Use of regularly scheduled albuterol treatment in asthma: Genotype-stratified, randomised, placebo-controlled cross-over trial

Elliot Israel, Vernon M. Chinchilli, Jean G. Ford, Homer A. Boushey, Reuben Cherniack, Timothy J. Craig, Aaron Deykin, Joanne K. Fagan, John V. Fahy, James Fish, Monica Kraft, Susan J. Kunselman, Stephen C. Lazarus, Robert F. Lemanske, Stephen B. Liggett, Richard J. Martin, Nandita Mitra, Stephen P. Peters, Eric Silverman, Christine A. SorknessStanley J. Szefler, Michael E. Wechsler, Scott T. Weiss, Jeffrey M. Drazen

Research output: Contribution to journalArticle

Abstract

Background The issue of whether regular use of an inhaled β 2-adrenergic agonist worsens airflow and clinical outcomes in asthma is controversial. Retrospective studies have suggested that adverse effects occur in patients with a genetic polymorphism that results in homozygosity for arginine (Arg/Arg), rather than glycine (Gly/Gly), at aminoacid residue 16 of the β 2-adrenergic receptor. However, the existence of any genotype-dependent difference has not been tested in a prospective clinical trial. Methods Patients with mild asthma, not using a controller medication, were enrolled in pairs matched for forced expiratory volume in 1 s (FEV 1) according to whether they had the Arg/Arg (n=37; four of 41 matches withdrew before randomisation) or Gly/Gly (n=41) genotype. Regularly scheduled treatment with albuterol or placebo was given in a masked, cross-over design, for 16-week periods. During the study, as-needed albuterol use was discontinued and ipratropium bromide was used as needed. Morning peak expiratory flow rate (PEFR) was the primary outcome variable. The primary comparisons were between treatment period for each genotype; the secondary outcome was a treatment by genotype effect. Analyses were by intention to treat. Findings During the run-in period, when albuterol use was kept to a minimum, patients with the Arg/Arg genotype had an increase in morning PEFR of 23 L/min (p=0·0162); the change in patients with the Gly/Gly genotype was not significant (2 L/min; p=0·8399). During randomised treatment, patients with the Gly/Gly genotype had an increase in morning PEFR during treatment with regularly scheduled albuterol compared with placebo (14 L/min [95% CI 3 to 25]; p=0·0175). By contrast, patients with the Arg/Arg genotype had lower morning PEFR during treatment with albuterol than during the placebo period, when albuterol use was limited (-10 L/min [-19 to -2]; p=0·0209). The genotype-attributable treatment difference was therefore -24 L/min (-37 to -12; p=0·0003). There were similar genotype-specific effects in FEV 1, symptoms, and use of supplementary reliever medication. Interpretation Genotype at the 16th aminoacid residue of the β 2-adrenergic receptor affects the long-term response to albuterol use. Bronchodilator treatments avoiding albuterol may be appropriate for patients with the Arg/Arg genotype.

Original languageEnglish (US)
Pages (from-to)1505-1512
Number of pages8
JournalThe Lancet
Volume364
Issue number9444
DOIs
StatePublished - Oct 23 2004
Externally publishedYes

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Albuterol
Cross-Over Studies
Asthma
Genotype
Placebos
Peak Expiratory Flow Rate
Therapeutics
Forced Expiratory Volume
Adrenergic Receptors
Ipratropium
Adrenergic Agonists
Intention to Treat Analysis
Bronchodilator Agents
Genetic Polymorphisms
Random Allocation
Glycine
Arginine
Retrospective Studies
Clinical Trials

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Israel, E., Chinchilli, V. M., Ford, J. G., Boushey, H. A., Cherniack, R., Craig, T. J., ... Drazen, J. M. (2004). Use of regularly scheduled albuterol treatment in asthma: Genotype-stratified, randomised, placebo-controlled cross-over trial. The Lancet, 364(9444), 1505-1512. https://doi.org/10.1016/S0140-6736(04)17273-5

Use of regularly scheduled albuterol treatment in asthma : Genotype-stratified, randomised, placebo-controlled cross-over trial. / Israel, Elliot; Chinchilli, Vernon M.; Ford, Jean G.; Boushey, Homer A.; Cherniack, Reuben; Craig, Timothy J.; Deykin, Aaron; Fagan, Joanne K.; Fahy, John V.; Fish, James; Kraft, Monica; Kunselman, Susan J.; Lazarus, Stephen C.; Lemanske, Robert F.; Liggett, Stephen B.; Martin, Richard J.; Mitra, Nandita; Peters, Stephen P.; Silverman, Eric; Sorkness, Christine A.; Szefler, Stanley J.; Wechsler, Michael E.; Weiss, Scott T.; Drazen, Jeffrey M.

In: The Lancet, Vol. 364, No. 9444, 23.10.2004, p. 1505-1512.

Research output: Contribution to journalArticle

Israel, E, Chinchilli, VM, Ford, JG, Boushey, HA, Cherniack, R, Craig, TJ, Deykin, A, Fagan, JK, Fahy, JV, Fish, J, Kraft, M, Kunselman, SJ, Lazarus, SC, Lemanske, RF, Liggett, SB, Martin, RJ, Mitra, N, Peters, SP, Silverman, E, Sorkness, CA, Szefler, SJ, Wechsler, ME, Weiss, ST & Drazen, JM 2004, 'Use of regularly scheduled albuterol treatment in asthma: Genotype-stratified, randomised, placebo-controlled cross-over trial', The Lancet, vol. 364, no. 9444, pp. 1505-1512. https://doi.org/10.1016/S0140-6736(04)17273-5
Israel, Elliot ; Chinchilli, Vernon M. ; Ford, Jean G. ; Boushey, Homer A. ; Cherniack, Reuben ; Craig, Timothy J. ; Deykin, Aaron ; Fagan, Joanne K. ; Fahy, John V. ; Fish, James ; Kraft, Monica ; Kunselman, Susan J. ; Lazarus, Stephen C. ; Lemanske, Robert F. ; Liggett, Stephen B. ; Martin, Richard J. ; Mitra, Nandita ; Peters, Stephen P. ; Silverman, Eric ; Sorkness, Christine A. ; Szefler, Stanley J. ; Wechsler, Michael E. ; Weiss, Scott T. ; Drazen, Jeffrey M. / Use of regularly scheduled albuterol treatment in asthma : Genotype-stratified, randomised, placebo-controlled cross-over trial. In: The Lancet. 2004 ; Vol. 364, No. 9444. pp. 1505-1512.
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abstract = "Background The issue of whether regular use of an inhaled β 2-adrenergic agonist worsens airflow and clinical outcomes in asthma is controversial. Retrospective studies have suggested that adverse effects occur in patients with a genetic polymorphism that results in homozygosity for arginine (Arg/Arg), rather than glycine (Gly/Gly), at aminoacid residue 16 of the β 2-adrenergic receptor. However, the existence of any genotype-dependent difference has not been tested in a prospective clinical trial. Methods Patients with mild asthma, not using a controller medication, were enrolled in pairs matched for forced expiratory volume in 1 s (FEV 1) according to whether they had the Arg/Arg (n=37; four of 41 matches withdrew before randomisation) or Gly/Gly (n=41) genotype. Regularly scheduled treatment with albuterol or placebo was given in a masked, cross-over design, for 16-week periods. During the study, as-needed albuterol use was discontinued and ipratropium bromide was used as needed. Morning peak expiratory flow rate (PEFR) was the primary outcome variable. The primary comparisons were between treatment period for each genotype; the secondary outcome was a treatment by genotype effect. Analyses were by intention to treat. Findings During the run-in period, when albuterol use was kept to a minimum, patients with the Arg/Arg genotype had an increase in morning PEFR of 23 L/min (p=0·0162); the change in patients with the Gly/Gly genotype was not significant (2 L/min; p=0·8399). During randomised treatment, patients with the Gly/Gly genotype had an increase in morning PEFR during treatment with regularly scheduled albuterol compared with placebo (14 L/min [95{\%} CI 3 to 25]; p=0·0175). By contrast, patients with the Arg/Arg genotype had lower morning PEFR during treatment with albuterol than during the placebo period, when albuterol use was limited (-10 L/min [-19 to -2]; p=0·0209). The genotype-attributable treatment difference was therefore -24 L/min (-37 to -12; p=0·0003). There were similar genotype-specific effects in FEV 1, symptoms, and use of supplementary reliever medication. Interpretation Genotype at the 16th aminoacid residue of the β 2-adrenergic receptor affects the long-term response to albuterol use. Bronchodilator treatments avoiding albuterol may be appropriate for patients with the Arg/Arg genotype.",
author = "Elliot Israel and Chinchilli, {Vernon M.} and Ford, {Jean G.} and Boushey, {Homer A.} and Reuben Cherniack and Craig, {Timothy J.} and Aaron Deykin and Fagan, {Joanne K.} and Fahy, {John V.} and James Fish and Monica Kraft and Kunselman, {Susan J.} and Lazarus, {Stephen C.} and Lemanske, {Robert F.} and Liggett, {Stephen B.} and Martin, {Richard J.} and Nandita Mitra and Peters, {Stephen P.} and Eric Silverman and Sorkness, {Christine A.} and Szefler, {Stanley J.} and Wechsler, {Michael E.} and Weiss, {Scott T.} and Drazen, {Jeffrey M.}",
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TY - JOUR

T1 - Use of regularly scheduled albuterol treatment in asthma

T2 - Genotype-stratified, randomised, placebo-controlled cross-over trial

AU - Israel, Elliot

AU - Chinchilli, Vernon M.

AU - Ford, Jean G.

AU - Boushey, Homer A.

AU - Cherniack, Reuben

AU - Craig, Timothy J.

AU - Deykin, Aaron

AU - Fagan, Joanne K.

AU - Fahy, John V.

AU - Fish, James

AU - Kraft, Monica

AU - Kunselman, Susan J.

AU - Lazarus, Stephen C.

AU - Lemanske, Robert F.

AU - Liggett, Stephen B.

AU - Martin, Richard J.

AU - Mitra, Nandita

AU - Peters, Stephen P.

AU - Silverman, Eric

AU - Sorkness, Christine A.

AU - Szefler, Stanley J.

AU - Wechsler, Michael E.

AU - Weiss, Scott T.

AU - Drazen, Jeffrey M.

PY - 2004/10/23

Y1 - 2004/10/23

N2 - Background The issue of whether regular use of an inhaled β 2-adrenergic agonist worsens airflow and clinical outcomes in asthma is controversial. Retrospective studies have suggested that adverse effects occur in patients with a genetic polymorphism that results in homozygosity for arginine (Arg/Arg), rather than glycine (Gly/Gly), at aminoacid residue 16 of the β 2-adrenergic receptor. However, the existence of any genotype-dependent difference has not been tested in a prospective clinical trial. Methods Patients with mild asthma, not using a controller medication, were enrolled in pairs matched for forced expiratory volume in 1 s (FEV 1) according to whether they had the Arg/Arg (n=37; four of 41 matches withdrew before randomisation) or Gly/Gly (n=41) genotype. Regularly scheduled treatment with albuterol or placebo was given in a masked, cross-over design, for 16-week periods. During the study, as-needed albuterol use was discontinued and ipratropium bromide was used as needed. Morning peak expiratory flow rate (PEFR) was the primary outcome variable. The primary comparisons were between treatment period for each genotype; the secondary outcome was a treatment by genotype effect. Analyses were by intention to treat. Findings During the run-in period, when albuterol use was kept to a minimum, patients with the Arg/Arg genotype had an increase in morning PEFR of 23 L/min (p=0·0162); the change in patients with the Gly/Gly genotype was not significant (2 L/min; p=0·8399). During randomised treatment, patients with the Gly/Gly genotype had an increase in morning PEFR during treatment with regularly scheduled albuterol compared with placebo (14 L/min [95% CI 3 to 25]; p=0·0175). By contrast, patients with the Arg/Arg genotype had lower morning PEFR during treatment with albuterol than during the placebo period, when albuterol use was limited (-10 L/min [-19 to -2]; p=0·0209). The genotype-attributable treatment difference was therefore -24 L/min (-37 to -12; p=0·0003). There were similar genotype-specific effects in FEV 1, symptoms, and use of supplementary reliever medication. Interpretation Genotype at the 16th aminoacid residue of the β 2-adrenergic receptor affects the long-term response to albuterol use. Bronchodilator treatments avoiding albuterol may be appropriate for patients with the Arg/Arg genotype.

AB - Background The issue of whether regular use of an inhaled β 2-adrenergic agonist worsens airflow and clinical outcomes in asthma is controversial. Retrospective studies have suggested that adverse effects occur in patients with a genetic polymorphism that results in homozygosity for arginine (Arg/Arg), rather than glycine (Gly/Gly), at aminoacid residue 16 of the β 2-adrenergic receptor. However, the existence of any genotype-dependent difference has not been tested in a prospective clinical trial. Methods Patients with mild asthma, not using a controller medication, were enrolled in pairs matched for forced expiratory volume in 1 s (FEV 1) according to whether they had the Arg/Arg (n=37; four of 41 matches withdrew before randomisation) or Gly/Gly (n=41) genotype. Regularly scheduled treatment with albuterol or placebo was given in a masked, cross-over design, for 16-week periods. During the study, as-needed albuterol use was discontinued and ipratropium bromide was used as needed. Morning peak expiratory flow rate (PEFR) was the primary outcome variable. The primary comparisons were between treatment period for each genotype; the secondary outcome was a treatment by genotype effect. Analyses were by intention to treat. Findings During the run-in period, when albuterol use was kept to a minimum, patients with the Arg/Arg genotype had an increase in morning PEFR of 23 L/min (p=0·0162); the change in patients with the Gly/Gly genotype was not significant (2 L/min; p=0·8399). During randomised treatment, patients with the Gly/Gly genotype had an increase in morning PEFR during treatment with regularly scheduled albuterol compared with placebo (14 L/min [95% CI 3 to 25]; p=0·0175). By contrast, patients with the Arg/Arg genotype had lower morning PEFR during treatment with albuterol than during the placebo period, when albuterol use was limited (-10 L/min [-19 to -2]; p=0·0209). The genotype-attributable treatment difference was therefore -24 L/min (-37 to -12; p=0·0003). There were similar genotype-specific effects in FEV 1, symptoms, and use of supplementary reliever medication. Interpretation Genotype at the 16th aminoacid residue of the β 2-adrenergic receptor affects the long-term response to albuterol use. Bronchodilator treatments avoiding albuterol may be appropriate for patients with the Arg/Arg genotype.

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