Breathe easy: Updates on asthma management

Abstract

Several asthma trials have been published in recent months evaluating key treatments such as long-acting beta-2 agonists (LABAs), inhaled corticosteroids (ICSs), and tiotropium (Spiriva— oehringer Ingelheim, Pfizer). Studies have questioned the recommendation to discontinue LABAs; compared the efficacy of intermittent, symptom-based ICS use with scheduled inhalations in adults with mild to moderate persistent asthma; evaluated the effects of ICS use in children on their adult height; and evaluated the role of tiotropium in the management of uncontrolled asthma. Several asthma trials have been published in recent months evaluating key treatments such as long-acting beta-2 agonists (LABAs), inhaled corticosteroids (ICSs), and tiotropium (Spiriva— oehringer Ingelheim, Pfizer). Studies have questioned the recommendation to discontinue LABAs; compared the efficacy of intermittent, symptom-based ICS use with scheduled inhalations in adults with mild to moderate persistent asthma; evaluated the effects of ICS use in children on their adult height; and evaluated the role of tiotropium in the management of uncontrolled asthma. Several asthma trials have been published in recent months evaluating key treatments such as long-acting beta-2 agonists (LABAs), inhaled corticosteroids (ICSs), and tiotropium (Spiriva—Boehringer Ingelheim, Pfizer). Studies have questioned the recommendation to discontinue LABAs; compared the efficacy of intermittent, symptom-based ICS use with scheduled inhalations in adults with mild to moderate persistent asthma; evaluated the effects of ICS use in children on their adult height; and evaluated the role of tiotropium in the management of uncontrolled asthma. An extensive meta-analysis and systematic review of five trials concluded that discontinuing LABA therapy in adults and older children with asthma who are controlled with a combination regimen consisting of an ICS and LABA may be associated with an increase in asthma-related impairment, according to the October 8 issue of the Archives of Internal Medicine. ■LABA step-off in asthma may do more harm than good.■ICS studies support scheduled doses and show minimal impact on adult heights.■www.pharmacist.com■Unlabeled tiotropium shows promise for asthma in clinical trial. ■LABA step-off in asthma may do more harm than good.■ICS studies support scheduled doses and show minimal impact on adult heights.■www.pharmacist.com■Unlabeled tiotropium shows promise for asthma in clinical trial. Investigators evaluated the evidence assessing LABA step-off therapy in patients well controlled on combination LABA and ICS therapies. Data from five randomized controlled trials involving adults and pediatric patients 15 years of age and older with asthma controlled on the combination regimen were assessed. LABA step-off was associated with worse asthma outcomes compared with no change in treatment. LABA step-off also resulted in worse Asthma Quality of Life Questionnaire scores, worse Asthma Control Questionnaire scores, fewer symptom-free days, and greater risk of withdrawal from the study because of lack of efficacy or loss of asthma control. Patients who discontinued LABAs required more puffs per day of rescue bronchodilators and were at an increased risk for needing to use oral corticosteroids. FDA currently recommends that once asthma is controlled, LABA therapy should be withdrawn because of safety concerns. The investigators noted that their results are in contrast with current FDA recommendations. “It is possible that step-off can be safe in a subset of patients. Individual-level data from the studies conducted to date could help identify characteristics of these patients; such data were not available for this meta-analysis,” wrote the authors. They concluded that additional data from LABA safety studies are needed, and until such data are available, clinicians must evaluate the risk-benefit ratio of LABAs for their individual patients. New research published in the September 12 issue of JAMA suggests that use of daily scheduled ICS therapy in adults with mild to moderate persistent asthma is just as effective as ICS therapy used only when symptoms occur. The BASALT (Best Adjustment Strategy for Asthma in the Long Term) trial compared the efficacy of three methods aimed at adjusting ICS doses (physician assessment-based adjustment [i.e., standard of care], biomarker-based adjustment [i.e., based on measurement of exhaled nitric oxide], and symptom-based adjustment [i.e., dose adjustment performed by matching ICS use on a puff-per-puff basis with as-needed albuterol use]) on the primary outcome of time to treatment failure. The study was conducted in 342 adults with mild to moderate asthma controlled on low-dose ICS. The investigators reported that time to treatment failure did not differ significantly among the three treatment groups, with 9-month failure rates ranging from 15% to 22% among the groups. No differences were noted for asthma exacerbations, mean proportion of treatment failures progressing to exacerbations, and measures of lung function and asthma symptoms among the three groups. The investigators also reported that mean monthly ICS use was shown to be the lowest in the symptom-based adjustment group. “Symptom-based adjustment strategies are appealing because they are simple to use and empower patients,” wrote the investigators. Additional data are needed before this strategy can be recommended to patients. The Respimat delivery device used in the trials is different from the dry-powder formulation available in the United States and may result in improved drug delivery and higher plasma tiotropium concentrations. A new study published in the September 6 issue of the New England Journal of Medicine suggests that initial decreases in attained height associated with use of ICSs in prepubertal children persist as a reduction in adult height. Researchers assessed adult height in 943 patients who participated in the Childhood Asthma Management Program. Patients in this program had mild to moderate asthma and were randomly assigned to treatment with budesonide 400 μg, nedocromil 16 mg, or placebo daily for 4 to 6 years, starting at 5 to 13 years of age. These patients had their adult height determined at a mean age of 25 years. The adjusted mean adult height was 1.2 cm lower in the ICS group compared with placebo (P=0.001), with similar adult height observed in the nedocromil and placebo groups (P=0.61). A larger daily dose of ICS in the first 2 years of treatment was associated with a lower adult height compared with that seen after 2 years of treatment. “In the information about inhaled glucocorticoids and their side effects that is provided to parents, the potential effect on adult height must be balanced against the large and well-established benefit of these drugs in controlling persistent asthma,” the investigators concluded. They noted that clinicians should strive to use the lowest effective ICS dose to control symptoms to minimize the concerns caregivers may have about the long-term effects these agents may have on adult height. Some patients with asthma continue to have symptoms despite being on combination therapy such as high-dose ICS with a LABA. Clinicians are always on the lookout for agents that may be effective for patients with hard-to-control asthma symptoms. Although tiotropium is not approved for the management of asthma and is not mentioned in current practice guidelines, its use was evaluated as a potential add-on treatment option for patients with symptomatic asthma despite being on controller therapy. In two identical, 48-week, double-blind, placebo-controlled trials in the September 6 issue of the New England Journal of Medicine, a total of 912 patients with a mean baseline forced expiratory volume in 1 second (FEV1) of 62% of the predicted value and at least one severe exacerbation in the previous 12 months were randomized to tiotropium 5 μg (n=456) or placebo (n=456) given once daily in the morning via a soft-mist Respimat inhaler. Results for the two co-primary lung-function endpoints showed that treatment with tiotropium significantly reduced airflow obstruction and increased the time to first exacerbation compared with placebo. At 24 weeks, the mean difference between the tiotropium and placebo groups in peak FEVj from baseline to the first 3 hours after administration was 86 mL in the first trial (P=0.01) and 154 mL in the second trial (P<0.001). Similar results were observed for changes in trough FEV1 at week 24. In addition, improvements in peak FEV1 were maintained over the full 48-week duration of the trials. Time to first exacerbation was increased by 56 days in the active treatment group, which corresponded to a reduction of 21% in the risk of exacerbation in those treated with tiotropium (hazard ratio 0.79 [95% CI 0.62-1.00], P=0.03). Adverse events occurred at a similar rate in the two groups (73.5% in the tiotropium group compared with 80.3% in the placebo group), and cardiac events were rare, occurring in less than 2% of patients. In an accompanying editorial, Elisabeth Bel, MD, PhD, noted that the current results are promising, but there are some key limitations. She pointed out that adherence to background ICS and LABA treatments was not carefully assessed, which may have left room for additional bronchodilation by tiotropium. Bel noted that the results cannot be applied to all patients with poorly controlled asthma since the trial selectively enrolled those with persistent airflow limitation. Last, she explained that the Respimat delivery device used in the trials is different from the dry-powder formulation available in the United States. Bel noted that this device may result in improved drug delivery and higher plasma concentrations, which may correlate to an increased risk of death from cardiovascular causes, according to results from a systemic review and meta-analysis. “Before recommending tiotropium [delivered by the Respimat device] as add-on therapy to all patients with uncontrolled asthma despite the use of ICSs and LABAs, a word of caution seems appropriate,” Bel wrote. The data presented above highlight the ever-changing field of asthma management. Some of the trials reached conclusions that differ from the standard of care. According to recent publications, LABA step-off therapy may not be the best option for patients with well-controlled asthma on combination LABA/ ICS therapy; intermittent ICS use may be a good option for those with mild to moderate asthma; and tiotropium may be a viable therapeutic option for the management of uncontrolled asthma.