Abstract: We included 23 studies that involved a total of 2724 enrolled participants. Most studies were rated at unclear or high risk of bias. Overall, participants receiving combination inhaled therapy were less likely to be hospitalised (RR 0.72, 95% CI 0.59 to 0.87; participants = 2120; studies = 16; I² = 12%; moderate quality of evidence). An estimated 65 fewer patients per 1000 would require hospitalisation after receiving combination therapy (95% 30 to 95), compared to 231 per 1000 patients receiving SABA alone. Although combination inhaled therapy was more effective than SABA treatment alone in reducing hospitalisation in participants with severe asthma exacerbations, this was not found for participants with mild or moderate exacerbations (test for difference between subgroups P = 0.02). Participants receiving combination therapy were more likely to experience improved forced expiratory volume in one second (FEV₁) (MD 0.25 L, 95% CI 0.02 to 0.48; participants = 687; studies = 6; I² = 70%; low quality of evidence), peak expiratory flow (PEF) (MD 36.58 L/min, 95% CI 23.07 to 50.09; participants = 1056; studies = 12; I² = 25%; very low quality of evidence), increased percent change in PEF from baseline (MD 24.88, 95% CI 14.83 to 34.93; participants = 551; studies = 7; I² = 23%; moderate quality of evidence), and were less likely to return to the ED for additional care (RR 0.80, 95% CI 0.66 to 0.98; participants = 1180; studies = 5; I² = 0%; moderate quality of evidence) than participants receiving SABA alone. Participants receiving combination inhaled therapy were more likely to experience adverse events than those treated with SABA agents alone (OR 2.03, 95% CI 1.28 to 3.20; participants = 1392; studies = 11; I² = 14%; moderate quality of evidence). Among patients receiving combination therapy, 103 per 1000 were likely to report adverse events (95% 31 to 195 more) compared to 131 per 1000 patients receiving SABA alone. Overall, combination inhaled therapy with SAAC and SABA reduced hospitalisation and improved pulmonary function in adults presenting to the ED with acute asthma. In particular, combination inhaled therapy was more effective in preventing hospitalisation in adults with severe asthma exacerbations who are at increased risk of hospitalisation, compared to those with mild-moderate exacerbations, who were at a lower risk to be hospitalised. A single dose of combination therapy and multiple doses both showed reductions in the risk of hospitalisation among adults with acute asthma. However, adults receiving combination therapy were more likely to experience adverse events, such as tremor, agitation, and palpitations, compared to patients receiving SABA alone.

Plain-language summary: We included 23 studies that compared the effectiveness of combined treatment with beta-agonists and anticholinergics versus treatment with beta-agonists alone. A total of 2724 adult participants were enrolled in the studies. Salbutamol (also called albuterol) was the most common beta-agonist investigated and ipratropium bromide was the most common anticholinergic assessed. We found that most studies did not report sources of funding (14 studies); one study was supported by a hospital; another received support from a pharmaceutical company, but indicated that there was no involvement from the company in conducting or reporting research. Two studies were part-funded and four were funded by pharmaceutical companies. Patients with severe asthma who received combined treatment of beta-agonists and anticholinergics were less likely to be admitted to hospital. An estimated 65 fewer patients per 1000 would require hospital admission after receiving combined inhaled therapy in the emergency department. Among patients with mild -to-moderate asthma, combined inhaled therapy was less effective in preventing admission to hospital compared with people with severe asthma. Patients receiving combined treatment were less likely to return to the emergency department with worsening asthma symptoms and had better outcomes in most lung function tests. On the other hand, 103 more participants per 1000 who receive combined inhaled therapy would experience side effects compared to people who receive beta-agonists alone. Quality of the evidence that combination inhaled therapy can improve health outcomes compared to treatment with beta-agonists alone ranged from very low to moderate. Our confidence about the effects of combination inhaled therapy on hospital admissions, peak expiratory flow, percent change in peak expiratory flow from baseline, and relapse was moderate because of the overall risk of bias among included studies. Factors associated with inconsistency and imprecision were additional aspects that reduced the quality of the evidence for forced expiratory volume in one second, and percent predicted peak expiratory flow.