National guidelines recommend increasing the dose of inhaled corticosteroid (ICS) or adding long-acting β-agonists (LABAs) when patients do not derive adequate control from low-dose ICSs. Recently, though, the US Food and Drug Administration raised concerns about the safety of LABAs, related to the possibility of increased risk for adverse events, including hospitalization and death, with their use.
Additional research has suggested that blacks may experience a disproportionate increase in adverse effects with LABAs, and that they may benefit less from their use, compared to people from other racial backgrounds. Variations in the Arg16Gly gene of the β2 adrenergic receptor (ADRB2) might explain these associations, but remains to be shown.
Now, a randomized controlled trial of over 1000 black adults with asthma suggests similar negative outcomes for the anticholinergic agent tiotropium compared to LABAs as add-on therapy to ICSs.1
The study also found that polymorphisms of the Arg16Gly gene did not affect the results. The study, called the Blacks and Exacerbations on LABA vs Tiotropium (BELT) study, was published in the October issue of JAMA.
“Among black adults with asthma treated with ICS, adding a LABA did not improve time to asthma exacerbation compared with adding tiotropium,” wrote first author Michael Wechsler, MD, Msc, of the National Jewish Health Center (Denver, Colorado) and colleagues. “These findings were not affected by polymorphisms at the Arg16Gly locus of ADRB2. These findings do not support the superiority of LABA + ICS compared with tiotropium + ICS for black patients with asthma.”
The open-label trial took place at 20 US primary care and specialty clinics in the US from March 2011 to July 2013. It included black adults with moderate to severe asthma who were eligible for step 3 or step 4 combination therapy according to National Heart, Lung and Blood Institute guidelines. Researchers randomized participants to ICS plus once-daily tiotropium (18 µg) (n=532) or ICS plus twice daily LABAs (salmeterol 50 µg or formoterol 9 µg) (n=538). Patients received genotyping, completed monthly standardized asthma control and asthma exacerbation questionnaires, and went to study visits at baseline, 1, 6, 12, and 18 months.
More than 75% of the patients were women, reflecting the fact that 62% of blacks with asthma are women, according to background information in the article. The mean duration of follow-up was 310 days. The median treatment adherence rate was 60% and both groups had similar rates of discontinuation (31% for LABA + ICS vs 35% for tiotropium + ICS).
Results showed no significant difference between groups for most outcomes:
►Time to first exacerbation: Mean number of exacerbations/person-year LABA 0.42 vs tiotropium 0.37 (rate ratio, 0.90 [95% CI, 0.73 to 1.11], P = .31)
►Probability of being symptom-free at 1 year: 74% for LABA vs 75.7% for tiotropium (HR 0.91 [95% CI 0.70 to 1.18, p=.47)
►Asthma control, asthma quality of life, asthma symptom-free days, FEV1, and rescue medication use were all similar
►Arg16Gly ADRB2 alleles: Hazard ratio for time to first exacerbation, Arg/Arg 0.84 (95% CI, 0.47 to 1.51) vs Arg/Gly or Gly/Gly 0.85 (95% CI, 0.63 to 1.15), (P=.97).
►Results were similar after adjusting for geographic region, age, sex, and baseline percentage of FEV1 predicted, study site, current and prior smoking history
► BUT: Patients with bronchodilator reversibility (>12% change in FEV1) at one month had lower likelihood of exacerbations with LABA vs tiotropium
Asthma-related adverse events and serious adverse events were also similar between groups (2% with LABA + ICS vs 3% with tiotropium + ICS, p=.16). Nineteen people in the tiotropium + ICS group and ten in the LABA + ICS group experienced asthma-related hospitalizations. Three participants died, all in the tiotropium group (p=.12), and two of these deaths were asthma-related (p=.25).
Even though more hospitalizations occurred in the tiotropium group compared to the LABA group, the authors noted that no conclusions can be drawn because the study was not powered enough to look at hospitalizations or death.
“Although we could not detect a difference in exacerbations between either combination therapy, we found that, despite combination therapy, this population experienced a high rate of exacerbations,” the authors concluded. “Additional targeted interventions and further study are needed to reduce the rate of asthma exacerbations in this population.”
Take Home Points
►Some research has suggested that black adults with asthma may experience increased adverse events and less benefit from LABAs
►An open-label randomized trial in black adults inadequately controlled on ICSs found adding twice daily LABAs was not superior to adding tiotropium in controlling asthma exacerbations
►Asthma deteriorations, lung function, and patient-reported asthma quality of life were similar for both combinations
►Participants with Arg16Gly genetic variants at the ADRB2 gene did not have significantly different responses to therapy.
Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting β-agonist in combination with inhaled corticosteroids in black adults with asthma. The BELT randomized clinical trial. JAMA. 2015;314:1720-1730. doi: 10.1001/jama.2015.13277.