For centuries the datura plant has been used for treatment of respiratory disease. The plant, also known as jimson weed or devil’s trumpet, is a potent member of the alkaloid family with antimuscarinic properties. American physicians in the 19th century would commonly recommend patients to smoke datura leaves for relief of asthma and obstructive airway diseases. However, for the past fifty years, antimuscarinic treatments have been largely replaced by beta agonists and inhaled glucocorticosteroids (ICS) as agents to treat persistent asthma. This week’s issue of NEJM presents an article by Kerstjens et al. that suggests we may want to revisit the use of antimuscarinic therapy in asthma.
Current asthma therapy involves a “step-up” approach to treatment. Some patients with intermittent symptoms can manage well only using a short-acting inhaled beta agonist as needed. Those with more persistent symptoms may be started on low-dose ICS. If this regimen is not sufficient, an inhaled long acting beta agonist (LABA) may be added. Other treatments such as higher dose inhaled glucocorticosteroids or additional agents such as leukotriene modifiers, theophylline, anti-IgE therapy, or oral glucocorticoids can be added if control is not achieved.
Tiotropium is a long acting antimuscarinic agent that blocks the contractile muscarinic activity of neurotransmitters released at airway smooth muscle cells, resulting in bronchodilation. It has been used in patients with chronic obstructive lung disease (COPD) for nearly ten years. Clinical studies of tiotropium found the drug to improve quality of life and reduce COPD exacerbations. However, there have been few data to support the use of this medication in asthma.
In 2010 Peters et al. published a study in NEJM of patients with uncontrolled asthma on low dose ICS; the study showed the addition of tiotropium to be superior to doubling inhaled corticosteroid dose and equivalent to addition of LABA. However, this study was of short duration, with treatment lasting only 14 weeks — leaving it underpowered to study exacerbations.
This week in NEJM, Kerstjens et al. present the results of two identical randomized control trials in patients with uncontrolled asthma. Patients enrolled in the study were symptomatic despite use of daily ICS and LABA and had experienced at least one asthma exacerbation in the past year. Nearly one thousand patients were enrolled; they all continued their current therapy, and they were randomized to receive daily inhaled tiotropium or a placebo inhaler. After two years of follow up, the patients randomized to receive inhaled tiotropium had improved lung function (FEV1) as well as a longer time to first severe exacerbation and an overall 21% reduction in risk of a severe exacerbation.
How should we interpret the results of this study? First, we must remember that this study population included patients with baseline reduction in lung function – not your typical asthma patient who is only symptomatic during episodic “attacks.” Also, we should consider that adherence with daily inhaler therapy can be difficult for many patients – thus it is essential to make sure that patients are using their inhalers as prescribed and with correct technique before adding additional medication. Although there was no increase in adverse events in the treatment group, patients were selected to be at low risk for cardiac disease; we do not know whether long-term use of tiotropium could result in excess cardiac events. Finally, tiotropium therapy can be quite expensive because of the patented soft mist inhaler that is used to administer the medication. While tiotropium may not be a panacea, it is an addition to our arsenal of controller therapies. Further investigation will help us decide whether antimuscarinic therapy will once again become a routine treatment for asthma, as it was long ago with the datura plant.