The effect of adding ipratropium bromide to salbutamol in the treatment of acute asthma - A pooled analysis of three trials

Objective: To assess the effect on FEV1 and clinical outcomes of adding ipratropium bromide to salbutamol in the treatment of acute asthma. Methods: We conducted a pooled analysis of three randomized double-blinded clinical trials conducted in the United States, Canada, and New Zealand. The studies enrolled 1,064 patients aged 18 to 55 years who presented at the emergency department with acute asthma. Patients were randomized to treatment with a combination of nebulized 2.5 mg salbutamol plus 0.5 mg ipratropium bromide, or 2.5 mg salbutamol alone. Medications were administered at baseline and; in the US at 45 min. FEV1 was measured at baseline, 45 min, and 90 min. Patients were followed up for 48 h after hospital discharge for occurrence of asthma exacerbation and hospitalization. Results: Treatment groups were comparable at baseline. Of the 1,064 patients randomized , 1,015 patients (95%) remained in the study for measurement at 45 min, and 961 patients (90%) completed the final measurement at 90 min. Comparison of overall improvement in FEV1 at 45 min indicated a better response for patients receiving combination therapy (mean difference=43 mL, 95% confidence interval [CI] = -20, 107). The distribution of change in FEV1 was skewed by a small number of patients with extreme values (38 of 1,064=3.6%) that may have been due to unreliable lung function testing. Removing these outliers produced a larger and more precise estimate of effect (mean diflference=55 mL, 95% CI=2,107). Because the distribution was skewed, we performed nonparametric analyses that showed evidence of a beneficial effect of combination therapy. The difference between median values at 45 min is 40 mL (Wilcoxon p value = 0.03). In addition, 4.9% (95% CI=-1%, 11%) more patients in the combination group achieved at least 20% of their potential improvement, as measured by the difference between their baseline FEV1 and their predicted FEV1. Patients receiving combination therapy had lower risk for each of three clinical outcomes: the need for additional treatment (relative risk [RR]=0.92, 95% CI=0.84, 1.0), risk of asthma exacerbation (RR=0.84, 95% CI=0.67, 1.04), and risk of hospitalization (RR=0.80, 95% CI=0.61, 1.06). Conclusion: Adding ipratropium bromide to salbutamol in the treatment of acute asthma produces a small improvement in lung function, and reduces the risk of the need for additional treatment, subsequent asthma exacerbations, and hospitalizations. These apparent benefits of adding ipratropium bromide were independent of the amount of beta-agonist that had been used earlier in the attack, and possibly related to a recent upper respiratory tract infection. Confirmatory studies are needed, especially for clinical outcomes.