Establishing the best step-up treatments for children with uncontrolled asthma despite inhaled corticosteroids: the EINSTEIN systematic review, network meta-analysis and cost-effectiveness analysis using individual participant data.

Background: There is no clear preferential option for initial step-up of treatment for children with uncontrolled asthma on inhaled corticosteroid.

Objectives: Evaluate the clinical effectiveness of pharmacological treatments to use in children with uncontrolled asthma on inhaled corticosteroid; identify and evaluate the potential for treatment effect modification to optimise treatment delivery; assess the cost-effectiveness of treatments.

Methods: Systematic review and individual participant data network meta-analysis. Studies were eligible if they were parallel or crossover randomised controlled trials comparing at least one of the pharmacological treatments of interest in participants aged < 18 years with uncontrolled asthma on any dose inhaled corticosteroid alone. We searched MEDLINE^®, Cochrane Library, Cochrane Central Register of Controlled Trials, EMBASE, National Institute for Health and Care Excellence Technology Appraisals, and the National Institute for Health and Care Research Health Technology Assessment series. Primary outcomes: exacerbation and asthma control. Secondary outcomes: health-related quality of life, mortality, forced expiratory volume in 1 second, adverse events, hospital admissions, symptoms (not analysed). We assessed the Risk Of Bias using the Cochrane Risk Of Bias tool and carried out Bayesian meta-analyses, network meta-analysis and network meta-regression, including treatment by covariate (age, sex, ethnicity, eczema, eosinophilia, asthma severity) interactions. A Markov decision-analytic model with a 12-month time horizon, which adopted the perspective of the National Health Service and Personal Social Services in the United Kingdom, was developed to compare alternative treatments. Cost-effectiveness was based on incremental costs per quality-adjusted life-years gained, with uncertainty considered in one-way, structural and probabilistic sensitivity analyses.

Results: We identified and screened 4708 publications from the search and confirmed 144 randomised controlled trials as eligible. We obtained individual participant data from 29 trials (5381 participants) and extracted limited aggregate data from a further 19 trials. The majority of trials had low risk of bias. The network meta-analysis suggests that medium-dose inhaled corticosteroid + long-acting β₂-agonist is the preferred treatment for reducing odds of exacerbation [odds ratio 95% credibility interval: 0.43 (0.20 to 0.92) vs. low-dose inhaled corticosteroid; 40 studies, 8168 patients] and increasing forced expiratory volume in 1 second [mean difference 95% credibility interval: 0.71 (0.35 to 1.06) vs. low-dose inhaled corticosteroid; 23 studies, 2518 patients] while leukotriene receptor antagonist alone is the least preferred. No clear differences were found for asthma control (16 studies, 3027 patients). Limited pairwise analyses suggest some improvement in health-related quality of life for medium-dose inhaled corticosteroid versus inhaled corticosteroid + long-acting β₂-agonist [two studies, paediatric asthma quality of life questionnaire, mean difference 95% credibility interval: 0.91 (0.29 to 1.53)]. The rate of hospitalisation due to an asthma attack ranged from 0.5% to 2.7% of patients across five trials. Slightly fewer patients reported neurological disorders (mild/moderate) on inhaled corticosteroid + long-acting β₂-agonist versus inhaled corticosteroid + leukotriene receptor antagonist [odds ratio 95% confidence interval: 0.09 (0.01 to 0.82), one study]. There were no deaths recorded. We did not find convincing, consistent evidence to suggest that age, sex, ethnicity, eczema, eosinophilia, asthma severity would be regarded as an effect modifier. The economic analysis indicated that low-dose inhaled corticosteroid was the most cost-effective treatment option while medium-dose inhaled corticosteroid (alone and + long-acting β₂-agonist) was associated with the highest number of quality-adjusted life-years, but their incremental cost-effectiveness exceeded the National Institute for Health and Care Excellence threshold.

Discussion: Medium-dose inhaled corticosteroid + long-acting β₂-agonist is recommended for children with asthma that is uncontrolled on inhaled corticosteroid alone; leukotriene receptor antagonist alone should be avoided. We could not include data from 67% of the eligible trials, conclusions should therefore be viewed with some caution.

Study registration: This study is registered as PROSPERO CRD42019127599.

Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/110/16) and is published in full in Health Technology Assessment; Vol. 29, No. 15. See the NIHR Funding and Awards website for further award information.