The Dose-Response of Inhaled Corticosteroids in Combination Inhaled Corticosteroid/Long Acting Beta2-Agonist Maintenance Therapy for Asthma: A Systematic Review and Meta-Analysis

Abstract

Background: High doses of a maintenance inhaled corticosteroids (ICSs) in asthma may achieve only modest additional clinical benefit beyond low-to-medium doses and are associated with an increased risk of adverse systemic effects. The ICS dose-response relationship when administered as maintenance combination ICS/long-acting beta₂-agonist (LABA) therapy is uncertain.

Research question: What is the ICS dose-response of maintenance ICS/LABA therapy?

Study design and methods: A systematic review was conducted using MEDLINE, Embase, the Cochrane Register of Controlled Trials, and ClinicalTrials.gov databases to identify randomized controlled trials that allocated participants to > 1 ICS dose category, per Global Initiative for Asthma categorization, administered in combination with ICS/LABA inhalers. Meta-analysis compared outcomes of high-dose (HD) and medium-dose (MD), HD and low-dose (LD), and MD and LD ICS/LABA. The primary outcome was the proportion of participants with ≥ 1 severe asthma exacerbation; secondary outcomes were patient-reported outcome measures of asthma control, spirometry, and serious adverse events. Certainty of evidence was assessed by using the Grading of Recommendations, Assessment, Development and Evaluations domains.

Results: Twelve randomized controlled trials (6,373 participants) were identified: 7 comparing HD vs MD ICS/LABA, 1 HD vs LD ICS/LABA, and 4 MD vs LD ICS/LABA. HD vs MD ICS/LABA reduced the odds of a severe asthma exacerbation (Peto's OR, 0.81; 95% CI, 0.67-0.98) with high certainty. There were no other clinically important differences in efficacy or safety outcomes of HD vs MD ICS/LABA. There was no difference in all outcomes comparing HD with LD or MD with LD ICS/LABA.

Interpretation: Our results showed that maintenance HD ICS/LABA reduced the odds of a severe exacerbation by about 20% compared with MD ICS/LABA. The absolute reduction in severe exacerbation risk with HD ICS/LABA is determined by patients' exacerbation risk, and this effect size may be clinically relevant for patients if this risk is high. Comparisons of other doses of ICS/LABA were limited by the number of identified studies, although no large difference in effect sizes were observed.

Keywords: asthma; combination inhaler therapy; corticosteroid stewardship; dose-response; inhaled corticosteroids.