What are the effectiveness and safety of dual therapies with varying doses of an inhaled corticosteroid (ICS) and a long-acting beta2 agonist (LABA) compared with triple therapies containing an ICS/LABA with varying steroid doses plus a long-acting muscarinic antagonist (LAMA) in adults and adolescents (12 years and older) with uncontrolled asthma?
Compared with medium-dose dual inhaler therapy (ICS/LABA), triple inhaler therapy (ICS/LABA/LAMA) reduces steroid-requiring asthma exacerbations in adults with asthma, but not asthma-related hospitalizations.1 (Strength of Recommendation [SOR]: A, consistent, good-quality patient-oriented evidence.)
High-dose triple therapy, but not medium-dose triple therapy, may be better tolerated than medium-dose dual therapy due to overall decreased adverse events. There is little to no difference in serious adverse events between dual and triple therapy.1 (SOR: A, consistent, good-quality patient-oriented evidence.)
Asthma is a chronic inflammatory disease of the lungs that affects people of all ages and is characterized by reversible airway obstruction. Approximately 24.9 million people in the United States have asthma, which resulted in 94,560 hospitalizations and 986,453 million emergency department visits in 2020.2 According to the Global Initiative for Asthma, the long-term goals of asthma management are to reduce severe exacerbation risk and control symptoms without causing adverse events.3 Effective management of asthma includes an algorithm for adjusting treatment for individual needs based on severity.
The authors of this Cochrane review sought to determine the effectiveness and safety of dual (ICS/LABA) and triple (ICS/LABA/LAMA) therapies compared with each other and with varying doses of an ICS in adolescents and adults with uncontrolled asthma.1 This Cochrane review included 17 randomized controlled trials with a median study duration of 26 weeks from 2008 to 2022. Data from 17,161 patients (mean age = 49.1 years) were included in a systematic review and network meta-analysis. The primary outcome was steroid-requiring moderate-to-severe asthma exacerbations and asthma-related hospitalization. Secondary outcomes were asthma control (measured using the Asthma Control Questionnaire), quality of life (measured using the Asthma Quality of Life Questionnaire), and adverse events. The dose of the ICS component in combination inhalers was classified as low, medium, or high based on clinical compatibility.3,4 The 17 trials included in this review excluded children (younger than 12 years), and the triple combination therapy trials excluded adolescents (between ages 12 to 17 years).
Medium-dose triple therapy reduced steroid-requiring asthma exacerbations compared with medium-dose dual therapy (hazard ratio [HR] = 0.84; 95% credible interval, 0.71 to 0.99; absolute risk reduction [ARR] = 31 per 1,000; number needed to treat [NNT] = 32; 95% credible interval, 17 to 500). High-dose triple therapy also reduced steroid-requiring asthma exacerbations compared with medium-dose dual therapy (HR = 0.69; 95% credible interval, 0.58 to 0.82; ARR = 61 per 1,000; NNT = 16; 95% credible interval, 12 to 28). Further, it is notable that high-dose triple therapy reduced steroid-requiring asthma exacerbations compared with medium-dose triple therapy (HR = 0.83; 95% credible interval, 0.69 to 0.99; ARR = 34 per 1,000; NNT = 29; 95% credible interval, 16 to 1,000). The associated reduction in steroid-requiring asthma exacerbations while on triple therapy was more likely in patients with a history of asthma exacerbation in the past year than in those without.
Medium-dose triple therapy and high-dose triple therapy did not reduce asthma-related hospitalizations compared with medium-dose dual therapy. The definition of moderate and severe exacerbations (requiring systemic steroids and hospitalization, respectively) varied among studies; therefore, the results reinforced the superiority of triple therapy to dual therapy in reducing steroid-requiring asthma exacerbations.5,6
For secondary outcomes, high-dose triple therapy resulted in a reduction of all-cause adverse events compared with medium-dose dual therapy (HR = 0.79; 95% credible interval, 0.69 to 0.90; ARR = 59 per 1,000; NNT = 17; 95% credible interval, 11 to 38); and reduced dropout rates due to adverse events (odds ratio = 0.5; 95% credible interval, 0.30 to 0.84). Little to no difference was noted between triple and dual therapy in all-cause or asthma-related serious adverse events. There was also no clinically significant difference in symptoms or quality-of-life scores when comparing high-dose or medium-dose triple therapy to medium-dose dual therapy.
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