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Original Investigation
May 19, 2021

Triple vs Dual Inhaler Therapy and Asthma Outcomes in Moderate to Severe Asthma: A Systematic Review and Meta-analysis

Author Affiliations
  • 1Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  • 2Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
  • 3The Research Institute of St Joe’s Hamilton, Hamilton, Ontario, Canada
JAMA. 2021;325(24):2466-2479. doi:10.1001/jama.2021.7872
Key Points

Question  Is adding a long-acting muscarinic antagonist (LAMA) to inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs) associated with differences in clinical outcomes and adverse events among individuals with moderate to severe persistent asthma?

Findings  In this systematic review and meta-analysis that included 20 randomized clinical trials and 11 894 patients, triple therapy (ICS, LABA, and LAMA), compared with dual therapy (ICS plus LABA), was significantly associated with fewer severe asthma exacerbations (risk ratio, 0.83) and slightly better asthma control, but no significant difference in quality of life or most adverse events.

Meaning  Among patients with moderate to severe asthma, triple therapy compared with dual therapy was significantly associated with fewer severe asthma exacerbations and modest improvements in asthma control but no significant difference in quality of life.

Abstract

Importance  The benefits and harms of adding long-acting muscarinic antagonists (LAMAs) to inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs) for moderate to severe asthma remain unclear.

Objective  To systematically synthesize the outcomes and adverse events associated with triple therapy (ICS, LABA, and LAMA) vs dual therapy (ICS plus LABA) in children and adults with persistent uncontrolled asthma.

Data Sources  MEDLINE, Embase, CENTRAL, ICTRP, FDA, and EMA databases from November 2017, to December 8, 2020, without language restriction.

Study Selection  Two investigators independently selected randomized clinical trials (RCTs) comparing triple vs dual therapy in patients with moderate to severe asthma.

Data Extraction and Synthesis  Two reviewers independently extracted data and assessed risk of bias. Random-effects meta-analyses, including individual patient-level exacerbation data, were used. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach was used to assess certainty (quality) of the evidence.

Main Outcomes and Measures  Severe exacerbations, asthma control (measured using the Asthma Control Questionnaire [ACQ-7], a 7-item list with each item ranging from 0 [totally controlled] to 6 [severely uncontrolled]; minimal important difference, 0.5), quality of life (measured using the Asthma-related Quality of Life [AQLQ] tool; score range, 1 [severely impaired] to 7 [no impairment]; minimal important difference, 0.5), mortality, and adverse events.

Results  Twenty RCTs using 3 LAMA types that enrolled 11 894 children and adults (mean age, 52 years [range, 9-71 years]; 57.7% female) were included. High-certainty evidence showed that triple therapy vs dual therapy was significantly associated with a reduction in severe exacerbation risk (9 trials [9932 patients]; 22.7% vs 27.4%; risk ratio, 0.83 [95% CI, 0.77 to 0.90]) and an improvement in asthma control (14 trials [11 230 patients]; standardized mean difference [SMD], −0.06 [95% CI, −0.10 to −0.02]; mean difference in ACQ-7 scale, −0.04 [95% CI, −0.07 to −0.01]). There were no significant differences in asthma-related quality of life (7 trials [5247 patients]; SMD, 0.05 [95% CI, −0.03 to 0.13]; mean difference in AQLQ score, 0.05 [95% CI, −0.03 to 0.13]; moderate-certainty evidence) or mortality (17 trials [11 595 patients]; 0.12% vs 0.12%; risk ratio, 0.96 [95% CI, 0.33 to 2.75]; high-certainty evidence) between dual and triple therapy. Triple therapy was significantly associated with increased dry mouth and dysphonia (10 trials [7395 patients]; 3.0% vs 1.8%; risk ratio, 1.65 [95% CI, 1.14 to 2.38]; high-certainty evidence), but treatment-related and serious adverse events were not significantly different between groups (moderate-certainty evidence).

Conclusions and Relevance  Among children (aged 6 to 18 years) and adults with moderate to severe asthma, triple therapy, compared with dual therapy, was significantly associated with fewer severe asthma exacerbations and modest improvements in asthma control without significant differences in quality of life or mortality.

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