Poorly Controlled Asthma: Is This Drug the Answer?
Kerstjens HA, Engel M, Dahl R, et al
N Engl J Med. 2012;367:1198-1207
Asthma can be reasonably well controlled in most patients with standard therapies, provided that the patient is compliant. The Global Initiative for Asthma (GINA) guidelines recommend maintenance use of an inhaled corticosteroid (ICS) supplemented with a short-acting beta-agonist metered-dose inhaler, used as needed.
This regimen is sufficient to control symptoms in most patients with asthma. However, the disease will remain poorly controlled in some patients despite compliance with these treatments. Usually, the next step would be to add a maintenance long-acting beta-agonist (LABA), often using one of the fixed combinations of an ICS and LABA. For the relatively small number of patients who still have poorly controlled disease and who continue to have acute exacerbations, the choices of treatment are problematic or expensive and include oral corticosteroids or monoclonal agents. An alternative might be use of the long-acting anticholinergic agent tiotropium.
Several recent trials have explored the potential role of tiotropium in patients with poorly controlled asthma despite conventional anti-asthma treatment. In an identical pair of such randomized, double-blind studies, 912 patients who had received inhaled corticosteroids and LABAs received, in addition, either 5 µg tiotropium or placebo administered with the Respimat® Soft Mist™ (Boehringer Ingelheim) inhalational delivery device once daily.
In these 48-week trials, baseline lung function was clinically and statistically significantly greater in the active treatment group. The time to the first acute exacerbation of asthma was delayed in the active treatment group, amounting to a 21% reduced risk for exacerbation. However, quality-of-life questionnaires showed no important differences between the treatment arms. There were no drug-related serious adverse events, and the rate of minor adverse events was similar between the groups except that allergic rhinitis was more common in the active treatment group.
These trials were well-designed and conducted. It is noteworthy that tiotropium improved lung function and delayed the onset of acute exacerbations despite maintenance use of a LABA and ICS. One disappointing outcome was that both questionnaires about asthma control and quality of life, although showing trends toward improvement, did not reach clinically relevant levels in the active treatment arms. Other clinical trials of tiotropium in asthma have reported similar results.
It has been known for many years that anticholinergic agents produce bronchodilation in both asthma and chronic obstructive pulmonary disease (COPD), but the originally used anticholinergic agents produced unpleasant side effects and were short-acting. The development of potent LABA bronchodilators supplanted their use in asthma. The latter agents were more effective and quicker-acting, and anticholinergic agents fell out of use for asthma.
However, newer anticholinergic agents proved to be at least as effective as beta-agonists in COPD, and tiotropium has become the most widely used bronchodilator in the world for COPD symptom relief. Now we are reminded that anticholinergic agents do produce bronchodilation in asthma, and they may have a useful role in asthma that is not well-controlled despite appropriate use of other agents.
How does an anticholinergic agent produce bronchodilation on top of a potent beta-adrenergic agent? The answer appears to be that receptors for beta-adrenergic and anticholinergic agents are in different sites in the airways. Would a different anticholinergic agent produce the same additive effect? That is unknown. It has recently been suggested that tiotropium has an anti-inflammatory effect in addition to its inhibitory effect on airway smooth muscle. That too remains to be proved.
Tiotropium by Respimat is not currently approved by the US Food and Drug Administration for treatment of asthma in the United States. It was approved for general use in asthma in Europe in 2014. It is possible that it will be similarly approved in the United States very soon.
Abstract
Tiotropium in Asthma Poorly Controlled With Standard Combination Therapy
Kerstjens HA, Engel M, Dahl R, et al
N Engl J Med. 2012;367:1198-1207
The Options for Uncontrolled Asthma
Asthma can be reasonably well controlled in most patients with standard therapies, provided that the patient is compliant. The Global Initiative for Asthma (GINA) guidelines recommend maintenance use of an inhaled corticosteroid (ICS) supplemented with a short-acting beta-agonist metered-dose inhaler, used as needed.
This regimen is sufficient to control symptoms in most patients with asthma. However, the disease will remain poorly controlled in some patients despite compliance with these treatments. Usually, the next step would be to add a maintenance long-acting beta-agonist (LABA), often using one of the fixed combinations of an ICS and LABA. For the relatively small number of patients who still have poorly controlled disease and who continue to have acute exacerbations, the choices of treatment are problematic or expensive and include oral corticosteroids or monoclonal agents. An alternative might be use of the long-acting anticholinergic agent tiotropium.
Several recent trials have explored the potential role of tiotropium in patients with poorly controlled asthma despite conventional anti-asthma treatment. In an identical pair of such randomized, double-blind studies, 912 patients who had received inhaled corticosteroids and LABAs received, in addition, either 5 µg tiotropium or placebo administered with the Respimat® Soft Mist™ (Boehringer Ingelheim) inhalational delivery device once daily.
In these 48-week trials, baseline lung function was clinically and statistically significantly greater in the active treatment group. The time to the first acute exacerbation of asthma was delayed in the active treatment group, amounting to a 21% reduced risk for exacerbation. However, quality-of-life questionnaires showed no important differences between the treatment arms. There were no drug-related serious adverse events, and the rate of minor adverse events was similar between the groups except that allergic rhinitis was more common in the active treatment group.
Viewpoint
These trials were well-designed and conducted. It is noteworthy that tiotropium improved lung function and delayed the onset of acute exacerbations despite maintenance use of a LABA and ICS. One disappointing outcome was that both questionnaires about asthma control and quality of life, although showing trends toward improvement, did not reach clinically relevant levels in the active treatment arms. Other clinical trials of tiotropium in asthma have reported similar results.
It has been known for many years that anticholinergic agents produce bronchodilation in both asthma and chronic obstructive pulmonary disease (COPD), but the originally used anticholinergic agents produced unpleasant side effects and were short-acting. The development of potent LABA bronchodilators supplanted their use in asthma. The latter agents were more effective and quicker-acting, and anticholinergic agents fell out of use for asthma.
However, newer anticholinergic agents proved to be at least as effective as beta-agonists in COPD, and tiotropium has become the most widely used bronchodilator in the world for COPD symptom relief. Now we are reminded that anticholinergic agents do produce bronchodilation in asthma, and they may have a useful role in asthma that is not well-controlled despite appropriate use of other agents.
How does an anticholinergic agent produce bronchodilation on top of a potent beta-adrenergic agent? The answer appears to be that receptors for beta-adrenergic and anticholinergic agents are in different sites in the airways. Would a different anticholinergic agent produce the same additive effect? That is unknown. It has recently been suggested that tiotropium has an anti-inflammatory effect in addition to its inhibitory effect on airway smooth muscle. That too remains to be proved.
Tiotropium by Respimat is not currently approved by the US Food and Drug Administration for treatment of asthma in the United States. It was approved for general use in asthma in Europe in 2014. It is possible that it will be similarly approved in the United States very soon.
Abstract
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