CLINICAL QUESTION

In adolescents and adults with uncontrolled asthma who are already taking a medium-dose inhaled corticosteroid (ICS), what are the effectiveness and safety of adding a long-acting beta₂ agonist (LABA) or a long-acting muscarinic antagonist (LAMA) vs. doubling the dose of the ICS compared with continuation of the medium-dose ICS?

EVIDENCE-BASED ANSWER

Adding a LABA to a medium- or high-dose ICS likely reduces the frequency of moderate to severe asthma exacerbations compared with continuing a medium-dose ICS alone.¹ (Strength of Recommendation [SOR]: A, consistent, good-quality patient-oriented evidence.)

Adding a LAMA to a medium-dose ICS possibly reduces the frequency of moderate to severe asthma exacerbations compared with continuing a medium-dose ICS alone.¹ (SOR: A, consistent, good-quality patient-oriented evidence.)

A high-dose ICS alone likely does not reduce the frequency of moderate to severe asthma exacerbations compared with a medium-dose ICS alone.¹ (SOR: B, inconsistent or limited-quality patient-oriented evidence.)

PRACTICE POINTERS

Asthma is a chronic inflammatory lung disease that affects people of all ages. It is characterized by reversible airway obstruction. Based on 2021 data, approximately 25 million people in the United States have asthma, which resulted in 94,560 hospitalizations and 986,453 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 The authors of this Cochrane review sought to determine the effectiveness and safety of dual therapies (a medium-dose ICS plus a LABA or a medium-dose ICS plus a LAMA) compared with a medium-dose ICS alone in adolescents and adults with uncontrolled asthma.¹

This Cochrane review included 35 randomized controlled trials with a median duration of 24 weeks from 2008 through 2022. Data from 38,276 participants 12 years and older (mean age = 44 years) were included in a systematic review and network meta-analysis. The primary outcome was asthma exacerbations. Moderate asthma exacerbations were defined as requiring a short course of oral corticosteroids, and severe exacerbations were defined as resulting in hospitalization, intubation requiring mechanical ventilation, or death. Secondary outcomes were Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) scores and adverse events (i.e., asthma-related and all-cause serious adverse events, drop-out rate due to adverse events). The dose of the ICS component combined with inhalers was classified as low, medium, or high.¹

A medium- and high-dose ICS plus a LABA likely reduces the number of moderate to severe asthma exacerbations compared with a medium-dose ICS alone (hazard ratio [HR] = 0.70; 95% credible interval, 0.59 to 0.82; number needed to treat [NNT] = 15 [95% credible interval, 11 to 24]; HR = 0.59; 95% credible interval, 0.46 to 0.76; NNT = 11 [95% credible interval, 8 to 19], respectively). A medium-dose ICS plus a LAMA possibly reduces the number of moderate to severe asthma exacerbations compared with a medium-dose ICS alone (HR = 0.56; 95% credible interval, 0.38 to 0.82; NNT = 10 [95% credible interval, 7 to 24]).¹ A high-dose ICS did not appear to reduce moderate to severe asthma exacerbations compared with a medium-dose ICS. No combination therapy or high-dose ICS appeared to reduce severe asthma exacerbations compared with a medium-dose ICS.

An ACQ responder is defined as someone who experiences a clinically meaningful improvement (0.5-point or greater improvement on a 7-point scale) on the ACQ score.1 A medium-and high-dose ICS plus a LABA increased the odds of patients being ACQ responders at 6 months (odds ratio [OR] = 1.47; 95% credible interval, 1.23 to 1.76; NNT = 11 [95% credible interval, 8 to 20]; and OR = 1.59; 95% credible interval, 1.31 to 1.94; NNT = 10 [95% credible interval, 7 to 16], respectively). A medium-dose ICS plus a LAMA increased the odds of patients being ACQ responders at 6 months (OR = 1.32; 95% credible interval, 1.11 to 1.57; NNT = 16 [95% credible interval, 10 to 40]) compared with a medium-dose ICS. There was no difference in quality of life on the AQLQ between dual and monotherapies.

A medium-dose ICS plus a LAMA probably reduced all-cause adverse events over a 6-month follow-up period (risk ratio = 0.86%; 95% CI, 0.77 to 0.96) compared with a medium-dose ICS.¹ However, there were no differences in asthma-related or all-cause serious adverse events or dropouts related to adverse events between combination therapies and a medium-dose ICS.

The studies in this review did not include children younger than 12 years; therefore, the conclusions cannot be applied to this age group.¹ Current guidelines suggest using a combined low-dose ICS plus formoterol (LABA) for both maintenance and reliever therapy.³ The ICS dose can be increased if symptoms remain uncontrolled. The guidelines also recommend initiating a LAMA in patients with uncontrolled asthma who already use a medium-dose dual maintenance and reliever inhaler.

Author’s Note: Network meta-analysis estimates are reported as hazard ratio. Results are expressed in credible intervals as opposed to CIs because a Bayesian analysis was conducted.

The practice recommendations in this activity are available at https://www-cochrane-org.lib3.cgmh.org.tw:30443/CD013797.