromide compared with fluticasone propionate alone, whereas in the latter, patients had at baseline a fraction of exhaled nitric oxide of 18.8 ppb and a sputum eosinophilia of 0.40 × 10 cells, and no treatment determined a significant change in these biomarkers.
In summary, the data obtained so far on the efficacy and safety of tiotropium in asthma show the following results:
Long-acting Anticholinergic Drugs in Asthma
Tiotropium is the first long-acting anticholinergic drug that has been developed in the early 1990s and approved for the management of stable COPD. The efficacy and safety of tiotropium in all stages of COPD severity has been largely demonstrated by several studies, including the recent 4-year UPLIFT study. Despite the large amount of data available on tiotropium in COPD, it is only recently that studies have been conducted in asthma. The decision of not promoting tiotropium in asthma was derived from the opinion that in COPD, and not in asthma, the cholinergic tone played a more relevant role on the airway caliber than the β2-agonist relaxation.
In the last 5 years, several studies have been performed in order to assess whether tiotropium might have positive effects in asthma. The first trials have been conducted in special subgroups of asthmatic patients (patients with asthma and COPD, and those with asthma with persistent bronchoconstriction) but, more recently, some randomized controlled trials (RCTs) have been completed in unselected asthma populations.
Six RCTs and one longitudinal open study included almost 1500 patients with asthma and compared at least 4-week tiotropium treatment (range: 4–16 weeks) added to inhaled corticosteroids (ICS) alone or combined with long-acting β2-agonists (LABAs), with placebo or salmeterol. Apart from the study by Magnussen et al. that took into account patients affected by COPD and asthma, the other studies excluded COPD patients and evaluated persistent asthmatics needing daily therapy. Only two studies were conducted on severe asthmatics with persistent bronchoconstriction who remained, symptomatic despite therapy with a high-dose ICS and LABA. These studies are summarized in Table 2.
The efficacy of tiotropium has been assessed primarily through its impact on lung function evaluated by spirometry or PEF. Moreover, other important outcomes, including symptoms and quality of life, were taken into account.
In a first pilot study by Fardon et al., 26 nonsmoking patients with severe persistent asthma (FEV1: 51% of predicted) were treated with hydrofluoralkanes (HFA)–fluticasone propionate 250 µg/salmeterol 50 µg twice daily plus tiotropium bromide 18 µg once daily, or HFA–fluticasone propionate 250 µg/salmeterol 50 µg twice daily and placebo, for 4 weeks after a run-in period of 4 weeks with HFA~fluticasone 500 µg twice daily. Patients underwent spirometry and body plethysmography in order to evaluate the effect of halving the fluticasone dose with the addition of salmeterol alone or salmeterol plus tiotropium. Adding either salmeterol alone or salmeterol/tiotropium to half the dose of fluticasone led to an improvement versus baseline in morning PEF (+41.5 l/min [p < 0.01] and +55.3 l/min [p < 0.01] respectively) and airway resistance (Raw); moreover, salmeterol/tiotropium also improved FEV1 (+0.17 l [p < 0.05]) and forced vital capacity (FVC; +0.24 l [p < 0.05]). There were no significant changes in symptoms or quality of life compared with baseline in both treatments, which were not significantly different between them.
Recently, a large randomized, crossover, placebo-controlled study has compared the addition of tiotropium bromide to ICS versus the addition of LABA to ICS versus double-dose ICS for 14 weeks, in 210 asthmatics with FEV1of more than 40% of the predicted value (mean prebronchodilator FEV1: 71.5%). The addition of tiotropium to ICS showed a superiority to the double-dose ICS for the morning PEF (mean difference 25.8 l/min [p < 0.001]), which was the primary outcome; and for most secondary outcomes, including evening PEF (mean difference 35.3 l/min [p < 0.00]), pre- and post-bronchodilator FEV1 (mean difference 0.10 l [p = 0.004] and 0.04 l [p = 0.01] respectively), number of asthma-control days (with a difference of 0.079; p = 0.01), daily symptoms score and Asthma Control Questionnaire (with a difference of -0.18 points; p = 0.02) (Figure 2). Moreover, the addition of salmeterol to ICS, compared with double-dose ICS, showed an improvement in these outcomes, except for the pre- and post-bronchodilator FEV1(in particular, for the morning PEF, the mean difference was 19.4 l/min [p < 0.001], and for the evening PEF, the mean difference was 24.7 l/min [p< 0.001]). There were no significant differences between tiotropium and salmeterol treatments with respect to morning PEF (mean difference in change from baseline for tiotropium vs salmeterol: +6.4 l/min), evening PEF, number of asthma-control days, daily symptoms score and Asthma Control Questionnaire. The tiotropium treatment was superior to the salmeterol treatment with respect to the pre- and post-bronchodilator FEV1 measured in the morning (mean difference: 0.11 l [p = 0.003] and 0.07 l [p < 0.001], respectively).
(Enlarge Image)
Figure 2.
Effects of tiotropium and salmeterol, added to low-dose inhaled corticosteroids versus double-dose inhaled corticosteroids, in a short-term crossover study in unselected moderate asthmatics not controlled by low-dose inhaled corticosteroids. Similar effects of tiotropium in comparison with salmeterol were demonstrated for (A) morning and (B) evening PEF, and (D) the percentage of days with asthma control, while (C) a better effect of tiotropium was demonstrated for prebronchodilator FEV1.FEV1: Forced expired volume in 1 s; PEF: Peak expiratory flow.Data taken from [28].
Further studies have confirmed this improvement in pulmonary function, but not in control of symptoms and quality of life. Kerstjens et al. performed a randomized, double-blind, crossover study on 107 patients with uncontrolled severe asthma (mean prebronchodilator FEV1: 58%), despite maintenance treatment with high-dose ICS plus LABA, in order to compare (vs placebo) the efficacy and safety of the addition of two doses of tiotropium (5 and 10 µg daily), administered through the Respimat® inhaler for 8 weeks. The mean peak FEV1response in the first 3 h after dosing at the end of the 8-week treatment period (the primary outcome) was significantly superior to placebo with both tiotropium doses (5 µg: difference from placebo 139 ml [p < 0.001], 10 µg: difference from placebo 170 ml [p < 0.001]). Both doses of tiotropium were significantly superior compared with placebo in all other functional assessments: trough FEV1 (5 µg: difference from placebo 86 ml [p < 0.001]; 10 µg: difference from placebo 113 ml [p < 0.001]), mean peak FVC in the first 3 h after dosing, trough FVC and FVC area under the curve (AUC) 0–3 h, the weekly mean predose morning and evening PEF for weeks 4–8 (for morning PEF, difference from placebo: 7.9 l/min (p = 0.02) with 5 µg, and 15.3 l/min (p < 0.001) with 10 µg). Despite these good results on lung function, no significant effect on clinical parameters was demonstrated. In fact, there were no significant differences among the three treatments in the rescue medication use, the mini-Asthma Quality of Life Questionnaire score (change over the entire period treatment: placebo: 0.108, tiotropium 5 µg: 0.205 and tiotropium 10 µg: 0.206) and in the symptom scores measured with an electronic asthma diary (for asthma symptom days, change over the entire period treatment: placebo: -0.121, for tiotropium 5 µg: -0.140 and for tiotropium 10 µg: -0.152). The lack of efficacy in the patient-reported outcomes can be related to the size of the study and to the design of the study, without an appropriate washout period before the beginning of the tiotropium treatment.
A particular consideration about the use of tiotropium in asthma is the potential interaction between muscarinic and β2-agonist receptors. For example, polymorphisms of the β2-agonist receptor might reduce the responsiveness to β2-agonists and then favorably influence responsiveness to anticholinergics. The polymorphism of the β2-agonist receptor, in particular related to the Arg/Arg versus Gly/Gly polymorphism in the 16th position, has been considered to be associated with a lower response to stimulation by β2-agonists, such as salbutamol, salmeterol and formoterol. In these subjects, anticholinergic drugs may have a more favorable effect than β2-agonists. In this regard, Park et al. studied 138 severe asthmatics, adding tiotropium to their conventional medication, in order to identify prognostic factors of response to tiotropium using a pharmacogenetic approach. These authors defined responders as those patients with an improvement of ≥15% (or 200 ml) in FEV1 that was maintained for at least 8 successive weeks. They reported a higher response rate to tiotropium in asthmatics with the B16 Arg/Arg genotype.
Based on this preliminary result, a recent large placebo-controlled study has been performed only in Arg/Arg patients with asthma noncontrolled with ICS alone. In this study, 388 asthmatics, after a 4-week run-in period with 50 µg of twice-daily salmeterol, were randomized to 16 weeks of treatment with 5 µg Respimat tiotropium once daily, 50 µg salmeterol twice daily, or placebo. The primary end point was the change in the weekly PEF from the last week of the run-in period to the last week of active treatment. Mean weekly morning predose PEF was maintained during the treatment period with tiotropium and salmeterol, but decreased in patients switched to placebo (-3.9 l/min for tiotropium, -3.2 l/min for salmeterol and -24.6 l/min for placebo; p < 0.05). Tiotropium was noninferior to salmeterol (estimated difference: -0.78 l/min), and both tiotropium and salmeterol were superior to placebo. Similar results were obtained for mean weekly evening PEF, FEV1 and FVC (for mean weekly predose FEV1: +0.01 l for tiotropium, -0.01 l for salmeterol and -0.10 l for placebo). The aim of this study was to demonstrate the similar efficacy of tiotropium and salmeterol in a group of asthmatics considered at increased risk of adverse effects by use of β2-agonists and possibly better responders to anticholinergics (on the basis of the study by Park et al.). Before the publication of this study, large prospective studies have shown the safety of the use of β2-agonists in Arg/Arg asthmatics, but the demonstration of a similar efficacy of LABA and tiotropium is still important from a clinical point of view. It is important to note that a similar improvement in pulmonary function was observed in the study by Bateman et al. (mean difference from placebo in morning PEF: 20.7 l/min and in prebronchodilator FEV1: 0.113 l) in comparison with the study by Peters et al. (mean difference from doubling dose ICS in morning PEF: 25.8 l/min and in prebronchodilator FEV1: 0.100 l). However, also in this study, the results on patient-related outcomes were more disappointing, with no significant improvement of tiotropium versus placebo on daytime asthma symptoms (change from baseline: placebo: 0.015; salmeterol: -0.221; tiotropium: -0.088; significant difference between placebo vs salmeterol but not between placebo vs tiotropium), rescue medication use (change from baseline: placebo: 0.294; salmeterol: -0.273; tiotropium: -0.074; significant difference of placebo vs salmeterol but not of placebo vs tiotropium) and quality of life (evaluated by Mini-Asthma Quality of Life Questionnaire; change from baseline: placebo: 0.039; salmeterol: 0.280; tiotropium: 0.131; significant difference of placebo vs salmeterol but not of placebo vs tiotropium). There was no significant difference between the two active treatments on these outcomes.
Another study that deserves to be mentioned is that of Magnussen et al., conducted in a subgroup of patients with COPD and a history of asthma diagnosed before 40 years of age. In this randomized, placebo-controlled study, 472 patients with diagnosis of asthma and COPD were treated with tiotropium or placebo for 12 weeks in addition to the current therapy. Patients were allowed to continue treatments with ICS (inhaled steroid use was an inclusion criteria), LABA, theophyllines, leukotriene inhibitors and/or oral corticosteroids. Tiotropium led to a significant improvement not only in the primary end point, which was the change in FEV1 AUC over 6 h (AUC0–6 h) after 12 weeks of treatment, but also in all secondary outcomes: morning predose FEV1, FVC AUC0–6 h, morning predose FVC, morning and evening PEF, and the use of rescue medications (the mean weekly number of daily puffs of salbutamol was reduced by 0.05 ± 0.12 puffs/day in the placebo group and by 0.50 ± 0.12 puffs/day in the tiotropium group at week 12; p < 0.05).
Another small study conducted by Iwamoto and colleagues on 17 severe persistent asthmatics suggested an association between the responsiveness to tiotropium and the type of inflammatory cells in the induced sputum. This author observed a positive correlation between sputum neutrophils and FEV1 improvement after 4 weeks of therapy, and an inverse correlation between sputum eosinophils and improvement in FEV1 after 4 weeks of therapy, suggesting that tiotropium may be particularly effective in noneosinophilic asthma.
Important outcomes that are not evaluated in all studies published until now are the reduction of exacerbations and the anti-inflammatory effects of tiotropium. Only the studies by Peters et al. and Magnussen et al. reported data about exacerbations. In the study by Peters et al., an asthma exacerbation (for which oral or intravenous glucocorticoids were administered) occurred in seven patients receiving tiotropium, in 13 receiving double-dose corticosteroids and in five receiving salmeterol. In the study by Magnussen et al., an exacerbation of COPD and asthma occurred in 28 patients (11.5%) receiving placebo and in 15 patients (6.6%) receiving tiotropium. These data suggest a possible role of tiotropium in reducing the exacerbation rate, but the observational period of these studies is too short to correctly assess an effect on the frequency of exacerbations.
In terms of a possible impact on airway inflammation, there are only small observations in the studies by Fardon et al. and Peters et al.. In the study by Fardon et al., there was a little but significant reduction (2.86 ppb) in the fraction of exhaled nitric oxide during treatment with fluticasone propionate/salmeterol/tiotropium bromide compared with fluticasone propionate alone, whereas in the latter, patients had at baseline a fraction of exhaled nitric oxide of 18.8 ppb and a sputum eosinophilia of 0.40 × 10 cells, and no treatment determined a significant change in these biomarkers.
In summary, the data obtained so far on the efficacy and safety of tiotropium in asthma show the following results:
A significant improvement in lung function, both when tiotropium was added to ICS alone in patients with moderate asthma, and when it was added to ICS plus LABA in patients with severe asthma and in patients with concomitant asthma and COPD. The comparison with salmeterol demonstrated similar improvements in morning PEF and similar or greater improvements in predose FEV1;
A mild improvement in the control of asthma symptoms and in quality of life, with a reduction in the use of rescue medications, in particular in patients with asthma and COPD, controversial results in patients with moderate asthma (improvement in proportion of asthma-control days, daily symptoms score and Asthma Control Questionnaire in the study by Peters et al., and no change in daytime asthma symptoms, use of rescue medications and quality of life in the study by Bateman et al.), and no change in symptom scores and quality of life in patients with severe asthma;
No significant effect on asthma exacerbations, although a trend was observed in two studies towards a better effect of tiotropium versus higher dose ICS (but not vs salmeterol) and of tiotropium versus placebo.