Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids

Abstract

Background: For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking.

Methods: We randomly assigned 182 children (6 to 17 years of age), who had uncontrolled asthma while receiving 100 microg of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 microg of fluticasone twice daily (ICS step-up), 100 microg of fluticasone plus 50 microg of a long-acting beta-agonist twice daily (LABA step-up), or 100 microg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up). We used a triple-crossover design and a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second) to determine whether the frequency of a differential response to the step-up regimens was more than 25%.

Results: A differential response occurred in 161 of 165 patients who were evaluated (P<0.001). The response to LABA step-up therapy was most likely to be the best response, as compared with responses to LTRA step-up (relative probability, 1.6; 95% confidence interval [CI], 1.1 to 2.3; P=0.004) and ICS step-up (relative probability, 1.7; 95% CI, 1.2 to 2.4; P=0.002). Higher scores on the Asthma Control Test before randomization (indicating better control at baseline) predicted a better response to LABA step-up (P=0.009). White race predicted a better response to LABA step-up, whereas black patients were least likely to have a best response to LTRA step-up (P=0.005).

Conclusions: Nearly all the children had a differential response to each step-up therapy. LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up. However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child's asthma therapy. (ClinicalTrials.gov number, NCT00395304.)

Figure 1. Enrollment and Outcomes and Schedule of Evaluations

Panel A shows the number of patients who enrolled in the study, underwent randomization, and completed the study. FEV₁ denotes forced expiratory volume in 1 second, PC₂₀ provocation concentration of methacholine causing a 20% fall in FEV₁, and PFT pulmonary-function test. Panel B shows the schedule for various tests and procedures and the administration of the Pediatric Asthma Quality of Life Questionnaire to assess asthma impairment at specific study visits. Visit 2a was the randomization visit. ACT denotes Asthma Control Test, BR4P bronchodilator response to four puffs of albuterol, c-ACT Childhood Asthma Control Test, FeNO fraction of exhaled nitric oxide, FO forced oscillometry, and QOL quality-of-life questionnaire.

Figure 2. Pairwise Comparison of Three Step-up Therapies and the Overall Probability of Best Response

Panel A shows pairwise comparisons of the three step-up therapies. The proportion of patients with a best response to a long-acting beta-agonist (LABA) step-up was higher than the proportion with a best response to a leuko triene-receptor antagonist (LTRA) step-up (52% vs. 34%, P = 0.02) or an inhaled corticosteroid (ICS) step-up (54% vs. 32%, P = 0.004); the best-response results for LTRA step-up were similar to those for an ICS step-up. Panel B shows the pattern of differential response according to the probability that the best response to a treatment occurred during the period in which that treatment was received; LABA step-up was most likely to provide the best response. Covariate-adjusted estimates were obtained from rank-ordered logistic-regression models; I bars indicate bootstrap-based 95% confidence intervals.

Figure 3. Primary Predictors of a Differential Response to Step-up Therapy

The four factors that are shown were preselected as potential predictors of a differential response among patients receiving step-up therapy with a long-acting beta-agonist (LABA), an inhaled corticosteroid (ICS), or a leukotriene-receptor antagonist (LTRA). Three of these factors did not identify distinct patterns of differential response: the meth choline provocation concentration causing a 20% fall (PC₂₀) in the forced expiratory volume in 1 second (Panel A), the fraction of exhaled nitric oxide (FeNO) (Panel B), and the genotype for the β₂-adrenergic receptor (Panel D). T fourth factor — the baseline score on the Asthma Control Test (for children 12 years of age or older, measured on scale of 5 to 25) or the Childhood Asthma Control Test (for children between the ages of 4 and 11 years, measured on a scale from 0 to 27, with higher scores on both tests indicating greater control) — did identify distinct patterns of differential response (P = 0.009), with scores of more than 19 predicting an increased likelihood of a best response to LABA step-up therapy (Panel C). Estimates were obtained from rank-ordered logistic-regression models; I bars indicate bootstrap-based 95% confidence intervals.

Figure 4. Secondary Predictors of a Differential Response to Step-up Therapy

Shown is the probability of a best response to step-up therapy with a long-acting beta-agonist (LABA), an inhaled corticosteroid (ICS), or a leuko-triene-receptor antagonist (LTRA), according to race or ethnic group, age, and the presence or absence of eczema, factors that were evaluated in post hoc analysis. Race or ethnic group was a significant predictor (P = 0.005), with Hispanic and non-Hispanic white patients most likely to have a best response to LABA step-up therapy and black patients equally likely to have a best response to LABA or ICS step-up and least likely to have a best response to LTRA step-up (Panel A). Age was not a significant predictor of a differential response (Panel B). Patients who did not have eczema were most likely to have a best response to LABA step-up therapy (P = 0.006) (Panel C). Estimates were obtained from rank-ordered logistic-regression models; I bars indicate bootstrap-based 95% confidence intervals. P values have not been corrected for multiple testing.