Do Long-Acting Beta-Agonists Increase the Risk of Fatal or Near-Fatal Asthma in Children? A Case-Control Study

S U N D A Y 309 Comparison of Ipratropium Bromide and Albuterol Sulfate Chlorofluorocarbon Metered-Dose Inhaler and Albuterol Hydrofluoroalkane Metered-Dose Inhaler in a Crossover Trial in Patients with Moderate-to-Severe Asthma E. R. Bleecker, W. W. Busse, J. F. Donohue, S. Garfinkel, T. Lystig, R. C. Manuel, R. Schlenker-Herceg, R. A. Wise; Wake Forest University Center of Genomics and Personalized Medicine, Winston-Salem, NC, University of Wisconsin, Madison, WI, University of North Carolina, Chapel Hill, NC, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, Johns Hopkins University School of Medicine, Baltimore, MD. RATIONALE: Compare the efficacy and safety of Combivent CFC MDI (CVT) to albuterol HFA MDI (ALB) in a multicenter, randomized study including a 4-week, 2-way crossover double-blind treatment phase. We hypothesized that albuterol and ipratropium bromide produce better bronchodilation than albuterol alone in patients with moderate-to-severe asthma. METHODS: Patients were randomized to two treatment sequences: CVT/ ALB or ALB/CVT. OnDays 1 and 29 of each period, serial spirometry was performed after clinic administration of study drug. Between clinic visits patients used studymedication ‘‘as needed’’ for relief. The co-primary endpoints were FEV1 area under the curve (AUC0-6h) above test-day baseline and peak FEV1 response after 4 weeks. Treatment effects were analyzed using repeated measures mixed-effects models. RESULTS: 226 patients were randomized: age 47 years, 43% men, postbronchodilator FEV1 2.56 L (78% predicted), and Asthma Control Questionnaire score 2.5. Estimated changes (mL) in peak FEV1 were 357 for ALB and 434 for CVT (delta577, p<0.0001). Estimated changes (mL) in FEV1 AUC0-6h were 167 for ALB and 252 for CVT (delta585, p<0.0001). Treatment differences favoring CVT were observed at every post-dose timepoint, ranging from 50-115 mL (6h, 4h) [all p<0.01]. 68 patients (29.2%) experienced adverse events. These were generally balanced between groups. More patients reported ‘‘cough’’ related to study drug CVT (11) compared to ALB (1). More asthma exacerbations were reported in CVT (6) than in ALB group (3); none of these were serious. CONCLUSIONS: CVT was safely used to provide improved acute bronchodilation over albuterol alone, after four weeks of ‘‘as-needed’’ use for symptom relief.