Asthma is respiratory condition marked by inflammation and narrowing of the airway, leading to breathing difficulty. Asthma represents the leading chronic respiratory disease in the world, affecting over 300 million people worldwide. Moreover, individuals with asthma present a significant burden on the healthcare system through direct medical costs and reduced productivity.
Over the years, a number of landmark clinical studies on asthma
have been published, shaping how we treat the disease today. Here are 5 of those that every pharmacist should know:
1. Salmeterol for asthma control (1992)1,2
Beta-agonists are one of medicines oldest classes of drugs, having been used to relieve bronchoconstriction for at least 5000 years. In 1940, isoproterenol became the first commercially available beta-agonist, with albuterol, a more selective beta-2 agonist, being developed in 1968.
For decades, albuterol and anti-inflammatory therapy were the mainstay of asthma treatment; however, in 1990 a long-acting chemical analogue of albuterol, called salmeterol, was released. Researchers theorized that a long-acting beta-agonist (LABA) could potentially benefit patients with uncontrolled asthma, but well-controlled trials were lacking.
As a result, researchers randomly assigned 234 patients with mild-to-moderate asthma in a multicenter, double-blind trial to receive salmeterol twice daily, albuterol 4 times daily, or placebo. All patients were allowed to use supplemental inhaled albuterol as needed for breakthrough symptoms.
After a 12-week treatment period, patients in the salmeterol group demonstrated superior results with all variables assessed, including PEF, pulmonary function tested by 12-hour evaluation, frequency of nocturnal awakenings, requirement of supplemental bronchodilators, and occurrence and severity of daily asthma symptoms. Following the study’s publications, LABAs started to become more commonly part of asthma management.
Salmeterol is superior to albuterol monotherapy for the treatment of mild-to-moderate asthma.
2. Scheduled versus as-needed albuterol (1996)3
Prior to 1990, a number of medical references recommended the use of inhaled beta-agonist medications to be used on a regular basis for the treatment of mild asthma. The belief was that chronic use would result in better control of symptoms; however, in the early 1990s, evidence started to emerge that this treatment approach may instead lead to diminished asthma control.
To further explore this question, researchers conducted a multicenter double-blind study of 255 patients with mild asthma to receive inhaled albuterol on a regular schedule or as needed basis. Patients were included in the analysis only if they had no history of corticosteroid use in the previous 6 weeks. The primary outcome was peak expiratory air flow measured in the morning.
After a 16 week follow-up, there was found to be no significant differences in peak expiratory air flow between the groups. Additionally, there were no significant differences in peak flow variability, FEV1
, supplemental albuterol use, quality of life, asthma exacerbations, or treatment failures. The statistically significant differences between the groups in evening peak flow and short-term bronchodilator response to inhaled albuterol were small and judged to be clinically unimportant by the investigators.
Regularly scheduled albuterol, as compared with as needed use, demonstrated no negative effects, but also no additional benefit.
3. FACET (1997)4
By the late 1990s, inhaled glucocorticoids had been widely considered to be first-line treatment for patients with moderate-to-severe, persistent asthma. Combination of an inhaled glucocorticoid plus a LABA had preliminary evidence to show benefit, although some studies suggested that long-term treatment with LABAs might result in tolerance to its effects or mask an increase in airway inflammation.
To further understand the effects of long-term combination use, researchers conducted a randomized, parallel-group study at 71 centers in 9 countries. A total of 852 patients aged 18 to 70 years old, who had asthma for at least 6 months and had been treated with an inhaled glucocorticoid for at least 3 months were enrolled.
After a 4-week run in period with high-dose budesonide, patients were randomly assigned to receive one of the following treatment groups for 12 months: low-dose budesonide plus placebo, low-dose budesonide plus formoterol, high-dose budesonide plus placebo, or high-dose budesonide plus formoterol.
Study results showed that adding formoterol to both doses of budesonide significantly reduced the rate of severe and mild asthma exacerbations per patient, improved lung function, and decreased asthma symptoms, compared with increasing the dose of budesonide alone. The lowest rates of asthma exacerbations were among the patients who received the high-dose budesonide plus formoterol.
Contrary to previous suggestions, researchers found no evidence of deterioration in the control of asthma over the course of a year when formoterol was added to budesonide therapy.
The addition of formoterol to budesonide therapy improves symptoms and lung function without lessening the control of asthma. Those in the high-dose budesonide plus formoterol group experienced the greatest benefit.
4. SMART (2006)5
By the early 2000s, there was an ongoing debate regarding the long-term safety of LABAs. Some studies and reports suggested this class of medications was a risk factor for increased asthma-related deaths; however, others attributed an increased risk to poorly controlled asthma.
In 2006, researchers published the results of a randomized, double-blind, placebo-controlled, observational surveillance study to further define the safety of salmeterol. The study was conducted at 6,163 sites in the United States and enrolled 26,355 subjects with asthma to receive salmeterol or placebo, in addition to standard asthma care. Those with a history of LABA use were excluded from the study.
Following an interim analysis, the study was terminated early. While the occurrence of the primary outcome, respiratory-related deaths or life-threatening experiences, was not significantly different between treatment groups, salmeterol was associated with significant increases in secondary outcomes. These include respiratory-related deaths, asthma-related deaths, and asthma-related deaths or life-threatening experiences. The imbalance occurred largely in the African-American subpopulation and those not taking an inhaled corticosteroid.
In the aftermath of the SMART trial, the 2007 NHLBI ECS 3 asthma guideline was updated to recommend adding a LABA to inhaled steroid therapy as step 3 of treatment for persistent asthma. In addition, FDA mandated a black box warning on LABA preparations due to their association with asthma-related deaths.
Salmeterol, as compared to placebo, increases the risk of respiratory-related deaths, particularly among the African American population and those not using an inhaled corticosteroid.
5. TALC (2010)6
Due to limited asthma treatment options and a potential concern for the safety of long-term LABA therapy, researchers began to consider alternative options. Long acting anticholinergic agents, such as tiotropium, had been used since 2004 for the treatment of chronic obstructive pulmonary disease (COPD); however, its use in asthma was unknown.
As a result, researchers conducted a randomized, triple-dummy, crossover trial in 210 patients with asthma inadequately controlled by a low dose of an inhaled glucocorticoid. After a 4-week run-in period with beclomethasone, patients were randomized to one of three arms: 1) doubling their current glucocorticoid dose, 2) adding salmeterol to beclomethasone, or 3) adding tiotropium to beclomethasone. All patients cycled through each of the three treatments in 14-week intervals. The primary outcome measure was the morning PEF.
After analysis of the data, tiotropium plus beclomethasone was shown to be statistically superior to a doubling of the dose of an inhaled glucocorticoid. Similar results favoring tiotropium were found for the evening PEF, pre-bronchodilator FEV1, proportion of asthma-control days, and score for daily symptoms. Additionally, tiotropium was non-inferior to salmeterol on the basis of the study’s predefined criteria.
In September 2015, the FDA approved Spiriva Respimat (tiotropium bromide) inhalation spray for maintenance treatment of asthma in patients 12 years of age and older. Although U.S. asthma treatment guidelines have not been updated since 2007, tiotropium has been included in the 2015 Global Initiative for Asthma report (GINA) for asthma management.
When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma.
Sears MR, Lötvall J. Past, present and future - β2-adrenoceptor agonists in asthma management. Respir Med. 2005 Feb;99(2):152-70.
Pearlman DS, Chervinsky P, LaForce C, et al. Comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med. 1992 Nov 12;327(20):1420-5.
Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. N Engl J Med. 1996 Sep 19;335:841-7.
Pauwels RA, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med. 1997. 337(20):1405-1411.
Nelson HS, Weiss ST, Bleecker ER, et al. The salmeterol multicenter asthma research trial. Chest. 2006. 129(1):15-26.
Peters S, Kunselman, Icitovic N, et al. Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma. N Engl J Med. 2010 Oct 28; 363(18): 1715–1726.