Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma

Abstract

Background: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients.

Methods: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry.

Results: When quintupling the dose of fluticasone (to 250 μg twice a day) was compared with adding salmeterol (50 μg twice a day) and doubling the fluticasone (to 100 μg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age.

Conclusions: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).

Copyright © 2019 Massachusetts Medical Society.

Figures

Figure 1.. Percentage of Black Children (5 to 11 Years of Age) with Asthma Who Had a Superior Response to Specific Treatments, According to the Composite Outcome, at 14 Weeks.

Shown are the five prespecified comparisons of the percentages of patients with a superior response among those receiving twice-daily treatment with a low-dose inhaled glucocorticoid (fluticasone propionate) at a dose of 50 μg (FP100, the double-fluticasone group); a dose of fluticasone doubled to 100 μg with the addition of a LABA (salmeterol) at a dose of 50 μg (FP100/SM50, the salmeterol–double-fluticasone group); a dose of fluticasone quintupled to 250 μg (FP250, the quintuple-fluticasone group); or a dose of fluticasone quintupled to 250 μg with the addition of salmeterol at a dose of 50 μg (FP250/SM50, the salmeterol–quintuple-fluticasone group) with respect to the hierarchical composite outcome that incorporated asthma exacerbations, asthma-control days, and change in the forced expiratory volume in 1 second (FEV1). The numbers in each bar represent the percentage of patients who had a superior response to that specific treatment, as compared with the alternative treatment. Gray bars indicate the percentage of patients in whom one treatment was not superior to the other. The P value reflects a test of the coprimary null hypothesis that the probability of a superior response to each treatment would not differ. T bars indicate 95% confidence intervals.

Figure 2.. Percentage of Black Adolescents and Adults with Asthma Who Had a Superior Response to Specific Treatments, According to the Composite Outcome, at 14 Weeks.

Shown are all the comparisons of the percentages of patients with a superior response among those receiving twice-daily treatment with fluticasone propionate at a dose of 100 μg plus salmeterol at a dose of 50 μg (FP100/SM50, the salmeterol–fluticasone group); a dose of fluticasone increased by a factor of 2.5 to 250 μg (FP250, the 2.5-fluticasone group); a dose of fluticasone quintupled to 500 μg (FP500, the quintuple-fluticasone group); or a dose of fluticasone increased by a factor of 2.5 to 250 μg with the addition of salmeterol at a dose of 50 μg (FP250/SM50, the salmeterol–2.5-fluticasone group) with respect to the hierarchical composite outcome that incorporated asthma exacerbations, asthma-control days, and the absolute change in the percentage of the predicted FEV1. The numbers in each bar represent the percentage of patients who had a superior response to that specific treatment, as compared with the alternative treatment. Gray bars indicate the percentage of patients in whom one treatment was not superior to the other. The P values reflect a test of the coprimary null hypotheses that the probability of a superior response to each treatment would not differ. T bars indicate 95% confidence intervals.

Figure 3.. Comparison of the Primary Composite Outcome in the Trial involving Adolescents and Adults and the Trial involving Children.

Shown are the prespecified comparisons of the percentages of patients with a superior response. Each panel shows a comparison of a similar step-up in therapy for children and for adolescents and adults. Shown are responses at 14 weeks in adolescents and adults and in children who at baseline had poorly controlled asthma while receiving twice-daily treatment with a low-dose inhaled glucocorticoid (fluticasone propionate) (50 μg in children and 100 μg in adolescents and adults). In children, the step-up trial treatments included doubling the dose of fluticasone to 100 μg (FP100, the double-fluticasone group); doubling the dose of fluticasone to 100 μg and adding salmeterol at a dose of 50 μg (FP100/SM50, the salmeterol–double-fluticasone group); quintupling the dose of fluticasone to 250 μg (FP250, the quintuple-fluticasone group); or quintupling the dose of fluticasone to 250 μg and adding salmeterol at a dose of 50 μg (FP250/SM50, the salmeterol–quintuple-fluticasone group). In adolescents and adults, the step-up interventions included adding salmeterol to the baseline dose of fluticasone (FP100/SM50, the fluticasone–salmeterol group), increasing the dose of fluticasone by a factor of 2.5 (FP250, the 2.5-fluticasone group), increasing the dose of fluticasone by a factor of 2.5 and adding salmeterol (FP250/SM50, the salmeterol–2.5-fluticasone group), or quintupling the dose of fluticasone (FP 500). A superior response was determined with respect to the hierarchical composite outcome that incorporated asthma exacerbations, asthma-control days, and the change in the FEV1. The numbers in each bar represent the percentage of patients who had a superior response to that specific treatment as compared with the alternative treatment. Gray bars indicate the percentage of patients in whom one treatment was not superior to the other. The two groups of patients (patients from the trial involving children and those from the trial involving adolescents and adults) were compared to identify interactions between the two groups and the composite superiority outcome. T bars indicate 95% confidence intervals.