Taking four times the usual dose of inhaled corticosteroids for up to two weeks can modestly reduce the chance of asthma worsening.
This NIHR-funded trial assessed increasing the inhaled corticosteroid dose compared with staying on the usual dose, as part of a self-management plan. Participants were adults and adolescents with uncontrolled asthma and had at least one exacerbation needing additional medical attention in the year before the trial.
Quadrupling the inhaled corticosteroid dose when asthma worsens is already recommended by NICE guidance, but previously there was little research evidence to support the clinical practice. What there was, suggested that doubling the dose of inhaled corticosteroids was not effective and quadrupling the dose had been tested in trials with very few people. The results of this trial increase the confidence in this as a valid approach.
Why was this study needed?
Around 5.4 million people in the UK receive treatment for asthma. Asthma narrows the airways causing shortness of breath, wheezing and coughing.
People often have asthma for a long time (chronic asthma), though it varies in severity at different times. Worsening asthma that needs additional treatment is known as an exacerbation.
Exacerbations can be triggered, for example, by breathing allergens or pollution, or by infections. Exacerbations may need hospital treatment and can be life-threatening in the most severe cases.
Previous evidence on increasing the dose of inhaled corticosteroids early in an exacerbation had been conflicting. A 2016 Cochrane review found that doubling the dose of inhaled corticosteroids did not prevent exacerbations or reduce the recovery time, whereas other studies had found small benefits from increased dosage. This study aimed to clear up this uncertainty.
What did this study do?
This pragmatic randomised controlled trial randomised a total of 1,922 participants to two strategies, a self-management plan that included a four-fold increase in inhaled steroids (the quadrupling plan) if asthma worsened, and a self-management plan where people increased reliever (blue) inhaler use only on signs of worsening asthma. Everyone included in the trial had asthma treated with inhaled corticosteroids and had an exacerbation needing systemic steroid treatment in the past year. Participants could be taking other medications for their asthma as their GP saw fit. At the start of the study, 78% of participants were on a low dose of inhaled corticosteroids, and 70% used a combined steroid and long-acting beta agonist inhaler.
Worsening asthma was defined as one or more of: using a reliever inhaler more often, having difficulty sleeping because of asthma, and having peak breath flow less than 80% of the person’s normal level.
If asthma worsened, people in both groups could use their reliever inhaler as needed, record their symptoms and medication use and have access to appointments with an asthma nurse.
As a practical, real-life trial, people knew which treatment group they were in, and there was no placebo.
What did it find?
- During the study, 45% of people on the quadrupling plan and 52% of those on the usual care plan had a severe exacerbation. A severe exacerbation was defined as the person needing systemic steroids or making an unplanned visit to their GP. For every 15 patients with a dose-quadrupling self-management plan, one severe asthma attack could be prevented: the number needed to treat was 15 (95% confidence interval [CI], 9 to 43). This is a smaller benefit than was thought important at the start of the study but might still be useful.
- Overall, people on the quadrupling plan modestly lengthened the time until a first severe exacerbation by 19% (hazard ratio 0.81, 95% CI 0.72 to 0.92). The result was the same when the patients’ baseline smoking status or use of high- or low-dose inhaled corticosteroids, were considered in the analysis.
- People on the quadrupling plan were slightly less likely to have an unscheduled consultation (41% of patients) than those who did not (47% of patients) (incidence rate ratio [IRR] 0.86, 95% CI 0.75 to 0.99).
- Oral corticosteroids (a sign of moderately severe asthma) were used by 33% of patients on a quadrupling plan and 40% in the non-quadrupling group (IRR 0.82, 95% CI 0.70 to 0.96).
- The fungal infection oral candidiasis, a side effect of steroid inhalers, occurred 19 times in the quadrupling group and seven times in the non-quadrupling group.
- Adherence to the self-management plan was moderate at 50% in the quadrupling group and 42% in the non-quadrupling group, as assessed by a researcher. This may have reduced the apparent benefit of quadrupling.
What does current guidance say on this issue?
NICE’s 2017 guideline on asthma recommends considering quadrupling the regular dose of inhaled steroids when asthma deteriorates within a self-management programme. This should not exceed the maximum licensed dose.
What are the implications?
This study strengthens the evidence for asthma self-management and the strategy of quadrupling the dose of inhaled corticosteroid to reduce exacerbations.
Although it follows recommendations in the existing NICE guideline, previous evidence had not been strong. This study’s findings increase confidence in the research underlying current recommendations and give a quantitative estimate of the benefit.
The trial was designed to follow usual care as much as possible, so the findings should generally apply to asthma care in the UK.
Citation and Funding
McKeever T, Mortimer K, Wilson A, et al. Quadrupling inhaled glucocorticoid dose to abort asthma exacerbations. N Engl J Med. 2018;378:902-10.
This project was funded by the National Institute for Health Research Health Technology Assessment Programme (project number 10/143/01).
Kew KM, Quinn M, Quon BS, et al. Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children. Cochrane Database Syst Rev. 2016;(6):CD007524.
NHS website. Asthma. London: Department of Health and Social Care; updated 2018.
NICE. Asthma: diagnosis, monitoring and chronic asthma management. NG80. London: National Institute for Health and Care Excellence; 2017.
Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre