Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial.
BACKGROUND
The issue of whether regular use of an inhaled beta2-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 beta2-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 (FEV1) 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.


RESULTS
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 FEV1, symptoms, and use of supplementary reliever medication.


CONCLUSIONS
Genotype at the 16th aminoacid residue of the beta2-adrenergic receptor affects the long-term response to albuterol use. Bronchodilator treatments avoiding albuterol may be appropriate for patients with the Arg/Arg genotype.
Israel
Elliot
E
Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. eisraelasst@partners.org
Chinchilli
Vernon M
VM
Ford
Jean G
JG
Boushey
Homer A
HA
Cherniack
Reuben
R
Craig
Timothy J
TJ
Deykin
Aaron
A
Fagan
Joanne K
JK
Fahy
John V
JV
Fish
James
J
Kraft
Monica
M
Kunselman
Susan J
SJ
Lazarus
Stephen C
SC
Lemanske
Robert F
RF
Liggett
Stephen B
SB
Martin
Richard J
RJ
Mitra
Nandita
N
Peters
Stephen P
SP
Silverman
Eric
E
Sorkness
Christine A
CA
Szefler
Stanley J
SJ
Wechsler
Michael E
ME
Weiss
Scott T
ST
Drazen
Jeffrey M
JM
D000280:Administration, Inhalation; D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage*; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005541:Forced Expiratory Volume; D005838:Genotype; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D008875:Middle Aged; D010366:Peak Expiratory Flow Rate; D011110:Polymorphism, Genetic; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D016037:Single-Blind Method
D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D000420:Albuterol