BARD Trials Show Disparity in Black Children, Adult Asthma Therapy Response

Michael E. Wechsler, MD, MMSc

Investigators reported an even split in benefit among black children with poorly controlled asthma, in findings from a trial which compared 2 different dose increases of fluticasone, with or without salmeterol, to assess the efficacy of increased glucocorticoid doses versus the addition of long-acting beta agonists (LABAs).

A pair of prospective, randomized, double-blind trials comparing quintupled fluticasone dose to doubled fluticasone dose and added salmeterol among black children, adolescents, and adults with inadequately controlled asthma found conflicting results among the older patient population, versus the younger population.

The parallel Best African American Response to Asthma Drug (BARD) Trials—led by Michael E. Wechsler, MD, MMSc, of National Jewish Health—leave investigators with uncertain determination of the preferred step-up strategy for black children with poorly controlled asthma.

Previous recommendation for patients with asthma not controlled by first-line inhaled glucocorticoid therapy calls for the addition of a LABA. That said, Wechsler and colleagues noted, this recommendation is based on studies with a limited black patient population, and ones which do not consider differences in patient genetic history.

Epidemiologic trials involving US patients with asthma show persons identified as “black” experience more burden in terms of exacerbations, hospitalizations, and even mortality than persons who identify as “white.” Though other factors may play into differing asthma morbidity among races and ethnicities, trends in worse disease persist after study adjustments have been made for such factors.

“Studies show that black patients often have differential responses to medications for asthma, and they have more glucocorticoid resistance, less cellular sensitivity to glucocorticoids, and more eosinophilic inflammation during inhaled glucocorticoid treatment than do white patients,” investigators wrote.

Additionally, asthma pharmacotherapy response could be influenced by genetic variants derived from a person’s race and ancestral background. As such, these variants may explain differences found in black and white patient response to inhaled glucocorticoids and LABAs.

Wechsler and colleagues sought to determine the most ideal step-up therapy regimen in 2 black poorly-controlled asthma patient populations separated by age groups, with additional assessments set on which biomarkers, patient characteristics, and variation in ancestry were most predictive of treatment response.

Both trials’ patients were required to have at least 1 grandparent who had identified as black, and had inadequately controlled asthma while taking inhaled glucocorticoids.

Investigators compared a quintupled dose of fluticasone (250 mcg twice daily) to a regimen of added salmeterol (50 mcg twice daily) and doubled fluticasone (100 mcg twice daily). In adolescents and adults, they compared low-dose fluticasone plus salmeterol to medium-dose fluticasone, then medium-dose fluticasone plus salmeterol to high-dose fluticasone.

The children-based assessment included 280 patients aged 5-11 years old, with a mean age of 8.5±1.8 years. A majority (n = 170; 60.7%) of patients were male, with a median African ancestry of 81.0% (IQR, 73.4-85.6). More than 88% of pediatric patients were on inhaled or nebulized glucocorticoid monotherapy in the previous 12 months.

The adolescent and adult-based assessment included 294 patients aged ≥12 years, with a mean age of 37.3±16.1 years. Just one-third (n = 95; 32.3%) were male, with a median African ancestry of 82.1% (IQR, 75.3-87.6). Though still a majority of patients, a notably lesser rate of adults and adolescents were on glucocorticoid monotherapy in the previous 12 months (65.6%).

In the children population, 46% of patients reported a superior response to quintupled fluticasone dose—the same rate of children to report a superior response to doubled fluticasone plus LABA (P = .99).

A greater rate of adolescents and adults reported superior response to LABA-added therapy than increased fluticasone in both dosing increases (49% vs 28% [P = .003]; 49% vs 31% [P = .02], respectively).

Investigators did not observe a superior response to specific treatments based on patient African ancestry nor baseline biomarkers. In previous trials, they noted, African ancestry was associated with asthma-related phenotypes such as low lung function and exacerbations.

“A larger trial might have the power to determine which phenotypic or specific pharmacogenetic variant panels could have the power to detect such differences,” they wrote.

Increased inhaled glucocorticoids was associated with decreased urinary cortisol-creatine ration in children younger than 8 years old. However, the trial did not continue long enough to see worsened effects or possible harm to children’s development or growth.

The team concluded the prospective trials indicated differing treatment outcomes among black children and adults with inadequately controlled asthma—and even differing treatment response between black children and that observed by white children with similar asthma.

Their findings warrant further assessment.

“A larger, more simplified trial should be undertaken to determine the best treatment approach for black children with poorly controlled asthma despite the use of standard doses of an inhaled glucocorticoid,” Wechsler and colleagues wrote.

The study, “Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma,” was published online in The New England Journal of Medicine.