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

Educational Objective
To review therapeutic strategies for patients with persistent uncontrolled asthma.
1 Credit CME
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.


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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Article Information

Corresponding Author: Derek K. Chu, MD, PhD, Division of Clinical Immunology and Allergy, Department of Medicine and Department of Health Research Methods, Evidence, and Impact, McMaster University Medical Centre, 1280 Main St W, Room 3V41, Hamilton, ON L8S 4K1, Canada (chudk@mcmaster.ca).

Accepted for Publication: April 30, 2021.

Published Online: May 19, 2021. doi:10.1001/jama.2021.7872

Author Contributions: Drs Kim and Chu had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Kim, Saleh, Whalen-Browne, Chu.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Kim, Saleh, Whalen-Browne, Chu.

Statistical analysis: Kim, Chu.

Administrative, technical, or material support: Kim, Whalen-Browne, Chu.

Supervision: Chu.

Conflict of Interest Disclosures: Dr O'Byrne reported receipt of grants from AstraZeneca, GlaxoSmithKline (GSK), Medimmune, Genentech, Bayer, Merck, and Novartis; and personal fees from AstraZeneca, GSK, Covis, Teva, Sage, and Chiesi, during the conduct of the study. Dr Chu reported receipt of the CAAIF-AllerGen NCE-CSACI Emerging Clinician Scientist Award (Canadian Allergy, Asthma and Immunology Foundation [CAAIF]-AllerGen NCE [Allergy, Genes and Environment Network]-Canadian Society of Allergy and Clinical Immunology [CSACI]), all of which are nonprofits or federally funded (Canadian Institutes of Health Research). No other disclosures were reported.

Meeting Presentation: Presented at the American Thoracic Society 2021 international conference (virtual meeting); May 19, 2021.

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