Tripe vs Dual Inhaler Therapy for Treatment of Persistent Uncontrolled Asthma

Tripe vs Dual Inhaler Therapy for Treatment of Persistent Uncontrolled Asthma
Sara Leistico, PharmD, Minnesota Direct Care and Treatment

Background: Inhalers are commonly used for the treatment of persistent asthma. For patients ≥6 years of age with moderate to severe asthma, international guidelines recommend dual therapy with an inhaled corticosteroid (ICS) and a long-acting inhaled β2 agonist (LABA). There are only weak recommendations for adding a long-acting muscarinic antagonist (LAMA) to treatment in patients who continue to have uncontrolled symptoms. Other therapy escalations include oral corticosteroids, which have a higher risk of adverse effects and biologics, which have a substantially higher cost for treatment. If triple inhaler therapy controls a patient’s asthma symptoms, systemic therapies like corticosteroids and biologics can be avoided.

Purpose: To compare dual inhaler therapy (ICS plus LABA) and triple therapy (ICS, LABA, and LAMA) outcomes and adverse events in adults and children with persistent uncontrolled asthma.

Study Design: Studies for this systematic review and meta-analysis were selected independently by two investigators. They selected randomized controlled trials (RCTs) comparing triple vs dual inhaler therapy in patients with moderate to severe asthma from data sources: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials , the World Health Organization International Clinical Trials Registry , Food and Drug Administration , and European Medicines Agency databases from November 2017 to December 8, 2020, without language restrictions. Two independent reviews extracted data and assessed the risk of bias. Random-effects meta-analyses were used, including patient-level exacerbation data. Studies were excluded if they were observational, preclinical, or limited to patients with chronic respiratory diseases other than asthma. All disagreements were resolved through consensus and authors were contacted in instances of unclear or missing data. GRADE (Grading of Recommendations, Assessment, Development and Evaluation) and the Cochrane approaches were used to guide the conduct of the review which was prospectively registered. In addition, the study was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines.

Results: Twenty RCTs enrolling 11,894 children and adults (mean age, 52 years [range, 9 – 71 years], 57.7% female) were included in the review. Compared to dual inhaler therapy, triple therapy was significantly associated with a reduction in severe exacerbation risk (9 trials [9,932 patients]; 22.7% vs 27.4%; risk ratio, 0.83 [95% CI 0.77 - 0.90]). Results for milder exacerbations were similar. Triple therapy was also significantly associated with improvement in asthma control (14 trials [11,230 patients]; standardized mean difference [SMD], −0.06 [95% CI −0.10 - −0.02]; mean difference in ACQ-7 scale, −0.04 [95% CI −0.07 - −0.01]). In addition, triple therapy was significantly associated with spirometry indices improvement as measured by trough FEV1 (18 trials [11,715 patients]; mean difference, 0.08 L [95% Cl 0.07 - 0.10] I2 = 0%; high-certainty evidence). No significant differences between dual vs triple therapy were found in asthma-related quality of life (7 trials [5247 patients]; SMD, 0.05 [95% CI −0.03 - 0.13]; mean difference in AQLQ score, 0.05 [95% Cl −0.03 - 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 - 2.75]; high-certainty evidence). Increase in dry mouth and dysphonia was significantly associated with triple inhaler therapy (10 trials [7395 patients]; 3.0% vs 1.8%; risk ratio, 1.65 [95% CI 1.14 - 2.38]; high-certainty evidence). However, treatment-related and serious adverse events were not significantly different between triple and dual therapy based on moderate-certainty evidence.

Conclusions: The results of this meta-analysis and systematic review support the use of triple inhaler therapy for children (≥6 years old) and adults with moderate to severe asthma. Among this population, triple therapy was significantly associated with fewer severe asthma exacerbations and modest improvements in asthma control compared to dual therapy. There were no significant differences in quality of life or mortality between triple and dual inhaler therapy.

Key Point: In patients ≥6 years of age with persistent moderate to severe asthma, triple inhaler therapy can be used to improve asthma control in order to avoid prescribing systemic therapies like steroids and biologics that may increase adverse events and cost. 



  1. Kim LH, Saleh C, Whalen-Browne A, O’Byrne PM, Chu DK. Triple vs Dual Inhaler therapy and ASTHMA outcomes in moderate to severe asthma. JAMA. 2021;325(24):2466. doi:10.1001/jama.2021.7872