Tiotropium in the Treatment of Patients With Asthma
Tiotropium in the Treatment of Patients With Asthma
All of the studies included in this review noted improvement in spirometry associated with tiotropium. This improvement was reported in patients with both moderate and severe asthma, uncontrolled on previous regimens, treated with low- to high-dose ICS regimens, and with and without LABA therapy.
Although significant, the degree of improvement in spirometric measures with tiotropium reported in these studies is small. The mean change in FEV1 with tiotropium as compared with controls reported across studies ranged from 0.086 to 0.170 L, which is less than the minimal value associated with a patient-perceivable improvement in symptoms. This improvement was seen in patients with moderate to severe asthma and those receiving concomitant ICS and LABA therapy. Small improvements in FEV1 may have clinical significance when considering the use of tiotropium in patients with the dual burden of disease severity and poor control despite standard therapies.
The evidence supporting an improvement in clinical outcomes with tiotropium is mixed. The strongest evidence comes from Kerstjens et al, who reported a decrease in the frequency of severe asthma exacerbation and an increase in time to first exacerbation. Two other studies noted no significant trend toward fewer asthma exacerbations among tiotropium intervention groups. Study design, low power, and short treatment period likely limited their ability to detect a statistically significant difference.
The impact of tiotropium on asthma symptom measures remains inconclusive. Although smaller studies reported improvement in asthma control days and symptom scores with tiotropium, larger randomized studies have failed to consistently replicate these findings. It is unclear why the majority of studies have failed to show improvements in asthma symptom measures; disease severity, level of control, and small overall improvement in spirometric indices may be causes. At this time, there is insufficient evidence to support the argument that tiotropium therapy leads to improvements in asthma symptom measures, asthma control days, quality-of-life scores, or rescue inhaler use.
Some investigators speculate that the benefits of tiotropium seen in individual studies are the result of the use of this medication in asthma patients with persistent airflow limitation and a more a COPD- like disease profile. Patients with asthma with persistent airflow limitation have blunted bronchodilator responses. Evidence suggests that persistent airflow limitation arises from longstanding airway inflammation. Patients with asthma with persistent airflow limitation may have a more robust response to tiotropium than other subtypes of asthma patients, given the drug's known benefits in COPD. In addition, each of the studies selected patients with a limited smoking history. There may be parallels between patients with asthma with a significant smoking history and COPD.
Moore et al described the phenotype of asthma patients in a cluster analysis of the Severe Asthma Research Program population. In this analysis, cluster 4 included patients with severe airflow obstruction that was reversible with bronchodilators and cluster 5 included patients with persistent airflow limitation. The baseline FEV1 in these clusters is similar to the populations included in the tiotropium studies. Three studies required reversibility of 12% to 15% in their study patients and can be considered to have spirometric measures similar to the patients in cluster 4. Both studies by Kerstjens and colleagues selectively included patients with persistent airflow limitation, thereby making these patients similar to those in cluster 5. Improvements in spirometry with tiotropium were demonstrated using both patient populations. Further investigation is needed to determine whether tiotropium has variable efficacy in various subtypes with asthma.
Our review suggests that tiotropium may play a versatile role in the treatment of asthma. First, tiotropium may have utility when escalating therapy in patients with severe asthma receiving ICS and LABA therapy. In patients with severe asthma receiving high-dose ICS and LABA therapy, the addition of tiotropium leads to improvements in spirometric measures. This suggests that tiotropium may have a role as a step-up agent when escalating treatment in patients with severe asthma already taking ICS and LABA.
Second, tiotropium may be useful as a steroid-sparing agent. Fardon et al found that the addition of tiotropium allowed for halving the steroid dose while still yielding improvements in spirometric indices in patients with severe asthma taking high-dose ICS. Peters et al found that adding tiotropium was superior to doubling the dose of ICS in patients with moderate asthma. This suggests that tiotropium may be considered an alternative to ICS therapy and could allow for the deescalation of steroid dosing.
Lastly, tiotropium also may be considered an alternative to LABA or ICS therapy in patients with moderate asthma. In patients with moderate asthma as noted by an FEV1 >60% predicted on low- to moderate-dose ICS, the addition of tiotropium was associated with improvement in spirometric parameters. Peters et al found that tiotropium was superior to doubling the dose of ICS, and both studies concluded that tiotropium was noninferior to LABA in improving spirometric measures. This suggests that tiotropium may be considered an alternative to initiating LABA therapy or escalating ICS therapy in patients with moderate asthma.
There is a lack of randomized controlled trials investigating the clinical impact of tiotropium in patients with mild asthma and its use at the early stages of asthma treatment. Tiotropium may be beneficial in patients with mild asthma, because evidence demonstrates a prolonged bronchodilatory response and protection against methacholine challenge in patients with mild asthma. There are no studies reviewing/investigating tiotropium in conjunction or in comparison with alternate therapies such as leukotriene inhibitors or anti-immunoglobulin E therapies. Trials studying the effectiveness of tiotropium in smokers and children with moderate to severe asthma (details available at www.clinicaltrials.gov) are ongoing. Further investigation is needed to assess the utility of tiotropium in patients with mild asthma, in combination with other asthma therapies, and in the early stages of asthma treatment.
In the studies presented, the dose of tiotropium varied from 5 to 18 μg daily via HandiHaler and the Respimat Soft Mist inhaler. Although evidence suggests a dose-response bronchodilator effect in patients with COPD, Kerstjens et al found no significant therapeutic difference between tiotropium 5 μg and 10 μg daily dosage in patients with asthma. The HandiHaler and the Respimat Soft Mist inhaler delivery methods have not been compared directly in patients with asthma. In patients with COPD, the safety profile and efficacy of the lower-dose tiotropium Respimat Soft Mist inhaler was noninferior to the higher-dose tiotropium HandiHaler.
Tiotropium appears to have both anti-inflammatory and bronchodilatory effects. As an anticholinergic agent, it inhibits smooth muscle contraction leading to bronchodilation. In animal models of asthma, tiotropium produced effects outside the neural-mediated bronchodilation, suggesting a complementary inflammatory mediated mechanism of action. Tiotropium decreases smooth muscle thickness, cellular metaplasia, peribronchial collagen deposition, and airway fibrosis. It also decreases cytokines such as leukotriene B4 and tumor necrosis factor-[alpha] levels and reduces the generation of reactive oxygen species in human alveolar macrophages. This suggests that tiotropium may modulate the inflammatory reaction by impairing macrophage-mediated chemotaxis of neutrophils and release of reactive oxygen species.
As a therapeutic option, tiotropium has distinct advantages. It reaches peak plasma levels quickly and has a sustained bronchodilatory effect for 24 hours, allowing for once-daily dosing as compared with the four times per day dosing of ipratropium bromide. In addition, tiotropium has a documented adverse effect and safety profile from its use in COPD treatment.
Our review has several limitations. First, heterogeneity across all studies in terms of sample size, dose of tiotropium, type of inhaler used, severity of asthma, and spirometric measure reported made direct comparisons difficult. Second, the studies vary in the detail used in reporting asthma severity and control variables. This makes it difficult to compare asthma control and severity across studies. Third, short treatment periods in some studies mean a smaller window was available to determine an impact on a chronic disease. Fourth, some studies were limited by their small sample size. Fifth, limited descriptions of patient referral or selection criteria raise the possibility of selection bias. Sixth, two studies were limited by the use of historical controls, allowing for natural regression to the mean to be misinterpreted as a positive intervention effect. Finally, limited or absent washout periods and short treatment periods can lead to carryover and confounding.
Discussion
All of the studies included in this review noted improvement in spirometry associated with tiotropium. This improvement was reported in patients with both moderate and severe asthma, uncontrolled on previous regimens, treated with low- to high-dose ICS regimens, and with and without LABA therapy.
Although significant, the degree of improvement in spirometric measures with tiotropium reported in these studies is small. The mean change in FEV1 with tiotropium as compared with controls reported across studies ranged from 0.086 to 0.170 L, which is less than the minimal value associated with a patient-perceivable improvement in symptoms. This improvement was seen in patients with moderate to severe asthma and those receiving concomitant ICS and LABA therapy. Small improvements in FEV1 may have clinical significance when considering the use of tiotropium in patients with the dual burden of disease severity and poor control despite standard therapies.
The evidence supporting an improvement in clinical outcomes with tiotropium is mixed. The strongest evidence comes from Kerstjens et al, who reported a decrease in the frequency of severe asthma exacerbation and an increase in time to first exacerbation. Two other studies noted no significant trend toward fewer asthma exacerbations among tiotropium intervention groups. Study design, low power, and short treatment period likely limited their ability to detect a statistically significant difference.
The impact of tiotropium on asthma symptom measures remains inconclusive. Although smaller studies reported improvement in asthma control days and symptom scores with tiotropium, larger randomized studies have failed to consistently replicate these findings. It is unclear why the majority of studies have failed to show improvements in asthma symptom measures; disease severity, level of control, and small overall improvement in spirometric indices may be causes. At this time, there is insufficient evidence to support the argument that tiotropium therapy leads to improvements in asthma symptom measures, asthma control days, quality-of-life scores, or rescue inhaler use.
Some investigators speculate that the benefits of tiotropium seen in individual studies are the result of the use of this medication in asthma patients with persistent airflow limitation and a more a COPD- like disease profile. Patients with asthma with persistent airflow limitation have blunted bronchodilator responses. Evidence suggests that persistent airflow limitation arises from longstanding airway inflammation. Patients with asthma with persistent airflow limitation may have a more robust response to tiotropium than other subtypes of asthma patients, given the drug's known benefits in COPD. In addition, each of the studies selected patients with a limited smoking history. There may be parallels between patients with asthma with a significant smoking history and COPD.
Moore et al described the phenotype of asthma patients in a cluster analysis of the Severe Asthma Research Program population. In this analysis, cluster 4 included patients with severe airflow obstruction that was reversible with bronchodilators and cluster 5 included patients with persistent airflow limitation. The baseline FEV1 in these clusters is similar to the populations included in the tiotropium studies. Three studies required reversibility of 12% to 15% in their study patients and can be considered to have spirometric measures similar to the patients in cluster 4. Both studies by Kerstjens and colleagues selectively included patients with persistent airflow limitation, thereby making these patients similar to those in cluster 5. Improvements in spirometry with tiotropium were demonstrated using both patient populations. Further investigation is needed to determine whether tiotropium has variable efficacy in various subtypes with asthma.
Our review suggests that tiotropium may play a versatile role in the treatment of asthma. First, tiotropium may have utility when escalating therapy in patients with severe asthma receiving ICS and LABA therapy. In patients with severe asthma receiving high-dose ICS and LABA therapy, the addition of tiotropium leads to improvements in spirometric measures. This suggests that tiotropium may have a role as a step-up agent when escalating treatment in patients with severe asthma already taking ICS and LABA.
Second, tiotropium may be useful as a steroid-sparing agent. Fardon et al found that the addition of tiotropium allowed for halving the steroid dose while still yielding improvements in spirometric indices in patients with severe asthma taking high-dose ICS. Peters et al found that adding tiotropium was superior to doubling the dose of ICS in patients with moderate asthma. This suggests that tiotropium may be considered an alternative to ICS therapy and could allow for the deescalation of steroid dosing.
Lastly, tiotropium also may be considered an alternative to LABA or ICS therapy in patients with moderate asthma. In patients with moderate asthma as noted by an FEV1 >60% predicted on low- to moderate-dose ICS, the addition of tiotropium was associated with improvement in spirometric parameters. Peters et al found that tiotropium was superior to doubling the dose of ICS, and both studies concluded that tiotropium was noninferior to LABA in improving spirometric measures. This suggests that tiotropium may be considered an alternative to initiating LABA therapy or escalating ICS therapy in patients with moderate asthma.
There is a lack of randomized controlled trials investigating the clinical impact of tiotropium in patients with mild asthma and its use at the early stages of asthma treatment. Tiotropium may be beneficial in patients with mild asthma, because evidence demonstrates a prolonged bronchodilatory response and protection against methacholine challenge in patients with mild asthma. There are no studies reviewing/investigating tiotropium in conjunction or in comparison with alternate therapies such as leukotriene inhibitors or anti-immunoglobulin E therapies. Trials studying the effectiveness of tiotropium in smokers and children with moderate to severe asthma (details available at www.clinicaltrials.gov) are ongoing. Further investigation is needed to assess the utility of tiotropium in patients with mild asthma, in combination with other asthma therapies, and in the early stages of asthma treatment.
In the studies presented, the dose of tiotropium varied from 5 to 18 μg daily via HandiHaler and the Respimat Soft Mist inhaler. Although evidence suggests a dose-response bronchodilator effect in patients with COPD, Kerstjens et al found no significant therapeutic difference between tiotropium 5 μg and 10 μg daily dosage in patients with asthma. The HandiHaler and the Respimat Soft Mist inhaler delivery methods have not been compared directly in patients with asthma. In patients with COPD, the safety profile and efficacy of the lower-dose tiotropium Respimat Soft Mist inhaler was noninferior to the higher-dose tiotropium HandiHaler.
Tiotropium appears to have both anti-inflammatory and bronchodilatory effects. As an anticholinergic agent, it inhibits smooth muscle contraction leading to bronchodilation. In animal models of asthma, tiotropium produced effects outside the neural-mediated bronchodilation, suggesting a complementary inflammatory mediated mechanism of action. Tiotropium decreases smooth muscle thickness, cellular metaplasia, peribronchial collagen deposition, and airway fibrosis. It also decreases cytokines such as leukotriene B4 and tumor necrosis factor-[alpha] levels and reduces the generation of reactive oxygen species in human alveolar macrophages. This suggests that tiotropium may modulate the inflammatory reaction by impairing macrophage-mediated chemotaxis of neutrophils and release of reactive oxygen species.
As a therapeutic option, tiotropium has distinct advantages. It reaches peak plasma levels quickly and has a sustained bronchodilatory effect for 24 hours, allowing for once-daily dosing as compared with the four times per day dosing of ipratropium bromide. In addition, tiotropium has a documented adverse effect and safety profile from its use in COPD treatment.
Our review has several limitations. First, heterogeneity across all studies in terms of sample size, dose of tiotropium, type of inhaler used, severity of asthma, and spirometric measure reported made direct comparisons difficult. Second, the studies vary in the detail used in reporting asthma severity and control variables. This makes it difficult to compare asthma control and severity across studies. Third, short treatment periods in some studies mean a smaller window was available to determine an impact on a chronic disease. Fourth, some studies were limited by their small sample size. Fifth, limited descriptions of patient referral or selection criteria raise the possibility of selection bias. Sixth, two studies were limited by the use of historical controls, allowing for natural regression to the mean to be misinterpreted as a positive intervention effect. Finally, limited or absent washout periods and short treatment periods can lead to carryover and confounding.
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