Source: Sobieraj DM, Weeda ER, Nguyen E, et al. Association of inhaled corticosteroids and long-acting b-agonists as controller and quick relief therapy with exacerbations and symptom control in persistent asthma: a systematic review and meta-analysis. JAMA 2018;319:1485–96.
Study Population: 22,748 patients (aged ≥5 years) with persistent asthma, already receiving inhaled corticosteroids from 16 randomized clinical trials
Efficacy Endpoints: Asthma exacerbations defined as requiring systemic use of corticosteroids, hospitalization, ED visits, intensive care admission, or intubation
Harm Endpoints: Harms were not assessed
Narrative: Asthma is a chronic respiratory disease affecting 235 million people worldwide,1 burdening both patients, their families, and society in terms of lost work and school, lessened quality-of-life, avoidable emergency department (ED) visits, hospitalizations, and deaths. Data from the Centers for Disease Control and Prevention report that asthma affects roughly 8% of the U.S. population (approximately 26 million people), accounting for 2 million ED visits, 480,000 hospitalizations, and 3,400 deaths annually with an economic burden of about $82 billion.2, 3
The National Asthma Education and Prevention Program (NAEPP) guidelines (1991, 1997, 2002) were last updated in 2007 with the Expert Panel Report 3 (EPR-3). The NAEPP–EPR-3 guidelines highlighted a new focus on monitoring asthma control (degree to which manifestations are minimized by interventions) compared to asthma severity (intrinsic disease intensity) as the therapeutic goal with new foci on impairment (symptom frequency, intensity, functional limitations) and risk (exacerbation likelihood, decline in lung function, medication adverse events).4 The stepwise treatment approach is illustrated in Data Supplement S1 (available as supporting information in the online version of this paper, which is available at http://onlinelibrary. wiley.com/doi/10.1111/acem.13659/full).4 For patients with worsening symptoms, a step-up in treatment may be indicated.
Given the shortage of primary care physicians, the ED is the primary source of care for many asthmatics, with asthma-related ED visits increasing by 13% over the past decade.5, 6 Emergency physicians must be familiar with various proper treatment strategies. Single maintenance and reliever therapy (SMART) is an emerging strategy aimed at reducing asthma exacerbations. The aim of this evidence-based medicine summary is to familiarize emergency physicians with the SMART regimen. While we are keenly aware that some may perceive controller medication to be a primary care provider issue, the onus of mitigating asthma’s $82 billion footprint falls on all involved providers.
Patients with severe persistent asthma (3%–10% of asthmatics) have a sixfold higher risk of exacerbations and treatment costs compared to nonsevere asthmatics.7 Asthma therapy is centered on inhaled delivery of anti-inflammatory agents and bronchodilators. In the traditional stepwise asthma guideline regimen (Data Supplement S1), therapy is added based on symptom control, with most patients using separate inhalers for controller versus reliever purposes. Controller inhalers are typically an inhaled corticosteroid alone (ICSmono) or in combination with a long-acting beta-agonist (LABA), while relievers are typically short-acting beta-agonists (SABA; e.g., albuterol) or anticholinergics.8 During periods of worsened control, patients increase their beta-agonist therapy using the SABA reliever, and when control remains inadequate despite higher ICSmono doses a LABA is added. Recently, however, use of the ICS + LABA as both controller and reliever therapy has become popular, termed single inhaler therapy or SMART.9 Theoretical benefits for using an ICS + LABA combination such as formoterol-budesonide (Symbicort, AstraZeneca) for both roles includes: 1) ICS dose varies per symptoms and 2) LABA onset-of-action is nearly as rapid as SABA but allows for more sustained relief.10 Together, these may lower exacerbation rates. In this review (and the source meta-analysis), the terms same dose and higher dose reflect the controller ICS dose (not the LABA) in the traditional stepwise approach. Although used in the traditional stepwise regimen, SABA is not used in the SMART regimen.
The meta-analysis discussed here, assesses the effectiveness of the SMART regimen for decreasing asthma exacerbations defined as requiring systemic steroids (≥3 days), ED visit, hospitalization, intensive care admissions, or intubation.11 The meta-analysis included 16 randomized controlled clinical trials enrolling 22,748 patients.11 The SMART regimen was compared to same-dose ICSmono, higher-dose ICSmono, same-dose ICS + LABA, and higher-dose ICS + LABA. In patients≥12 years of age, SMART reduced exacerbation rates compared to same-dose ICSmono (relative risk [RR] = 0.64, 95% confidence interval [CI] = 0.53 to 0.78, absolute risk difference [ARD] = 8.1%, number needed to treat [NNT] = 12; quality of evidence = moderate), and higher-dose ICSmono (RR = 0.59, 95% CI = 0.49 to 0.71, ARD = 11%, NNT = 9; quality of evidence = low).11 Additionally, SMART reduced exacerbation rates compared to same-dose ICS + LABA (RR = 0.68, 95% CI = 0.58–0.80, ARD = 6.3%, NNT = 16; quality of evidence = High), and higherdose ICS + LABA (RR = 0.77, 95% CI = 0.60–0.98, ARD = 2.7%, NNT = 37; quality of evidence = high).11
Caveats: There have been no additional trials published on this subject since this meta-analysis11 was conducted. Most trials had a low risk of bias for random sequence generation, allocation concealment, incomplete data reporting, and other types of bias.11 Six studies had a high risk of bias for blinding methods (performance and detection biases) and nine had an unclear risk of bias for selective outcome reporting (reporting bias).11 This degree of performance, detection, and reporting bias may limit one’s capacity to make valid inferences about intervention effects. Unfortunately, a subgroup analysis after excluding these trials was not performed.
While statistical heterogeneity was low (I2 <50%), clinical heterogeneity was substantial. Studies variably included patients based on control and severity classification or symptoms. The existing discrepancies between the severity classifications schemes adds to this heterogeneity. For example, the NAEPP–EPR-3 uses symptom severity,4 whereas guidelines by the American Thoracic Society and The European Respiratory Society (ATS/ ERS) rely on medication need plus control.12 As emergency physicians’ encounter a wide range of asthma patients, baseline severity classification during the visit may not be as important as acute symptom management and return visit prevention.
Other outcomes (e.g. all-cause mortality) were rare. Most trials lasted only 6 to 12 months, so long-term outcomes data are not available. Improvement in forced expiratory volume in 1 second (FEV1) was inconsistently reported and fell short of the threshold difference of 0.2 L.11 Asthma control (defined by the asthma control test and the asthma control questionnaire) did not support the SMART regimen.11 Additionally, since the trials reported a composite endpoint, it is unclear which outcome(s) drove most of the result. Separating the outcomes would improve clarity; however, individual outcomes were rarely reported in the included trials. However, it is reassuring to note that this composite outcome (systemic corticosteroids, hospitalizations, and ED visits) is standard in most asthma trials.
While attractive, the SMART regimen has limitations. For example, the only SMART medication studied (budesonide-formoterol, Symbicort) was a dry powder inhaler, but only the metered-dose inhaler (MDI) is available in the United States. This may not be of great significance as data suggest therapeutic equivalence between the two forms.14
Long-term SMART adherence also appears to be poor, with up to 53% of patients reinitiating their SABA reliever within 1 year.15 Of concern, physician insight into SMART application appears to be poor. In one study, 72% of physicians prescribed SMART, but a majority (91%) also prescribed a SABA at some point.16 Limited data also suggest that asthma control with combination budesonide-formoterol is poorer in younger patients (age <30 years) and those with a newer diagnosis (<5 years).17 Moreover, the influence of additional factors (e.g., smoking) remains unclear.18
Finally, cost may be a prohibitive barrier for some patients. It’s been reported that the annual (per-person) cost of asthma was $3,266 in 2013 ($1,830 for prescriptions), translating to roughly $82 billion per year.2 In multiple “Express Scripts Drug Trend” reports, asthma inhalers are consistently among the top 10 most expensive prescribed medications for a chronic condition, with costs increasing 50% on average since 2009. Symbicort costs $350 to $400 per inhaler in the United States. While it is tempting to assume that the SMART regimen would inflate costs by increasing Symbicort use, costs may be offset at least in part by decreased exacerbations (direct savings) and fewer work-days lost (indirect savings). Finally, it remains unclear how insurance companies will handle prescription reimbursement in the setting of decreased longevity of individual Symbicort MDIs. It is important to note that the U.S. Food and Drug Administration removed the Black Box Warning for ICS + LABA asthma medications in January 2018.
In conclusion, moderate quality evidence suggests that SMART decreases asthma exacerbation. However, possible harms associated with this treatment have not been assessed or reported. Therefore, we have assigned a yellow color recommendation (unclear if benefits) to this strategy.
The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.
Author: Arjun Mohan, MD; Gregory D. Kearney, DrPH, MPH; Andrew C. Miller, MDSupervising Editor: Shahriar Zehtabchi, MD
Published/Updated: March 5, 2019
The title bar is color-coded with our overall recommendation.