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

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.

Figure 1.. Study Identification and Review for the Comparison of Triple vs Dual Therapy for Moderate to Severe Asthma

^aThe 18 articles indicated 20 unique randomized clinical trials. Two publications included 2 trials each.^,

Figure 2.. Severe Asthma Exacerbations in Randomized Trials of Triple vs Dual Therapy

Error bars indicate 95% CI of the rate ratio estimates. ^aSevere asthma exacerbation was defined by a need for systemic steroids for ≥3 days, hospitalization, intensive care admission or intubation, or emergency department visits. The mean annualized exacerbation rate indicates the mean number of exacerbations per patient per year (the total number of exacerbations in a group divided by the total follow-up time of the group). ^bRepeated source names are not duplicates; they indicate 2 comparisons within a single report. ^cEstimated from life table.

Figure 3.. Kaplan-Meier Failure Curves of Time to First Severe Exacerbation in Patients Assigned to Triple vs Dual Asthma Inhaler Therapy

Severe asthma exacerbation was defined by a need for systemic steroids for ≥3 days, hospitalization, intensive care admission or intubation, or emergency department visits. Triple therapy indicates inhaled corticosteroids (ICS), long-acting β₂-agonists (LABAs), and long-acting muscarinic antagonists (LAMAs), and dual therapy indicates ICS with a LABA. Hazard ratio (0.84 [95% CI, 0.77-0.92]) was calculated from Cox regression model with shared frailty by study. Per-patient summary statistics on observation time: mean (SD), 37.8 (16.5) weeks; median, 46.4 weeks (range, 0.2-52 weeks [interquartile range [IQR], 35.3-52.0 weeks, calculated under the assumption that IQR = 1.35 × SD).

Figure 4.. Asthma Control and Asthma-Related Quality of Life in Randomized Trials of Triple vs Dual Therapy

^aThe Asthma Control Questionnaire (ACQ) has 3 versions: ACQ-7 is a 7-item list that contains 5 symptom-based questions, 1 question about rescue bronchodilator use, and 1 question about forced expiratory volume in the first second (FEV₁, reported in liters), with each item scored on a 7-point scale (0 [no impairment] to 6 [maximum impairment]); ACQ-6 contains all items of the ACQ-7 except FEV₁ assessment^,; and ACQ-5 contains only the 5 symptom-based questions. The questions are equally weighted and the ACQ score is the mean of the included questions (range, 0 [totally controlled] to 6 [severely uncontrolled]). Minimal important difference for a change in ACQ is 0.5 for all 3 questionnaires. The Asthma Control Test (ACT) is a 5-item list with each item scored on a 5-point scale (for symptoms and activity-related rating: 1 [all the time] to 5 [not at all]; for asthma control rating: 1 [not controlled at all] to 5 [completely controlled]). The total score ranges from 5 (poor control of asthma) to 25 (complete control of asthma). Minimal important difference for a change in ACT is 3. The Asthma-related Quality of Life (AQLQ) and Mini-AQLQ versions are as follows: AQLQ score is a 32-item list with each item scored on a 7-point scale (1 [severely impaired] to 7 [not impaired at all]); and the Mini-AQLQ is a shorter 15-item list version of AQLQ. The higher score on both questionnaires correlates with better quality of life.^, The minimal important difference for a change in both AQLQ and Mini-AQLQ is 0.5. The ACQ-5, ACQ-6, ACQ-7, and ACT were pooled together using standardized mean difference (SMD). To facilitate interpretability, these pooled SMDs were converted to the most familiar scale, which was the ACQ-7 (see eFigures 4, 5, 6, 7, and 8 in the Supplement for asthma worsening [defined as a progressive increase in ≥1 asthma symptoms or a decline in lung function for ≥2 consecutive days that does not meet the definition of severe asthma exacerbation), serious and nonserious adverse events, treatment-related adverse events, breakdown of adverse events, and all-cause mortality.

Figure 5.. Lung Function as Measured by FEV₁ in Randomized Trials of Triple vs Dual Therapy

FEV₁ indicates forced expiratory volume in the first second of expiration.