Asthma and lower airway disease
Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma

https://doi.org/10.1016/j.jaci.2011.06.004Get rights and content

Background

The efficacy and safety of inhaled long-acting β2-adrenergic agonists in asthmatic patients with the B16-Arg/Arg genotype has been questioned, and the use of antimuscarinics has been proposed as an alternative in patients whose symptoms are not controlled by inhaled corticosteroids (ICSs).

Objective

We compared the efficacy and safety of the long-acting anticholinergic tiotropium with salmeterol and placebo added to an ICS in B16-Arg/Arg patients with asthma that was not controlled by ICSs alone.

Methods

In a double-blind, double-dummy, placebo-controlled trial, after a 4-week run-in period with 50 μg of twice-daily salmeterol administered through a metered-dose inhaler, 388 asthmatic patients were randomized 1:1:1 to 16 weeks of treatment with 5 μg of Respimat tiotropium administered daily in the evening, 50 μg of salmeterol administered twice daily through a metered-dose inhaler, or placebo. Patients aged 18 to 67 years demonstrated reversibility to bronchodilators, and their symptoms were uncontrolled by regular ICSs (400-1000 μg of budesonide/equivalent). ICS regimens were maintained throughout the trial. The mean weekly morning peak expiratory flow (PEF) before randomization was 358 ± 115.7 L/min (range, 80.3-733.0 L/min).

Results

Changes in weekly PEF from the last week of the run-in period to the last week of treatment (primary end point: change in PEF) were −3.9 ± 4.87 L/min (n = 128) for tiotropium and −3.2 ± 4.64 L/min (n = 134) for salmeterol, and these were superior to placebo (−24.6 ± 4.84 L/min, n = 125, P < .05). Tiotropium was noninferior to salmeterol (estimated difference, −0.78 L/min [95% CI, −13.096 to 11.53]; P = .002; α = .025, 1-sided; noninferiority, 20 L/min). Tiotropium and salmeterol were numerically superior to placebo in some patient-reported secondary outcomes. Adverse events were comparable across treatments.

Conclusion

Tiotropium was more effective than placebo and as effective as salmeterol in maintaining improved lung function in B16-Arg/Arg patients with moderate persistent asthma. Safety profiles were comparable.

Section snippets

Methods

Details of the methods, patients, and statistical analyses are provided in this article’s Online Repository at www.jacionline.org.

Results

Patients were enrolled in outpatient clinics between July 2006 and April 2008. Of 4225 patients screened for ADRB2 polymorphisms, 715 were B16-Arg/Arg positive, 530 were eligible for the trial, and 388 were randomized (Fig 2).

The most frequent reason for ineligibility was failure to meet the lung function inclusion criteria. Adherence to treatment was good (89% to 92%) and balanced between treatment groups; mean treatment exposure was comparable across groups (109.6-111.8 days). Demographic

Discussion

This study provides evidence that tiotropium administered once daily in the evening is not inferior to continued twice-daily salmeterol treatment in maintaining the lung function improvement achieved with salmeterol in B16-Arg/Arg asthmatic patients whose symptoms are not controlled by continued, stable, moderate-to-high doses of ICSs. By contrast, substitution of salmeterol by a placebo was associated with rapid deterioration in lung function (ie, both active treatments were superior to

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    Supported by Boehringer Ingelheim and Pfizer.

    Disclosure of potential conflict of interest: E. D. Bateman and L. M. Fabbri have consultant arrangements with, are lecturers for, are on the Advisory Board for, and receive research support from Boehringer Ingelheim and are lecturers and members of the Advisory Board for Pfizer. O. Kornmann has received research support from Boehringer Ingelheim. The rest of the authors have declared that they have no conflict of interest.

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