Efficacy and safety of ipratropium bromide/albuterol compared with albuterol in patients with moderate-to-severe asthma: a randomized controlled trial

Abstract

Background: Many patients with asthma require frequent rescue medication for acute symptoms despite appropriate controller therapies. Thus, determining the most effective relief regimen is important in the management of more severe asthma. This study's objective was to evaluate whether ipratropium bromide/albuterol metered-dose inhaler (CVT-MDI) provides more effective acute relief of bronchospasm in moderate-to-severe asthma than albuterol hydrofluoroalkaline (ALB-HFA) alone after 4 weeks.

Methods: In this double-blind, crossover study, patients who had been diagnosed with asthma for ≥1 year were randomized to two sequences of study medication "as needed" for symptom relief (1-7 day washout before second 4-week treatment period): CVT-MDI/ALB-HFA or ALB-HFA/CVT-MDI. On days 1 and 29 of each sequence, 6-hour serial spirometry was performed after administration of the study drug. Co-primary endpoints were FEV1 area under the curve (AUC0-6) and peak (post-dose) forced expiratory volume in 1 s (FEV1) response (change from test day baseline) after 4 weeks. The effects of "as needed" treatment with ALB-HFA/CVT-MDI were analyzed using mixed effect model repeated measures (MMRM).

Results: A total of 226 patients, ≥18 years old, with inadequately controlled, moderate-to-severe asthma were randomized. The study met both co-primary endpoints demonstrating a statistically significant treatment benefit of CVT-MDI versus ALB-HFA. FEV1 AUC0-6h response was 167 ml for ALB-HFA, 252 ml for CVT-MDI (p <0.0001); peak FEV1 response was 357 ml for ALB-HFA, 434 ml for CVT-MDI (p <0.0001). Adverse events were comparable across groups.

Conclusions: CVT-MDI significantly improved acute bronchodilation over ALB-HFA alone after 4 weeks of "as-needed" use for symptom relief, with a similar safety profile. This suggests additive bronchodilator effects of β2-agonist and anticholinergic treatment in moderate-to-severe, symptomatic asthma.

Trial registration: ClinicalTrials.gov No.: NCT00818454 ; Registered November 16, 2009.

Keywords: Acute symptom relief; Albuterol hydrofluoroalkaline; Anticholinergic/β2-agonist; As-needed; Bronchodilation; Ipratropium bromide; Ipratropium bromide/albuterol metered-dose inhaler; Moderate-to-severe asthma; Randomized controlled trial.

Figures

Fig. 1

Consolidated Standards of Reporting Trials (CONSORT) flowchart of patient disposition

Fig. 2

Change from test-day baseline (SE) in FEV1 AUC0–6 and peak FEV1 after 4 weeks. Mean (adjusted) change and post-hoc analysis of mean ratio of change from test-day baseline (SE) in FEV1 AUC0–6 and peak FEV1 after 4 weeks using the mixed-effect model repeated measures (MMRM). a Mean (adjusted) change from test-day baseline in FEV1 AUC 0–6 (ml) (95 % CI of the difference: (0.058, 0.112) p <0.0001); b Mean ratio of change from test-day baseline in FEV1 AUC0-6 (%) (95 % CI of the difference: (0.032, 0.061) p <0.0001); c Mean (adjusted) change from test-day baseline in peak FEV1 (ml) (95 % CI of the difference: (0.047, 0.107) p <0.0001); d Mean ratio of change from test-day baseline in peak FEV1 (%) (95 % CI of the difference: (0.027, 0.060) p <0.0001)

Fig. 3

Changes from test-day baseline in FEV1. Estimated mean (adjusted) changes from test-day baseline in FEV1 at post-dose time-points after 4 weeks using the mixed-effect model repeated measures (MMRM) (day 29; range of difference 50 ml to 115 ml, p <0.006 for all comparisons)

Fig. 4

Forest plot of all subgroups for FEV1 AUC0–6

Fig. 5

Forest plot of all subgroups for Peak FEV1