Asthma is a common chronic disorder in both children and adults. Asthma involves airflow obstruction, bronchial hyperresponsiveness, and underlying inflammation. For patients not currently controlled on a low dose inhaled glucocorticoid, the next step up is to either double the glucocorticoid dose or add a long-acting beta-agonist (LABA).1 Doubling the dose of a inhaled glucocorticoid has not been shown in studies to improve asthma.2 Moreover, LABAs are an effective treatment option, but there is an increased concern about the safety of LABAs.3 Currently, tiotropium is only approved for the use in COPD.4 Tiotropium might be a potential alternative to the current step-up therapy treatment options.
A recent three-way, double-blind, triple-dummy crossover trial involving 210 patients was conducted by Peters and colleagues1 to evaluate the addition of tiotropium bromide to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (beclomethasone) or the addition of the long-acting B2 agonist (salmeterol) in asthma patients. The study design included a 4-week run-in period where all patients were treated with beclomethasone at a dose of 80 mcg twice daily. Patients were treated for a 14-week period with either the run-in dose of beclomethasone plus inhaled tiotropium bromide at a dose of 18 mcg every morning plus a salmeterol placebo inhaler, or a 160 mcg twice daily dose of beclomethasone plus a tiotropium placebo inhaler and salmeterol placebo inhaler, or the run-in dose of beclomethasone plus salmeterol 50 mcg twice daily plus a tiotropium placebo. To be included in the run-in period, patients had to be at least 18 years of age and have had a history of asthma, FEV1 of more than 40% of the predicted value, and had a nonsmoking status. To continue with the study after the 4-week run-in period, patients had to have a 75% adherence to the run-in protocol, FEV1 of 70% or less of the predicted value, no need for additional asthma medications, no medical contraindication to tiotropium, and during the final 2 weeks of the run-in period, have symptoms 6 or more day per week or used a rescue inhaler 6 or more days per week. The predetermined primary outcome measure was the morning peak expiratory flow (PEF). Predetermined secondary outcome measures included the FEV1 before bronchodilation, the number of asthma-control days, asthma symptoms, rescue-bronchodilator use, asthma exacerbations, use of health care services, biomarkers of airway inflammation, and results from questionnaires.
For the results of the primary outcome, patients receiving tiotropium had a morning PEF that was 25.8 liters per minute higher than that of patients receiving a double dose of the glucocorticoid (95% CI, 14.4 to 37.1; P<0.001). There was no significant difference between tiotropium and salmeterol treatment in regards to the morning PEF, which was 6.4 liters per minute higher among patients receiving tiotropium (95% CI, -4.8 to 17.5; P=0.26). The secondary outcomes comparing double dose glucocorticoid vs. tiotropium included the prebronchodilator FEV1 with a difference of 0.10 liters (95% CI, 0.03 to 0.17; P=0.01); score for daily symptoms, with a difference of -0.11 points (95% CI, -0.16 to-0.06; P<0.001); the score on the Asthma Control Questionnaire, with a difference of -0.18 points (95% CI, -0.34 to -0.03; P=0.02); and the FEV1 after four puffs of albuterol, with a difference of 0.04 liters (95% CI, 0.01 to 0.08; P=0.01). The secondary outcomes comparing tiotropium to salmeterol treatment found the proportion of asthma control days, with a difference of -0.009 (95% CI, -0.070 to 0.053; P=0.78); the score for daily symptoms, with a difference of -0.04 points (95% CI, -0.09 to 0.01; P=0.10); the score on the Asthma Control Questionnaire, with a difference of 0.09 (95% CI, -0.04 to 0.23; P=0.18). The prebronchodilator FEV1 favored tiotropium, with an increase of 0.11 liters (95% CI, 0.04 to 0.18; P=0.003). Also, the FEV1 after four puffs of albuterol favored tiotropium, with an increase of 0.07 liters (95% CI, 0.05 to 0.10; P<0.001). Another aspect of the trial looked at the comparison of salmeterol and double-dose glucocorticoid. The investigators found that salmeterol was superior to the double dose of beclomethasone in regards to the morning PEF, with a difference of 19.4 liters per minutes (95% CI, 9.4 to 29.4; P<0.001). There were no significant differences among the groups for serious adverse events; however, no other adverse events were presented.
The authors concluded that the use of tiotropium was superior to a doubling of the dose of an inhaled glucocorticoid in asthma patients with uncontrolled asthma symptoms. Furthermore, the study found tiotropium to be noninferior to salmeterol based on predefined criteria. The trial provides adequate evidence that double dose glucocorticoid may not be the best ...