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Meta-Analysis
. 2022 Mar 1;5(3):e220615.
doi: 10.1001/jamanetworkopen.2022.0615.

Evaluation of Budesonide-Formoterol for Maintenance and Reliever Therapy Among Patients With Poorly Controlled Asthma: A Systematic Review and Meta-analysis

Richard Beasley  1   2   3 , Tim Harrison  4   5 , Stefan Peterson  6 , Per Gustafson  7 , Angus Hamblin  8 , Thomas Bengtsson  6 , Malin Fagerås  7
Affiliations
Meta-Analysis

Evaluation of Budesonide-Formoterol for Maintenance and Reliever Therapy Among Patients With Poorly Controlled Asthma: A Systematic Review and Meta-analysis

Richard Beasley et al. JAMA Netw Open. .

Erratum in

  • Error in Figure 2B.
    [No authors listed] [No authors listed] JAMA Netw Open. 2022 May 2;5(5):e2216068. doi: 10.1001/jamanetworkopen.2022.16068. JAMA Netw Open. 2022. PMID: 35583874 Free PMC article. No abstract available.

Abstract

Importance: The Global Initiative for Asthma (GINA) recommends 2 alternative treatments for patients receiving treatment at steps 3 to 5: single inhaler combination inhaled corticosteroid-formoterol as both maintenance and reliever (SMART) or inhaled corticosteroid-long-acting β2-agonist as maintenance plus short-acting β2-agonist as reliever.

Objective: To assess whether switching to SMART is associated with longer time to first severe asthma exacerbation compared with a step up or continuation of GINA treatment step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever among patients with poorly controlled asthma.

Data sources: For this systematic review and meta-analysis, the literature, internal study databases at AstraZeneca and the Medical Research Institute of New Zealand, and references from a previous systematic review and meta-analysis on SMART were searched to identify randomized clinical trials published from January 1990 to February 2018, that compared budesonide-formoterol by SMART with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever.

Study selection: Trials of at least 24 weeks' duration were included if they reported baseline data on GINA treatment step, asthma control status, and efficacy measures of severe exacerbations. Included patients were adults and adolescents with asthma and baseline Asthma Control Questionnaire 5-item version scores of 1.5 or higher.

Data extraction and synthesis: Patient-level data were identified by independent extraction, and analyses were performed using a fixed-effect model. Data analysis was performed from August 2018 to November 2021.

Main outcomes and measures: The primary outcome was time to first severe asthma exacerbation associated with each treatment, analyzed by Cox proportional hazards regression.

Results: Overall, 4863 patients were included (3034 [62.4%] female; mean [SD] age, 39.8 [16.3] years). Switching patients with uncontrolled asthma at GINA step 3 (n = 1950) to SMART at either step 3 or 4 was associated with a prolonged time to first severe asthma exacerbation, with a 29% reduced risk compared with stepping up to step 4 inhaled corticosteroid-long-acting β2-agonist maintenance plus short-acting β2-agonist reliever (hazard ratio, 0.71; 95% CI, 0.52-0.97). For patients with uncontrolled asthma at step 3 and step 4 (n = 2913), switching to SMART was associated with a prolonged time to first severe asthma exacerbation and a 30% reduced risk compared with remaining at the same treatment step (hazard ratio, 0.70; 95% CI, 0.58-0.85).

Conclusions and relevance: In this systematic review and meta-analysis, for patients with poorly controlled asthma, SMART was associated with longer time to first severe asthma exacerbation compared with a step up or continuation of GINA step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever. These findings suggest that if an adult or adolescent receiving treatment at GINA step 3 or 4 has poorly controlled asthma, it is preferable to switch to the SMART regimen rather than to step up or continue the GINA treatment step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever therapy.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Beasley reported receiving grants from AstraZeneca, Cure Kids, the Health Research Council of New Zealand, Genentech and GlaxoSmithKline; receiving personal fees from AstraZeneca, Avillion, Cipla, and Theravance; serving on advisory boards for AstraZeneca, Avillion, and Theravance; and serving as the chair of the adolescent and adult asthma guidelines group for the Asthma and Respiratory Foundation NZ outside the submitted work. Dr Harrison reported receiving personal fees and grants from AstraZeneca and being an employee and shareholder of AstraZeneca during the conduct of the study and receiving grants from AstraZeneca outside the submitted work. Dr Peterson reported receiving payment for statistical analysis from AstraZeneca and being an employee of StatMind during the conduct of the study. Dr Gustafson reported being an employee and shareholder of AstraZeneca during the conduct of the study and outside the submitted work. Mr Hamblin reported being an employee and shareholder of AstraZeneca during the conduct of the study and outside the submitted work. Mr Bengtsson reported receiving payment for statistical analysis from AstraZeneca and being an employee of StatMind during the conduct of the study. Dr Fagerås reported being a full-time employee and shareholder of AstraZeneca during the conduct of the study.

Figures

Figure 1.
Figure 1.. Flow Diagram of Patients Included in the Analysis
The initial total of 10 262 patients excludes the patients in the as-needed formoterol-only arm of the SMILE trial. The 1493 patients excluded because of lack of data for comparison refers to patients receiving Global Initiative for Asthma (GINA) step 4 treatment in the SMILE and SAKURA trials, who corresponded to a step down in treatment level. ACQ indicates Asthma Control Questionnaire; ICS, inhaled corticosteroid; ITT, intention to treat; LABA, long-acting β2-agonist; SABA, short-acting β2-agonist; SMART, single maintenance and reliever therapy.
Figure 2.
Figure 2.. Meta-analysis of the Association of Single Inhaler Maintenance and Reliever Therapy (SMART) vs Inhaled Corticosteroid–Long-acting β2-Agonist (ICS-LABA) Maintenance Plus Short-acting β2-Agonist (SABA) Reliever With Time to First Severe Exacerbation
In the COMPASS trial, the 2 comparator arms were pooled into 1 fixed ICS-LABA treatment arm. GINA indicates Global Initiative for Asthma; HR, hazard ratio.
Figure 3.
Figure 3.. Meta-analysis of the Association of Single Inhaler Maintenance and Reliever Therapy (SMART) vs Inhaled Corticosteroid–Long-acting β2-Agonist (ICS-LABA) Maintenance Plus Short-acting β2-Agonist (SABA) Reliever With Secondary End Points
Whiskers and shading represent 95% CIs; and dotted lines, the minimal clinically important differences. ACQ-5 indicates Asthma Control Questionnaire 5-item version; FEV1, forced expiratory volume in 1 second; GINA, Global Initiative for Asthma.
See this image and copyright information in PMC

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