Anticholinergic vs long-acting β-Agonist in combination with inhaled corticosteroids in black adults with asthma

The BELT randomized clinical trial

Michael E. Wechsler, Barbara P. Yawn, Anne L. Fuhlbrigge, Wilson D. Pace, Michael J. Pencina, Gheorghe Doros, Shamsah Kazani, Benjamin A. Raby, Jane Lanzillotti, Suzanne Madison, Elliot Israel, Asif Ansari, Donald Raum, Manuja Marthur, Pedro Avila, James E. Bailey, William Calhoun, Ku Lang Chang, Mario Coto, Cedrice Davis & 8 others Rosalind Dawson, M. LaFrance Ferguson, Mark T. Dransfield, Frances Ferguson, Allen Greiner, Ahmad Jingo, William Pankey, Martin Schear

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

IMPORTANCE: The efficacy and safety of long-acting β-agonists (LABAs) have been questioned. Black populations may be disproportionately affected by LABA risks. OBJECTIVE: To compare the effectiveness and safety of tiotropium vs LABAs, when used with inhaled corticosteroids (ICS) in black adults with asthma and to determine whether allelic variation at the Arg16Gly locus of the β2-adrenergic receptor (ADRB2) gene is associated with treatment response. DESIGN, SETTING, AND PARTICIPANTS: A multisite (n = 20), open-label, parallel-group, pragmatic randomized clinical trial conducted from March 2011 through July 2013, enrolling black adults with moderate to severe asthma in the United States. INTERVENTIONS: Patients eligible for, or receiving, step 3 or step 4 combination therapy per National Heart, Lung, and Blood Institute guidelines, received ICS plus either once-daily tiotropium (n = 532) or twice-daily LABAs (n = 538,) and were followed up for up to 18 months. Patients underwent genotyping, attended study visits at baseline, 1, 6,12, and 18 months, and completed monthly questionnaires. MAIN OUTCOMES AND MEASURES: The primary outcome was time to asthma exacerbation, defined as a worsening asthma event requiring oral or parenteral corticosteroids. Secondary outcomes included patient-reported outcomes (Asthma Quality of Life Questionnaire, Asthma Control Questionnaire [ACQ], Asthma Symptom Utility Index, and Asthma Symptom-Free Days questionnaire), spirometry (FEV1), rescue medication use, asthma deteriorations, and adverse events. RESULTS: There was no difference between LABA + ICS vs tiotropium + ICS in time to first exacerbation (mean No. of exacerbations/person-year, 0.42 vs 0.37 (rate ratio, 0.90 [95% CI, 0.73 to 1.11], log-rank P =.31). There was no difference in change in FEV1 at 12 months (0.003 L for LABA + ICS vs-0.018 Lfor tiotropium + ICS; between-group difference, 0.020 [95% CI, -0.021 to 0.061], P=.33) and at 18 months (-0.053 Lvs-0.078 L; between-group difference, 0.025 [95% CI, -0.045 to 0.095], P =.49). There were no differences in ACQ score at 18 months (change in score from baseline, -0.68 for LABA + ICS vs-0.72 for tiotropium + ICS; between-group difference, 0.04 [95% CI, -0.18 to 0.27], P =.70). There were no differences in other patient-reported outcomes. Arg16Gly ADRB2 alleles were not associated with differences in the effects of tiotropium + ICS vs LABA + ICS (hazard ratio for time to first exacerbation, 0.84 [95% CI, 0.47 to 1.51] for Arg/Arg vs 0.85 [95% CI, 0.63 to 1.15] for Arg/Gly or Gly/Gly, P =.97). CONCLUSIONS/RELEVANCE: Among black adults with asthma treated with ICS, adding a LABA did not improve time to asthma exacerbation compared with adding tiotropium. 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.

Original languageEnglish (US)
Pages (from-to)1720-1730
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume314
Issue number16
DOIs
StatePublished - Oct 27 2015
Externally publishedYes

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Cholinergic Antagonists
Adrenal Cortex Hormones
Asthma
Randomized Controlled Trials
Pragmatic Clinical Trials
National Heart, Lung, and Blood Institute (U.S.)
Safety
Tiotropium Bromide
Spirometry
Adrenergic Receptors

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Anticholinergic vs long-acting β-Agonist in combination with inhaled corticosteroids in black adults with asthma : The BELT randomized clinical trial. / Wechsler, Michael E.; Yawn, Barbara P.; Fuhlbrigge, Anne L.; Pace, Wilson D.; Pencina, Michael J.; Doros, Gheorghe; Kazani, Shamsah; Raby, Benjamin A.; Lanzillotti, Jane; Madison, Suzanne; Israel, Elliot; Ansari, Asif; Raum, Donald; Marthur, Manuja; Avila, Pedro; Bailey, James E.; Calhoun, William; Chang, Ku Lang; Coto, Mario; Davis, Cedrice; Dawson, Rosalind; Ferguson, M. LaFrance; Dransfield, Mark T.; Ferguson, Frances; Greiner, Allen; Jingo, Ahmad; Pankey, William; Schear, Martin.

In: JAMA - Journal of the American Medical Association, Vol. 314, No. 16, 27.10.2015, p. 1720-1730.

Research output: Contribution to journalArticle

Wechsler, ME, Yawn, BP, Fuhlbrigge, AL, Pace, WD, Pencina, MJ, Doros, G, Kazani, S, Raby, BA, Lanzillotti, J, Madison, S, Israel, E, Ansari, A, Raum, D, Marthur, M, Avila, P, Bailey, JE, Calhoun, W, Chang, KL, Coto, M, Davis, C, Dawson, R, Ferguson, ML, Dransfield, MT, Ferguson, F, Greiner, A, Jingo, A, Pankey, W & Schear, M 2015, 'Anticholinergic vs long-acting β-Agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial', JAMA - Journal of the American Medical Association, vol. 314, no. 16, pp. 1720-1730. https://doi.org/10.1001/jama.2015.13277
Wechsler, Michael E. ; Yawn, Barbara P. ; Fuhlbrigge, Anne L. ; Pace, Wilson D. ; Pencina, Michael J. ; Doros, Gheorghe ; Kazani, Shamsah ; Raby, Benjamin A. ; Lanzillotti, Jane ; Madison, Suzanne ; Israel, Elliot ; Ansari, Asif ; Raum, Donald ; Marthur, Manuja ; Avila, Pedro ; Bailey, James E. ; Calhoun, William ; Chang, Ku Lang ; Coto, Mario ; Davis, Cedrice ; Dawson, Rosalind ; Ferguson, M. LaFrance ; Dransfield, Mark T. ; Ferguson, Frances ; Greiner, Allen ; Jingo, Ahmad ; Pankey, William ; Schear, Martin. / Anticholinergic vs long-acting β-Agonist in combination with inhaled corticosteroids in black adults with asthma : The BELT randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2015 ; Vol. 314, No. 16. pp. 1720-1730.
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title = "Anticholinergic vs long-acting β-Agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial",
abstract = "IMPORTANCE: The efficacy and safety of long-acting β-agonists (LABAs) have been questioned. Black populations may be disproportionately affected by LABA risks. OBJECTIVE: To compare the effectiveness and safety of tiotropium vs LABAs, when used with inhaled corticosteroids (ICS) in black adults with asthma and to determine whether allelic variation at the Arg16Gly locus of the β2-adrenergic receptor (ADRB2) gene is associated with treatment response. DESIGN, SETTING, AND PARTICIPANTS: A multisite (n = 20), open-label, parallel-group, pragmatic randomized clinical trial conducted from March 2011 through July 2013, enrolling black adults with moderate to severe asthma in the United States. INTERVENTIONS: Patients eligible for, or receiving, step 3 or step 4 combination therapy per National Heart, Lung, and Blood Institute guidelines, received ICS plus either once-daily tiotropium (n = 532) or twice-daily LABAs (n = 538,) and were followed up for up to 18 months. Patients underwent genotyping, attended study visits at baseline, 1, 6,12, and 18 months, and completed monthly questionnaires. MAIN OUTCOMES AND MEASURES: The primary outcome was time to asthma exacerbation, defined as a worsening asthma event requiring oral or parenteral corticosteroids. Secondary outcomes included patient-reported outcomes (Asthma Quality of Life Questionnaire, Asthma Control Questionnaire [ACQ], Asthma Symptom Utility Index, and Asthma Symptom-Free Days questionnaire), spirometry (FEV1), rescue medication use, asthma deteriorations, and adverse events. RESULTS: There was no difference between LABA + ICS vs tiotropium + ICS in time to first exacerbation (mean No. of exacerbations/person-year, 0.42 vs 0.37 (rate ratio, 0.90 [95{\%} CI, 0.73 to 1.11], log-rank P =.31). There was no difference in change in FEV1 at 12 months (0.003 L for LABA + ICS vs-0.018 Lfor tiotropium + ICS; between-group difference, 0.020 [95{\%} CI, -0.021 to 0.061], P=.33) and at 18 months (-0.053 Lvs-0.078 L; between-group difference, 0.025 [95{\%} CI, -0.045 to 0.095], P =.49). There were no differences in ACQ score at 18 months (change in score from baseline, -0.68 for LABA + ICS vs-0.72 for tiotropium + ICS; between-group difference, 0.04 [95{\%} CI, -0.18 to 0.27], P =.70). There were no differences in other patient-reported outcomes. Arg16Gly ADRB2 alleles were not associated with differences in the effects of tiotropium + ICS vs LABA + ICS (hazard ratio for time to first exacerbation, 0.84 [95{\%} CI, 0.47 to 1.51] for Arg/Arg vs 0.85 [95{\%} CI, 0.63 to 1.15] for Arg/Gly or Gly/Gly, P =.97). CONCLUSIONS/RELEVANCE: Among black adults with asthma treated with ICS, adding a LABA did not improve time to asthma exacerbation compared with adding tiotropium. 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.",
author = "Wechsler, {Michael E.} and Yawn, {Barbara P.} and Fuhlbrigge, {Anne L.} and Pace, {Wilson D.} and Pencina, {Michael J.} and Gheorghe Doros and Shamsah Kazani and Raby, {Benjamin A.} and Jane Lanzillotti and Suzanne Madison and Elliot Israel and Asif Ansari and Donald Raum and Manuja Marthur and Pedro Avila and Bailey, {James E.} and William Calhoun and Chang, {Ku Lang} and Mario Coto and Cedrice Davis and Rosalind Dawson and Ferguson, {M. LaFrance} and Dransfield, {Mark T.} and Frances Ferguson and Allen Greiner and Ahmad Jingo and William Pankey and Martin Schear",
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TY - JOUR

T1 - Anticholinergic vs long-acting β-Agonist in combination with inhaled corticosteroids in black adults with asthma

T2 - The BELT randomized clinical trial

AU - Wechsler, Michael E.

AU - Yawn, Barbara P.

AU - Fuhlbrigge, Anne L.

AU - Pace, Wilson D.

AU - Pencina, Michael J.

AU - Doros, Gheorghe

AU - Kazani, Shamsah

AU - Raby, Benjamin A.

AU - Lanzillotti, Jane

AU - Madison, Suzanne

AU - Israel, Elliot

AU - Ansari, Asif

AU - Raum, Donald

AU - Marthur, Manuja

AU - Avila, Pedro

AU - Bailey, James E.

AU - Calhoun, William

AU - Chang, Ku Lang

AU - Coto, Mario

AU - Davis, Cedrice

AU - Dawson, Rosalind

AU - Ferguson, M. LaFrance

AU - Dransfield, Mark T.

AU - Ferguson, Frances

AU - Greiner, Allen

AU - Jingo, Ahmad

AU - Pankey, William

AU - Schear, Martin

PY - 2015/10/27

Y1 - 2015/10/27

N2 - IMPORTANCE: The efficacy and safety of long-acting β-agonists (LABAs) have been questioned. Black populations may be disproportionately affected by LABA risks. OBJECTIVE: To compare the effectiveness and safety of tiotropium vs LABAs, when used with inhaled corticosteroids (ICS) in black adults with asthma and to determine whether allelic variation at the Arg16Gly locus of the β2-adrenergic receptor (ADRB2) gene is associated with treatment response. DESIGN, SETTING, AND PARTICIPANTS: A multisite (n = 20), open-label, parallel-group, pragmatic randomized clinical trial conducted from March 2011 through July 2013, enrolling black adults with moderate to severe asthma in the United States. INTERVENTIONS: Patients eligible for, or receiving, step 3 or step 4 combination therapy per National Heart, Lung, and Blood Institute guidelines, received ICS plus either once-daily tiotropium (n = 532) or twice-daily LABAs (n = 538,) and were followed up for up to 18 months. Patients underwent genotyping, attended study visits at baseline, 1, 6,12, and 18 months, and completed monthly questionnaires. MAIN OUTCOMES AND MEASURES: The primary outcome was time to asthma exacerbation, defined as a worsening asthma event requiring oral or parenteral corticosteroids. Secondary outcomes included patient-reported outcomes (Asthma Quality of Life Questionnaire, Asthma Control Questionnaire [ACQ], Asthma Symptom Utility Index, and Asthma Symptom-Free Days questionnaire), spirometry (FEV1), rescue medication use, asthma deteriorations, and adverse events. RESULTS: There was no difference between LABA + ICS vs tiotropium + ICS in time to first exacerbation (mean No. of exacerbations/person-year, 0.42 vs 0.37 (rate ratio, 0.90 [95% CI, 0.73 to 1.11], log-rank P =.31). There was no difference in change in FEV1 at 12 months (0.003 L for LABA + ICS vs-0.018 Lfor tiotropium + ICS; between-group difference, 0.020 [95% CI, -0.021 to 0.061], P=.33) and at 18 months (-0.053 Lvs-0.078 L; between-group difference, 0.025 [95% CI, -0.045 to 0.095], P =.49). There were no differences in ACQ score at 18 months (change in score from baseline, -0.68 for LABA + ICS vs-0.72 for tiotropium + ICS; between-group difference, 0.04 [95% CI, -0.18 to 0.27], P =.70). There were no differences in other patient-reported outcomes. Arg16Gly ADRB2 alleles were not associated with differences in the effects of tiotropium + ICS vs LABA + ICS (hazard ratio for time to first exacerbation, 0.84 [95% CI, 0.47 to 1.51] for Arg/Arg vs 0.85 [95% CI, 0.63 to 1.15] for Arg/Gly or Gly/Gly, P =.97). CONCLUSIONS/RELEVANCE: Among black adults with asthma treated with ICS, adding a LABA did not improve time to asthma exacerbation compared with adding tiotropium. 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.

AB - IMPORTANCE: The efficacy and safety of long-acting β-agonists (LABAs) have been questioned. Black populations may be disproportionately affected by LABA risks. OBJECTIVE: To compare the effectiveness and safety of tiotropium vs LABAs, when used with inhaled corticosteroids (ICS) in black adults with asthma and to determine whether allelic variation at the Arg16Gly locus of the β2-adrenergic receptor (ADRB2) gene is associated with treatment response. DESIGN, SETTING, AND PARTICIPANTS: A multisite (n = 20), open-label, parallel-group, pragmatic randomized clinical trial conducted from March 2011 through July 2013, enrolling black adults with moderate to severe asthma in the United States. INTERVENTIONS: Patients eligible for, or receiving, step 3 or step 4 combination therapy per National Heart, Lung, and Blood Institute guidelines, received ICS plus either once-daily tiotropium (n = 532) or twice-daily LABAs (n = 538,) and were followed up for up to 18 months. Patients underwent genotyping, attended study visits at baseline, 1, 6,12, and 18 months, and completed monthly questionnaires. MAIN OUTCOMES AND MEASURES: The primary outcome was time to asthma exacerbation, defined as a worsening asthma event requiring oral or parenteral corticosteroids. Secondary outcomes included patient-reported outcomes (Asthma Quality of Life Questionnaire, Asthma Control Questionnaire [ACQ], Asthma Symptom Utility Index, and Asthma Symptom-Free Days questionnaire), spirometry (FEV1), rescue medication use, asthma deteriorations, and adverse events. RESULTS: There was no difference between LABA + ICS vs tiotropium + ICS in time to first exacerbation (mean No. of exacerbations/person-year, 0.42 vs 0.37 (rate ratio, 0.90 [95% CI, 0.73 to 1.11], log-rank P =.31). There was no difference in change in FEV1 at 12 months (0.003 L for LABA + ICS vs-0.018 Lfor tiotropium + ICS; between-group difference, 0.020 [95% CI, -0.021 to 0.061], P=.33) and at 18 months (-0.053 Lvs-0.078 L; between-group difference, 0.025 [95% CI, -0.045 to 0.095], P =.49). There were no differences in ACQ score at 18 months (change in score from baseline, -0.68 for LABA + ICS vs-0.72 for tiotropium + ICS; between-group difference, 0.04 [95% CI, -0.18 to 0.27], P =.70). There were no differences in other patient-reported outcomes. Arg16Gly ADRB2 alleles were not associated with differences in the effects of tiotropium + ICS vs LABA + ICS (hazard ratio for time to first exacerbation, 0.84 [95% CI, 0.47 to 1.51] for Arg/Arg vs 0.85 [95% CI, 0.63 to 1.15] for Arg/Gly or Gly/Gly, P =.97). CONCLUSIONS/RELEVANCE: Among black adults with asthma treated with ICS, adding a LABA did not improve time to asthma exacerbation compared with adding tiotropium. 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.

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