Combined inhaled beta-agonists and anticholinergic agents in adults with asthma exacerbations

Dott. Paolo Balzaretti

What we already know about this topic

Short-acting inhaled beta-agonists (SABA), together with steroids and oxygen, are the mainstay of the treatment of acute asthma exacerbations in adult patients (1, 2). Among others therapeutic strategies, guidelines advice to consider the association of SABA with short-acting anti-cholinergics (SAAC) in patients with moderate-severe exacerbations (grade of recommendation 1++ for SIGN guidelines (2) and level of evidence A in GINA guidelines (1)). The biological rationale of this approach lies in the possibility of exploiting the faster and stronger bronchodilators effects of SABA coupled with the longer lasting, even if weaker, effects of SAAC, which act on different receptors and ensure also a reduction in airways secretions.
Previous systematic reviews failed to demonstrate any advantage in reduction of hospitalization (RR 0,80, IC 95% 0,61 – 1,06) of the combined SABA and SAAC therapy (3). The authors of the work we are going to talk about in this commentary aim to re-evaluate clinical efficacy of the association of SABA and SAAC association vs. SABA alone for the same outcome, taking into account of more recent evidence.

The Cochrane review (4)

Title: Combined inhaled beta-agonist and anti-cholinergic agents for emergency department management in adults with asthma.
Authors: Kirkland SW, Vandenberghe C, Voaklander B, Nikel T, Campbell S, Rowe BH.
Bibliographic citation: Cochrane Database Syst Rev 2017; (1): CD001284.
Objective: evaluation of the effectiveness of combined inhaled short-acting anti-cholinergics and short-acting beta-agonists vs. short-acting beta-agonists alone in reducing hospitalization in adult patients with exacerbations of asthma.
Intervention: inhaled short-acting beta-agonist (SABA) mostly used was salbutamol while preferred short-acting anti-cholinergic (SAAC) agent was ipatroprium bromide, which doses ranged from 1 to 5 puffs.
Type of included studies: randomized controlled clinical trials or controlled clinical trials.
Primary outcome: proportion of patients requiring hospitalization
Secondary outcomes of interest: adverse events, relapse proportions.
Number of included studies: 21
Quality of included studies: only one study was considered to be at low risk of bias. There was high or unclear risk of bias in all the methodological domains evaluated. No publication bias about the main outcome was detected using funnel plots.
Number of patients: 2724 patients




No. of patients
(No. of studies)

Relative effect (95% C.I.)

Quality of evidence


2120 (16)

0,72 (0,59 – 0,86)*


Total adverse events

1392 (11)

2,03 (1,28 – 3,20)**


Relapse rates

1180 (5)

0,80 (0,66 – 0,98)*


Table 1. Synopsis regarding principal outcomes. No results were reported regarding ED length of stay, symptoms score, quality of life, number of additional bronchodilator treatments required because of lack of data. *: relative risk; **: odds ratio.

Comment and conclusions

According to the results of this meta-analysis, combination therapy is more effective than SABA therapy alone in reducing hospital admissions in adult asthma patients; subgroup analysis has shown that this clinical efficacy is maintained in mild, moderate, and severe exacerbations. Adverse events appear to be more frequent with SABA and SAAC association therapy than with SABA therapy alone. Side effects reported were dry mouth, tremor, anxiety, agitation, palpitations, nausea, headache, and blurred vision; no differences in prevalence for any specific side effect was detected, probably because of insufficient study power.
Overall, this study has significant limitations. First of all, considered studies are small, with only eight including more the 100 and three more than 200 patients (Fitzgerald 1997, Garrett 1997, Karpel 1996). One previous systematic review (3), including only these three works (which individually failed to demonstrate significant differences between study arms regarding the main outcome), didn’t detect a reduction in hospitalization (RR 0,80, IC 95% 0,61 – 1,06). Small studies in meta-analyses are usually more heterogeneous (5), of lesser quality (6), and tend to overestimate clinical effect (7). The concerns about the low overall quality of the evidence are strengthened by the observation that the single study with low risk of bias (Cydulka 2000) didn’t show any difference in term of efficacy of the combined inhaled therapy.
The acceptable balance of combined therapy between reported clinical efficacy and adverse effects is counterbalanced by the relevant risk of bias of the included studies, which makes it hard to draw any meaningful conclusion. For these reasons, this systematic review doesn’t seem to support any change in the approach recommended by current guidelines, which limit its use to severe cases.


  1. Global Initiative for Asthma. Global strategy for asthma management and prevention, 2017. Available from: .
  2. British Thoracic Society, Scottish Intercollegiate Guidelines Network. SIGN 153 – British guideline on the management of asthma. A national clinical guideline. September 2016. Available at:
  3. Lanes SF, Garrett JE, Wentworth CE, Fitzgerald JM, Karpel JP. The effect of adding ipratropium bromide to salbutamol in the treatment of acute asthma. A pooled analysis of three trials. Chest 1998; 114:365-372.
  4. Kirkland SW, Vandenberghe C, Voaklander B, Nikel T, Campbell S, Rowe BH. Combined inhaled beta-agonist and anti-cholinergic agents for emergency department management in adults with asthma. Cochrane Database Syst Rev 2017; (1): CD001284.
  5. IntHout J, Ioannidis JPA, Borm GF, Goeman JJ. Small studies are more heterogenous than large one: a meta-meta-analysis. J Clin Epidemiol 2015; 68:860-868.
  6. Kjaergard LL, Villumsen JGluud G. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 2001; 135: 982-989.
  7. Sterne JAC, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in literature. J clin epidemiol 2000; 53:1119- 1129.