The SLT strategy was initially evaluated in moving from Step 2 to Step 3 care in adult patients whose asthma was not well controlled on low doses of ICS. Studies by both Greening et al.
) and Woolcock et al.
) using the SLT approach demonstrated that, in patients not well controlled on a low dose of ICS, the addition of a LABA was superior to increasing the dose of ICS for many outcome measures in the impairment domain. These observations were subsequently extended to the risk domain in the F
herapy (FACET) study (18
). This study evaluated the effect of adding a LABA to a fixed ICS dose, quadrupling the dose of ICS, or both, on reducing asthma exacerbations. For one year, patients were treated twice daily with 100 mcg of budesonide, 100 mcg of budesonide and 12 mcg of formoterol, 400 mcg of budesonide, or 400 mcg of budesonide and 12 mcg of formoterol. With the addition of LABA to lower dose ICS, severe exacerbations were reduced by 26% and mild exacerbations were reduced by 40% when compared to lower dose ICS alone. The higher dose of ICS alone reduced rates of severe exacerbations by 49% and mild exacerbations by 37%. When LABA was added to the higher dose of ICS, severe exacerbations were reduced by 63% and mild exacerbations were reduced by 62%. Both lung function and asthma symptoms improved with both higher ICS doses and formoterol, although the greatest improvements were achieved with formoterol.
The issue of which SLT intervention leads to better overall asthma control when choosing between more ICS versus adding a LABA was comprehensively studied by Batemen et al.
) in the G
(GOAL) study. This randomized, double-blind, parallel-group study assessed the ability of predefined, step-wise adjustments of fluticasone/salmeterol or fluticasone alone to achieve two predefined measures of asthma control. The definitions of control, included composite measures of peak expiratory flow (PEF), rescue medication use, daytime and nighttime symptoms, exacerbations, emergency visits and other adverse events, based on the GINA or National Institutes of Health (NIH) guidelines (4
). Unlike previous studies of controller therapy that focused on improvements with fixed doses of medications, the GOAL study allowed for dose escalation, in a stepwise approach, to achieve more comprehensive, sustained control. Phase I of the study was the dose escalation phase. During this time, treatment was stepped up every 12 weeks until asthma was totally controlled or until the medication reached 500 mcg of fluticasone twice daily or fluticasone/salmeterol 500/50mcg twice daily. Once asthma control was totally achieved, or after 12 weeks of maximal medication dosing, the patients were advanced to phase II, the constant phase. During this double blind treatment period, patients remained on the same dose of controller medication for 1 year. Of note, in an effort to determine if there were incremental effects over time of remaining on these medications there was no step-down treatment plan during this phase. While the majority of patients achieved well controlled or totally controlled asthma in this study, approximately 9% of patients in the fluticasone alone group and 5% of patients in the fluticasone/salmeterol group did not achieve well controlled asthma in phase I or phase II, requiring escalation to the maximum treatment phase or oral corticosteroids and fluticasone/salmeterol 500/50mcg. Nevertheless, the GOAL study provided strong evidence that patients with uncontrolled asthma, from a varied range of severity, were able to achieve and sustain guideline-defined control. It also demonstrated that stepping up therapy to achieve guideline-defined control, even in patients who didn't achieve the most stringent definitions of “total control,” still had significant improvements in health status and rates of exacerbation. Bateman et al.
did emphasize that many risks of sustained treatment may take years to become clinically significant, and further research into step-down therapy once control was achieved was indicated. Regardless, the possibility of achieving guide-line based total control through medication escalation provided solid evidence for a stepwise approach to asthma management.
A recent study completed by the Childhood Asthma Research and Education (CARE) Network has provided evidence to guide SLT in children
uncontrolled on low doses of ICS and needing Step 3 care. The B
d–on Therapy G
esponses (BADGER) trial was a double-blind, three-treatment, crossover trial, in children aged 6 to 17 years with asthma uncontrolled on 100 mcg twice daily of fluticasone (20
). The ICS step-up consisted of 250 mcg of fluticasone twice daily, the LABA step-up was fluticasone/salmeterol 100/50 mcg twice daily and the leukotriene receptor antagonist (LTRA) step-up was fluticasone 100 mcg twice daily plus 5 or 10mg of montelukast daily. The primary outcome was the differential response to each therapy based on a composite outcome of three measures in both the risk (exacerbations requiring oral prednisone) and impairment (the number of asthma control days and forced expiratory volume in 1 second (FEV1)) domains of asthma control. Remarkably, a differential response to therapy was demonstrable in 98% of the patients and there were no differences in response patterns based on age. Overall, LABA step-up led to the greatest likelihood of best response; however, some children had better responses with one of the other two therapies. This study emphasized the importance of regularly monitoring each child's response to medication and providing appropriate adjustment of therapy. Moreover, the findings also demonstrate that in the event that a child is not responding to a specific Step 3 therapy, rather than escalate to Step 4 care, alternative Step 3 treatments should be considered.
Safety concerns regarding the chronic use of LABA (21
) have provided impetus for evaluating additional options in moving from Step 2 to Step 3 care. In this regard, the efficacy of an inhaled anticholinergic medication (tiotropium bromide) in comparison to either doubling doses of ICS or the addition of a LABA was recently examined. Peters et al.
) hypothesized that the addition of tiotropium bromide in patients with inadequately controlled asthma would be more effective than doubling the dose of ICS, and that the addition of the long acting anticholinergic would not be inferior to the addition of a LABA. Compared with doubling glucocorticoid dosing, the use of tiotropium resulted in a greater improvement in morning and evening peak expiratory flow, pre-bronchodilator FEV1, daily symptom scores, and a greater proportion of asthma control days. Tiotropium also was non-inferior compared to the addition of salmeterol in all outcomes assessed. While the duration of treatment was limited to 14 weeks in this study, and long-term safety issues or rates of exacerbations could not be taken into account fully, the results suggest that another efficacious step-up treatment option when moving from Step 2 to Step 3 care may be the addition of a long acting cholinergic antagonist.
Step-up and step-down strategies using various biomarkers felt to be relevant to asthma pathophysiology have also been evaluated. Biomarkers evaluated have included methacholine airway hyperresponsiveness (23
), sputum eosinophils (24
), and exhaled nitric oxide (25
). While these approaches have shown promise in reducing exacerbations and/or improving asthma control, measurements of airway hyperresponsiveness and sputum eosinophil counts, although performed in many subspecialty practices and research centers, are not routinely available in most primary care practices. Exhaled nitric oxide levels are currently being measured in many outpatient settings, though their overall contribution to patient management, their cost effectiveness and specificity to asthma are still not definitively established (27
Strategies for choosing SLT to Steps 4 through 6 have not been evaluated as rigorously. However, recent work using interventions with monoclonal antibodies directed at either the allergic (e.g., omalizumab) or immunoinflammatory (mepolizumab) response have provided new insights regarding which patients should be considered for step-up involving these treatments. Humbert et al.
) examined the effect of monoclonal anti-immunoglobulin (Ig)E antibody (omalizumab) in patients whose severe allergic asthma was inadequately controlled despite high dose ICS and LABA therapy with a reduced lung function and a recent history of asthma exacerbations. In this randomized, double-blind, parallel-group, placebo controlled trial of 419 patients, patients were placed on omalizumab or placebo for 28 weeks. Following adjustment for baseline exacerbation history, there was a 26% reduction of clinically significant exacerbation rates in the omalizumab group compared to placebo. Omalizumab also improved morning peak expiratory flow, asthma symptoms scores, and asthma-related quality of life. Additionally, there were no significant side-effects associated with the omalizumab group, with the most common adverse event being a local injection site reaction. Therefore, Humbert et al
. concluded that omalizumab should be considered as a step-up option in patients with poorly controlled asthma despite high-dose ICS and LABA therapy. A recent study by Busse et al
) comparing the addition of omalizumab vs. placebo to guideline-based care in patients age 6–20 has also demonstrated its effectiveness in preventing asthma exacerbations across steps of asthma severity, suggesting that omalizumab may be considered for SLT in patients with frequent exacerbations. Currently, omalizumab is FDA approved for patients age 12 and above with moderate to severe allergic asthma (5
The efficacy of an anti-IL-5 monoclonal antibody (mepolizumab), known to decrease eosinophil recruitment and survival, has been recently studied as well. In an early study of anti-IL-5 in human subjects with mild asthma, anti-IL-5 treatment decreased sputum and blood eosinophils following inhaled allergen challenge, but had no effect on either the late phase response or post-allergen increase in airway responsiveness to histamine (31
). In another randomized, double-blind, placebo controlled trial, patients with severe asthma and persistent eosinophilia were given anti-IL-5 monoclonal antibody for one year. The treatment group had significantly less exacerbations, lower eosinophil counts, but no significant changes from baseline in symptoms, FEV1
, bronchodilator use or airway hyper-responsiveness (32
). Similar findings were seen in a study of mepolizumab in patients with persistent eosinophilia and corticosteroid dependent asthma. In addition to a significant decrease in the number of exacerbations, the treatment group also had a lower corticosteroid burden (33
While omalizumab and mepolizumab have shown efficacy for SLT in patients with more severe asthma, comparison studies are needed to provide the clinician with evidence to guide individualized approaches to choosing SLT regimens at steps 4–6 of asthma care.