Expert Review of Respiratory Medicine

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Symbicort® Maintenance and Reliever

Therapy (SMART) and the evolution of asthma
management within the GINA guidelines

Jiangtao Lin, Xin Zhou, Changzheng Wang, Chuntao Liu, Shaoxi Cai & Mao
Huang

To cite this article: Jiangtao Lin, Xin Zhou, Changzheng Wang, Chuntao Liu, Shaoxi Cai & Mao
Huang (2018): Symbicort® Maintenance and Reliever Therapy (SMART) and the evolution of
asthma management within the GINA guidelines, Expert Review of Respiratory Medicine, DOI:
10.1080/17476348.2018.1429921

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Published online: 05 Feb 2018.

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EXPERT REVIEW OF RESPIRATORY MEDICINE, 2018
[Link]

REVIEW

Symbicort® Maintenance and Reliever Therapy (SMART) and the evolution of

asthma management within the GINA guidelines
a
Jiangtao Lin , Xin Zhoub, Changzheng Wangc, Chuntao Liud, Shaoxi Caie and Mao Huangf
a
Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China; bDepartment of Respiratory Medicine, Shanghai
General Hospital, Shanghai, China; cDepartment of Respiratory Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, China;
d
Department of Respiratory Medicine, West China Hospital, West China School of Medicine, Chengdu, China; eDepartment of Respiratory Medicine,
Nanfang Hospital, Southern Medical University, Guangzhou, China; fDepartment of Respiratory Medicine, Jiangsu Province Hospital, Nanjing, China

ABSTRACT ARTICLE HISTORY

Introduction: The Global Initiative for Asthma (GINA) annual report summarizes the latest evidence for Received 25 October 2017
asthma management. GINA recommends stepwise pharmacological treatment, advocating inhaled Accepted 16 January 2018
corticosteroids (ICS) plus rapid, long-acting β2-agonists (LABA) delivered in a single inhaler for main- KEYWORDS
tenance and relief at Steps 3 (moderate persistent asthma requiring 1–2 controllers plus as-needed Asthma; budesonide;
reliever), 4 (severe persistent asthma requiring ≥2 controllers plus as-needed reliever), and 5 (higher formoterol; inhaled
level care and/or add-on treatment). corticosteroid; long-acting
Areas covered: Randomized controlled trials and real-world evidence demonstrate that flexibly dosed β2-agonist; maintenance;
budesonide/formoterol for maintenance and relief (Symbicort® Maintenance And Reliever Therapy reliever; single inhalation
[SMART]) is associated with reductions in severe exacerbations, prolongs time to first exacerbation, therapy
and provides fast symptom relief.
Expert commentary: SMART provides greater or equal levels of sustained asthma control than
similar or higher fixed doses of ICS/LABA plus short-acting β2-agonist (SABA) as needed or higher
ICS plus SABA as needed, with lower overall ICS doses and cost. The simplified dosing strategy
may improve adherence and overall asthma control but relies on patient education. Budesonide/
formoterol as needed in mild asthma (patients qualifying for regular low-dose ICS) is currently
under investigation in two double-blind randomized studies, SYGMA1/2 (NCT02149199/
NCT02224157), comparing budesonide/formoterol as needed with budesonide plus SABA and
SABA alone.

1. The Global Initiative for Asthma (2) Assess and monitor asthma severity with both symp-
The Global Initiative for Asthma (GINA) was established tom reports and, as much as possible, measurements of
following the 1995 publication of ‘Global Strategy for lung function
Asthma Management and Prevention,’ a joint workshop (3) Avoid or control asthma triggers
report by the World Health Organization and the National (4) Establish individual medication plans for long-term
Heart, Lung, and Blood Institute [1]. The GINA Science management
Committee reviews research on asthma management and (5) Establish plans for managing exacerbations
prevention and makes evidence-based recommendations for (6) Provide regular follow-up care
patient care in a yearly report [2].
The original 1995 report described a system of diagnosis Recommendations for pharmacological treatment were
and classification reliant on lung function tests (e.g. peak based on disease severity and followed a stepwise management
expiratory flow [PEF]) to categorize patients according to a pattern (Table 1, left side). The recommendations for therapy at
four-step severity system (intermittent, mild persistent, Step 3 included the following statement: ‘A long-acting β2-ago-
moderate persistent, and severe persistent) based on clin- nist may have a complementary effect to inhaled corticosteroids
ical features and the amount of daily controller medication. (ICS), although more data are necessary to establish the place of
A distinction was made between the prevention of the long-acting β2-agonist in asthma therapy’ [1, p.95] (Table 1).
initial development of asthma (primary) and the preven- The report concluded with recommendations in four areas:
tion of exacerbations in those with asthma (secondary). training (for health-care professionals [HCPs] and patients);
The report featured a six-part management program: health-care services (daily and long-term control); prevention
(reducing allergen and sensitizer exposure); and research (epi-
(1) Educate patients to develop a partnership in asthma demiological studies, noninvasive testing methods, and stra-
management tegies for determining efficacy and cost-effectiveness).

CONTACT Jiangtao Lin jiangtao_l@[Link] China-Japan Friendship Hospital, Beijing 100029, China
© 2018 Informa UK Limited, trading as Taylor & Francis Group
 2
J. LIN ET AL.

Table 1. Stepwise control of asthma as recommended in the original GINA 1995 report [1] and the current GINA 2017 report [2].
GINA 1995 GINA 2017
Step 1 2 3 4 1 2 3 4 5
Preferred controller Low-dose ICS Medium-/high- Medium-/high-dose Low-dose ICS Low-dose ICS/ Medium-/high- Refer for add-on treatment,
choice cromoglycate dose ICS and ICS and inhaled LABAa dose ICS/LABA e.g. tiotropiumb,c, anti-IgE,
or nedocromil inhaled LABA, LABA, sustained- or anti-IL-5b
sustained- release
release theophylline, or
theophylline, or oral LABA and
oral LABA OCS long term
Other controller options Increase ICS and Consider low-dose LTRA, low-dose Medium-/high- Add tiotropiumb,c, Add low-dose OCS
then add ICS theophyllineb dose ICS, low- high-dose ICS
inhaled LABA, dose ICS+(LTRA +(LTRA or
b
sustained- or theophylline ) theophyllineb)
release
theophylline, or
oral LABA
Reliever As-needed As-needed SABA not more than As-needed SABA As-needed SABA As-needed SABA or low-dose ICS/formoterold
SABA less three to four times per day
than once
a week
GINA: Global Initiative for Asthma; ICS: inhaled corticosteroid; IgE: immunoglobulin E; IL-5: interleukin-5; LABA: long-acting β2-agonist; LTRA: leukotriene receptor antagonist; OCS: oral corticosteroid; SABA: short-acting β2-
agonist.
a
For children 6–11 years old, the preferred Step 3 is medium-dose ICS.
b
Not for children <12 years old.
c
Tiotropium by mist inhaler is an add-on treatment for patients with a history of exacerbations; it is not indicated in children <12 years old.
d
Low-dose ICS/formoterol is the reliever medication for patients prescribed low-dose budesonide/formoterol or low-dose beclomethasone/formoterol maintenance and reliever therapy.
 EXPERT REVIEW OF RESPIRATORY MEDICINE 3

1.1. Key updates to the GINA report combination inhalers containing formoterol and budesonide
may be used for both rescue and maintenance’ [4, p.31].
1.1.1. GINA 2002 report
Following safety concerns [6–8], it was emphasized that
The GINA report was first updated in 2002 to include a revised
LABA should not be used as monotherapy and must only be
definition of asthma as a ‘chronic inflammatory disorder of the
used with an appropriate dose of ICS.
airways’ and included data on worldwide asthma prevalence,
host and environmental risk factors, and new pathophysiolo-
gical data on inflammation and airway remodeling [3]. The 1.1.3. GINA 2014 report
four-step severity system was updated: in a patient receiving The 2014 GINA report represented a major update with the spe-
treatment, classification should be based on both clinical fea- cific aim of improving accessibility. Practical summary tables and
tures and medication step. For instance, a patient with management flowcharts were included, and detailed background
ongoing symptoms of mild persistent asthma, despite receiv- information was moved to an online appendix. Asthma was
ing appropriate maintenance treatment for this step, should in defined clinically (as opposed to pathophysiologically) as: ‘a het-
fact be regarded as having moderate persistent asthma. The erogeneous disease, usually characterized by chronic airway
report also included recommendations for educational tools inflammation . . . defined by the history of respiratory symptoms
(for both patients and HCPs) and the scientific rationale for such as wheeze, shortness of breath, chest tightness, and cough
their use [3]. The management plan was updated to include that vary over time and in intensity, together with variable expira-
details of primary (before exposure to risk factors), secondary tory airflow limitation’ [9]. Assessment of two domains of asthma
(after primary sensitization to allergen(s) but before evidence control – symptom control and risk factors for adverse outcomes
of disease), and tertiary (prevention of exacerbations) preven- (also called ‘future risk’ [10]) – acknowledged that current symp-
tion of asthma. The report stated that ICS were the most tom control alone is insufficient, given that patients with few
effective controller medications, and the addition of a long- symptoms may nevertheless be at risk of exacerbations. A practical
acting inhaled β2-agonist (LABA) should be considered when algorithm for distinguishing between uncontrolled asthma and
introductory doses of ICS fail to achieve control of asthma severe asthma in primary care was introduced prioritizing inhaler
(Step 3) [3]. The report cited Grade B evidence that the use technique (which may be incorrect in 70–80% of patients and is a
of combined ICS/LABA was as effective as giving each drug common, correctable cause of poor asthma control [11,12]).
separately [3]. Recommendations for tailoring asthma treatment to indivi-
dual patients emphasized that predictors of individual risk and
1.1.2. GINA 2006 report response (e.g. hospitalizations for asthma in the previous year
The next major update, in 2006, recommended that asthma and smoking status) should be considered together with patient
management should be based on clinical control rather than goals and concerns. The report advocated a continuum of care
symptom severity [4]. The previous classification of asthma by for worsening asthma, from early self-management through to
severity, while still recommended for research, was replaced primary- and acute-care management. A novel probability-based
by a system based on control level (controlled, partly con- approach to diagnosing asthma in children ≤5 years was
trolled, and uncontrolled) that formed the basis of the one included, which considered the pattern, frequency, and severity
used today (Table 2). of symptoms. For the first time, GINA in collaboration with the
The 2006 report included revised epidemiological data Global Initiative for Chronic Obstructive Pulmonary Disease
from GINA’s 2004 Global Burden of Asthma report [5]. The (GOLD) [13] advocated a syndromic approach for patients with
concept of difficult-to-treat asthma was introduced, noting overlapping features of asthma and chronic obstructive pulmon-
that these patients were often relatively insensitive to ICS ary disease (COPD). New management recommendations based
and that increased use of reliever medication indicates the on the principles of ‘Assess’ (symptom control and risk factors),
need to reassess treatment. The role of several management ‘Adjust treatment’ (up or down), and ‘Review response’ (after 2 to
therapies was updated and a fifth treatment step was added. 3 months) were included together with a new table of evidence-
The report recommended the use of ICS/LABA as the preferred based recommendations for initiating controller treatment that
treatment when medium-dose ICS failed to achieve control of continues to be updated to this day [9]. Low- and medium-/high-
asthma (Step 3) and introduced the concept that ‘. . . dose ICS/LABA were the preferred controller choices for Steps 3

Table 2. Levels of asthma control introduced in the GINA 2006 report [4].
Controlled (all of the Partly controlled (any measure
Characteristics following) present in any week) Uncontrolled
Daytime symptoms None (twice or less/week) More than twice/week
Limitations of activities None Any
Nocturnal symptoms/awakening None Any Three or more features of partly controlled asthma
Need for reliever/rescue treatment None (twice or less/week) More than twice/week present in any week
Lung function Normal <80% predicted or personal best
(PEF or FEV1)a (if known)
Exacerbations None One or more/yearb One in any weekc
FEV1: forced expiratory volume in 1 second; GINA: Global Initiative for Asthma; PEF: peak expiratory flow.
a
Lung function is not a reliable test for children ≤5 years old.
b
Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate.
c
By definition, an exacerbation in any week makes that an uncontrolled asthma week.
4 J. LIN ET AL.

and 4/5 (Step 5 plus add-on treatment), respectively, with low- anti-inflammatory reliever for as-needed use [16]. The ben-
dose ICS/formoterol as a reliever in patients receiving these efit of budesonide/formoterol as a reliever relies on the
therapies at Step 3 or above. The recommendations challenged rapid bronchodilating effect of formoterol to provide fast
the notion that low-dose ICS should be reserved for patients with and sustained relief of symptoms [17], while the concomi-
symptoms on >2 days per week by lowering the threshold to tant administration of budesonide optimizes treatment of
include this regimen as an additional option at Step 1 in patients the underlying airway inflammation that is signaled by the
with >2 daytime symptoms per month. This approach was sub- onset of symptoms (Figure 1) [17]. As the patient’s as-
sequently validated in a post hoc analysis of the Steroid needed dose is driven by the day-to-day symptom level,
Treatment As Regular Therapy (START) study [14] and as a pre- the patient has access to higher doses of budesonide/for-
ferred treatment at Step 2. moterol when needed, while avoiding unnecessarily high
fixed doses for maintenance treatment [17].
1.1.4. GINA 2016 report
The 2016 GINA report extended the therapeutic recommenda-
tions to include tiotropium and mepolizumab as add-on thera-
2.1.1. ‘Window of opportunity’
The SMART approach is highly associated with reduction of
pies for Step 5 patients ≥12 years old and dosing information
severe exacerbations [16,18–20]. An analysis of 13 trials invol-
for the ICS fluticasone furoate in adults [15].
ving 21,095 patients showed a consistent benefit in prolong-
ing time until first exacerbation with SMART (the primary
1.1.5. GINA 2017 report
outcome in the majority of trials) [21].
Treatment options added in the 2017 report included sublin-
A post hoc analysis of the 425 severe exacerbations that
gual immunotherapy (SLIT) for Step 3 and 4 adult patients
occurred during the 12-month FACET (Formoterol and
with house-dust mite-sensitive asthma who experience
Corticosteroids Establishing Therapy) study noted that exacer-
exacerbations despite ICS treatment [2]. Reslizumab was
bations were characterized by a gradual reduction in PEF over
recommended as an add-on therapy for Step 5 patients
5 to 7 days, followed by a more rapid decline over 2 to 3 days
≥12 years old, and an add-on leukotriene receptor antagonist
[22]. This was paralleled by increasing symptoms and short-
(LTRA) was proposed as an option when down-titrating ICS [2].
acting β2-agonist (SABA) usage. This phenomenon represents
GINA’s 2017 stepwise approach to the management of asthma
a ‘window of opportunity,’ a period signaled by worsening
is shown in Table 1 (right side) [2].
symptoms, in which patients can take action to reduce exacer-
bation risk (Figure 2) [17,23].
2. SMART: Symbicort® (AstraZeneca) Maintenance With the SMART regimen, as-needed budesonide/formo-
And Reliever Therapy terol during this ‘window of opportunity’ provides both relief
of symptoms and treatment of the underlying inflammation.
2.1. Concept and mechanism
In this way, it may modify the course of the event to thereby
SMART (Symbicort® Maintenance And Reliever Therapy) is a prevent the exacerbation, i.e. periods of unstable asthma and
combination of budesonide and formoterol in a single inha- possible exacerbations may be rapidly aborted or occur less
ler used for both regular maintenance therapy and as an often under the SMART regimen [24].

Figure 1. Budesonide/formoterol mechanism of action.

Corticosteroids not only exert anti-inflammatory effects, but also increase β2 receptors. β2-agonists not only induce bronchodilation directly; they also act on glucocorticoid receptors to
enhance the anti-inflammatory effects of corticosteroids. GR, glucocorticoid receptor; GRE, glucocorticoid response element; LABA, long-acting β2-agonist (Reproduced from [17] with
permission of the ©ERS 2007. This material has not been reviewed prior to release; therefore, the European Respiratory Society may not be responsible for any errors, omissions or
inaccuracies, or for any consequences arising there from, in the content.)
 EXPERT REVIEW OF RESPIRATORY MEDICINE 5

addition of a LABA is associated with reducing the rate of

exacerbations requiring OCS and the use of SABA as rescue
medication and is associated with improvements in lung func-
tion and symptoms [27]. Furthermore, in patients uncontrolled
on low-dose ICS, adding a LABA is more effective than increas-
ing the dose of ICS across all these dimensions [28].

2.2.2. Randomized controlled trials of budesonide/

formoterol as maintenance and reliever therapy
Summarized below are the six main international, large-scale,
randomized, controlled, multicenter studies of budesonide/
formoterol maintenance and reliever therapy (SMART) invol-
ving over 14,000 patients (Figure 3) [29–34].
The STEAM study provided the first proof of concept that
control of mild-to-moderate asthma symptoms could be
Figure 2. ‘Window of opportunity’. improved using budesonide/formoterol in a single inhaler for
Representative daytime asthma scores and morning peak expiratory flow in the run up to both maintenance and as-needed relief, without a separate
an exacerbation at Time 0, showing the ‘window of opportunity’. PEF, peak expiratory flow.
reliever inhaler [29]. Over 6 months, 354 patients receiving
budesonide/formoterol 80 μg/4.5 μg two inhalations once
2.2. Development of SMART daily plus budesonide/formoterol as needed (SMART) had sig-
nificantly lower asthma symptom scores, more symptom-free
During the development of SMART and its subsequent applica-
days, and more asthma-control days compared with 342
tion in the clinic, there have been numerous trials; mentioning
patients receiving budesonide 160 μg two inhalations once
each of them here would be beyond the scope of this review. The
daily plus terbutaline 0.4 mg as needed [29]. SMART was also
following sections are designed to give broad coverage of the
associated with a 54% reduction in the risk of having a severe
development and usage of SMART by reviewing the key trials.
exacerbation [29]. In the STEP study, 1890 patients with mod-
erate-to-severe asthma were randomized to 12 months’ treat-
2.2.1. Advantages of ICS/LABA over ICS only ment with either budesonide/formoterol 160 μg/4.5 μg via a
While studies have shown that the use of intermittent ICS at single inhaler two inhalations once daily with additional inha-
the time of an exacerbation halves the likelihood of requiring lations as needed (SMART) or budesonide 160 μg two inhala-
oral corticosteroids (OCS) [25], simply increasing ICS dose does tions twice daily plus 0.4 mg terbutaline as needed [30].
not lead to a significant reduction in the odds of their use, SMART was as well tolerated as the higher fixed dose of
compared with a stable ICS dose in adults and children with budesonide plus as-needed SABA and provided superior
mild-to-moderate asthma [26]. In adult patients who are not asthma control, significantly reducing the time to first severe
adequately controlled on low to high doses of ICS, the exacerbation (primary end point) and the risk of a severe

Figure 3. The six major SMART trials.

Six major international, large-scale, multicenter studies of SMART involving over 14,000 patients (approximate timescale) [29–34]. BUD, budesonide; FLU, fluticasone; FOR, formoterol; SABA,
short-acting β2-agonist; SAL, salmeterol; SMART, Symbicort Maintenance And Reliever Therapy.
6 J. LIN ET AL.

exacerbation by 39%, reducing nocturnal asthma symptoms, exclude patients with comorbidities [36]. Furthermore, the correct
increasing asthma control days, and improving lung function use of SMART requires that additional inhalations are managed
[30]. The STAY study included 2419 adults and adolescents by patients themselves. In RCTs, there are strict instructions as
and 341 children (4–11 years old) randomized to budesonide/ well as guidance and monitoring from investigators for additional
formoterol 80 μg/4.5 μg twice daily with additional inhalations inhalations. Thus, patients usually manage additional inhalations
as needed (SMART) or budesonide/formoterol 80 μg/4.5 μg adequately, but this situation might be quite different in the real
twice daily plus 0.4 mg terbutaline as needed or budesonide world. Nevertheless, some RCTs that support the use of SMART
320 μg twice daily plus 0.4 mg terbutaline as needed (children attempted to mimic real-world situations by not formally mon-
received half the maintenance dose once daily) [31]. After itoring compliance [37], minimizing contact between patients
1 year of treatment, SMART reduced the risk and rate of severe and investigators [38], or adopting an open-label design [39–41].
exacerbations by 45–47% and the need for systemic steroids There is an increasing body of real-world evidence on SMART
and improved asthma symptoms, nocturnal awakenings, and including several large studies that included over 22,600 patients
lung function compared with fixed-dosing regimens [31]. The [40,42–49]. The COSMOS dose-titration study compared budeso-
results of STEAM, STEP, and STAY demonstrated that budeso- nide/formoterol 160 μg/4.5 μg via a single inhaler two inhala-
nide/formoterol as maintenance and as-needed reliever could tions twice daily plus additional inhalations as needed (SMART)
improve overall asthma control without the need for a sepa- with salmeterol/fluticasone 50 μg/250 μg twice daily plus salbu-
rate reliever. tamol for rescue medication in 2143 patients over 12 months
The 12-month SMILE study compared concomitant use as [40]. With SMART, the time to first severe exacerbation was
needed of 0.4 mg terbutaline, 4.5 μg formoterol, or 160 μg/4.5 prolonged, the total rate of severe exacerbations was 22%
μg budesonide/formoterol in 3394 patients receiving mainte- lower, and the overall exacerbation rate was reduced [40].
nance treatment with budesonide/formoterol 160 μg/4.5 μg Patients in the SMART group used 45% less as-needed medica-
twice daily [32]. Formoterol reliever therapy provided greater tion before dose titration and 35% less at study completion [40].
protection from severe exacerbations than terbutaline; how- COSMOS imitated real-world clinical settings and concluded that
ever, this effect was even more pronounced with SMART (33% budesonide/formoterol as maintenance and as-needed reliever
reduction versus formoterol and 48% versus terbutaline) [32]. delivered in the same inhaler demonstrated improved overall
SMILE demonstrated that both mono-components of budeso- asthma control compared with salmeterol/fluticasone plus SABA
nide/formoterol as needed contribute to the benefits of SMART. [40]. The CHAMPION program of studies compared SMART with
The COMPASS study randomized 3335 patients to budeso- physicians’ free choice in patients that were symptomatic on ICS
nide/formoterol 160 μg/4.5 μg twice daily plus as needed or stable/symptomatic on ICS/LABA. In an analysis of six open-
(SMART), salmeterol/fluticasone 25 μg/125 μg two inhalations label CHAMPION studies in 7855 patients [48], SMART was asso-
twice daily plus terbutaline 0.4 mg as needed, or budesonide/ ciated with reduced exacerbation rates with a lower corticoster-
formoterol 320 μg/9 μg twice daily plus terbutaline as needed oid load [48]. The EURO-SMART study compared two dosing
[33]. SMART prolonged the time to first severe exacerbation and schedules of budesonide/formoterol 160 μg/4.5 μg maintenance
reduced exacerbations by 28% and 39%, respectively, com- and reliever therapy (SMART [one versus two inhalations twice
pared with fixed-dose salmeterol/fluticasone and budesonide/ daily]) in 8424 patients with symptomatic asthma when using an
formoterol [33]. In the 6-month AHEAD study of 2309 patients ICS with or without a LABA [47]. Budesonide/formoterol deliv-
with uncontrolled asthma, despite not meeting the primary end ered by two inhalations twice daily prolonged the time to the
point of prolonging time to severe exacerbation, those rando- first severe exacerbation by 18% but at a higher medication load,
mized to budesonide/formoterol 160 μg/4.5 μg two inhalations and patients with poor lung function benefited most from the
twice daily and as needed (SMART) had a significantly lower higher maintenance dose [47]. The SATURN study of 4581
rate of hospitalizations (31%) and exacerbations (21%) than patients investigated whether any SMART regimens were asso-
those randomized to salmeterol/fluticasone 50 μg/500 μg ciated with an excess use of reliever medication and concluded
twice daily plus terbutaline as needed [34]. Together, that all regimens were associated with low as-needed doses [49].
COMPASS and AHEAD demonstrated better efficacy with bude-
sonide/formoterol maintenance and as-needed reliever than 2.2.4. Further evidence of SMART’s effectiveness
high- and fixed-dose, combined regimens plus SABA. A subanalysis of the AHEAD study in 222 Chinese patients with
The six SMART randomized controlled trials (RCTs) summar- persistent asthma found that SMART decreased severe and
ized above (STEAM, STEP, STAY, SMILE, COMPASS, and AHEAD) mild exacerbations, decreased reliever use, increased symp-
included 1845 adolescents (12–17 years). Subgroup analysis tom-free days, and improved morning/evening PEF compared
demonstrated that in the adolescent subpopulation, SMART with fixed-dose salmeterol/fluticasone [50]. SMART-ASIA was a
was similar to, or more effective than, comparators across all 12-week open-label study of budesonide/formoterol 160 μg/
studies for time to first severe exacerbation, with adolescents 4.5 μg one inhalation twice daily and as needed (SMART) in
having comparable outcomes to adults [35]. 862 patients with partly controlled or uncontrolled asthma
[44]. Patients experienced significant improvements in asthma
control and quality of life with a reduction in as-needed
2.3.3. Real-world evidence of budesonide/formoterol as medication use [44]. The 407 Chinese patients in a subanalysis
maintenance and reliever therapy of the SMART-ASIA study displayed significant improvements
Much of the initial SMART efficacy data were derived from RCTs in asthma control and quality of life with SMART compared
that may not be representative of clinical practice and often with their usual treatment [43].
 EXPERT REVIEW OF RESPIRATORY MEDICINE 7

3. Advantages of SMART best practice [41]. Economic analyses conducted in Italy, the
UK, and Australia have demonstrated significant reductions in
GINA outlines the long-term goals of asthma management as
total costs (direct and indirect) with SMART compared with
achieving good symptom control and maintaining normal
fixed maintenance dosing [57,59]. A Belgian economic analysis
activity levels while minimizing the future risk of exacerba-
demonstrated significantly lower asthma medication costs
tions, fixed airflow limitation, and side effects of treatment [2].
with SMART versus conventional best practice [39]. A subana-
The use of a single inhaler combining rapid-onset LABA (for-
lysis of the COMPASS study [33] examined economic data
moterol) and low-dose ICS (budesonide) as both the controller
from Argentina, Australia, Bulgaria, Czech Republic, Hungary,
and the reliever medication is effective in improving asthma
India, Malaysia, Mexico, the Netherlands, the Philippines,
control [51], and in at-risk patients, it reduces exacerbations
Poland, South Africa, South Korea, Thailand, the UK, and
requiring OCS and hospitalizations [16,18,20].
Vietnam. It calculated that daily use of SMART would have to
increase by 33% and 55% to equal the drug costs of the
3.1. Overall asthma control and control rate comparators, fixed-dose budesonide/formoterol plus as-
needed terbutaline and salmeterol/fluticasone plus as-needed
It is now established that the use of the SMART regimen is terbutaline, respectively [60].
associated with improved asthma control [29,30,41,43,44,47,52–
54]. In a post hoc analysis of five randomized, double-blind,
controlled trials involving 12,512 patients [30–34] retrospectively 3.4. Simplicity and improved treatment adherence
categorized by GINA treatment step at study entry based on
Inhaler mishandling is common and associated with reduced
patient diary cards, the authors concluded that SMART may be
disease control [11,12,61]. GINA recommends reducing the
a preferable option for patients on Steps 2–4 requiring a more
number of inhaler types used to improve adherence and
effective treatment [55]. When compared with other fixed-dose
inhaler technique/handling [2]. Adherence is an issue for all
alternatives, SMART was most effective for patients on the higher
formulations and inhaler types including ICS/LABA [62]; how-
treatment steps [55]. The analysis also showed that current con-
ever, adherence may be improved by the use of combination
trol of asthma predicts the future risk of instability and exacer-
ICS/LABA therapy [63]. Patients with poor adherence to their
bations [51].
usual ICS therapy (<70% of the expected number of prescrip-
tions for ICS collected in the year prior to the study) who
3.2. Safety switched to SMART almost doubled their dose of budesonide
in comparison to patients assigned budesonide plus their
Several studies have demonstrated that SMART reduces the
usual SABA [64]. In a study of patients with a recent exacer-
overall level of ICS used in comparison with budesonide/
bation, those using SMART had significantly fewer nonadher-
formoterol delivered as a fixed dose [54,56,57], higher doses
ent days compared with patients on fixed-dose budesonide/
of budesonide plus SABA [29], and conventional best prac-
formoterol plus salbutamol as needed [20]. Furthermore, a
tice/usual care [38,39,41]. SMART also reduces inhaled and
post hoc analysis demonstrated that SMART is associated
systemic corticosteroid load [58]. Trials comparing SMART
with reduced nonadherence with ICS during severe exacerba-
with fixed-dose budesonide/formoterol with as-needed
tions [65]. A study of Malaysian patients treated with SMART in
SABA demonstrated similar levels of mild-to-moderate
the primary care setting using the self-reported Satisfaction
adverse events (AEs) and AEs related to ICS (oral candidiasis)
with Asthma Treatment Questionnaire (SATQ) and the Asthma
or β2-agonists [29–31,33]. Comparisons of SMART with sal-
Control Test (ACT) demonstrated that a high level of satisfac-
meterol/fluticasone also reported similar levels of AEs
tion was correlated with high levels of asthma control and
[34,40,52] with some evidence of increased levels of discon-
adherence [66].
tinuations due to aggravated asthma [40] and AEs related to
ICS or β2-agonists [34] with salmeterol/fluticasone. Studies of
SMART versus fixed-dose budesonide/formoterol have 4. Future perspectives
shown similar numbers and frequencies of AEs in both
treatment groups [52,54,56]. Continuing experience of 4.1. Use of budesonide/formoterol as needed in mild
SMART in real-world settings shows that the approach asthma
remains well tolerated [43,44]. Low-dose ICS has been shown to be associated with reduced
risk of severe exacerbations in patients with intermittent
symptoms [67]. However, for many such patients, adhering
3.3. Pharmacoeconomics
to regular maintenance treatment can be challenging; patients
Many analyses conducted in different countries and health- often continue to over-rely on SABA, resulting in undertreat-
care systems have demonstrated that SMART is associated ment of the underlying inflammation [68]. As such, calls have
with reduced costs [33,39,41,54,56,57,59,60]. Canadian studies been made to study the benefits of ICS/rapid-β2-agonist com-
of SMART have demonstrated more effective asthma control binations as needed in patients with mild and intermittent
than fixed budesonide/formoterol dosing, resulting in lower symptoms [69]. The SYGMA1 (SYmbicort Given as needed in
total asthma medication costs, direct and total costs [54], Mild Asthma) trial is a randomized, double-blind trial compar-
lower asthma medication cost (by 28%), and lower total cost ing budesonide/formoterol as needed with terbutaline as
per patient per year (by 23%) with SMART versus conventional needed and budesonide twice daily plus terbutaline as
8 J. LIN ET AL.

needed in adult and adolescent patients who would qualify FEV1 and PEF versus placebo, but due to the heterogeneity
for low-dose ICS (or LTRA) [68]. SYGMA1’s primary outcome of trial designs and end points, it was unable to demon-
measure is the number of ‘well-controlled asthma weeks’ strate a clear advantage with respect to exacerbations,
(defined as two or more of the following: no more than efficacy, and safety in comparison with other ICS/LABA
2 days with a daily asthma symptom score >1; no more than combinations [74].
2 days of as-needed medication use, up to a maximum of four
occasions per week; morning PEF ≥80% of predicted normal
4.3. Biologics and targeted therapies
everyday plus no nighttime awakenings due to asthma; and
no additional inhaled and/or systemic glucocorticosteroid Antibodies and small molecules that modulate the immuno-
treatment due to asthma) over the course of a year [68]. The logic responses and inflammatory pathways characteristic of
primary outcome measure of the related SYGMA2 trial is the asthma are promising therapeutic strategies. Currently, in
annual severe asthma exacerbation rate with budesonide/for- patients uncontrolled on Step 4 treatment (ICS/LABA), GINA
moterol as needed versus budesonide twice daily plus terbu- recommends add-on therapy with omalizumab (an anti-immu-
taline as needed in a similar population [68]. In addition, Novel noglobulin E [IgE] antibody) for patients with moderate or
START (Symbicort® Turbuhaler Asthma Reliever Therapy) severe allergic asthma and mepolizumab and reslizumab
study is an ongoing open-label RCT comparing budesonide/ (anti-interleukin [IL]-5 antibodies) in patients ≥12 years old
formoterol as sole reliever therapy with two different com- with severe eosinophilic asthma [2].
parators: salbutamol as needed and budesonide twice daily Several other biologics, targeted and novel therapies are
plus salbutamol as needed [70]. A pragmatic open-label in development as exemplified by the following studies.
design was employed so that the potential real-world advan- Results of the ZONDA, SIROCCO, and CALIMA Phase III trials
tages of using a single inhaler as needed (without a separate of the anti-IL-5 receptor antibody benralizumab have
regular-dose ICS inhaler) could be identified and to ensure recently been published showing significantly lower annual
that the results were generalizable to clinical practice. The exacerbation rates, improved pre-bronchodilator FEV1, and
primary outcome of Novel START is exacerbation rate (worsen- improved total asthma symptom score in patients with per-
ing asthma resulting in urgent medical review, use of systemic sistent eosinophilic asthma [75–77]. The addition of the
corticosteroids for any duration, or high β2-agonist use [>16 investigational anti-IL-4 receptor antibody, dupilumab, in
actuations salbutamol or >8 actuations budesonide/formo- adults with persistent asthma uncontrolled with medium-/
terol within 24 h]), and secondary outcomes include propor- high-dose ICS/LABA was shown to be effective in a recent
tion of patients with ≥1 exacerbation, time to first pivotal Phase IIb trial [78]. Notably, lung function was
exacerbation, rate of and time to first severe exacerbation, improved and the rate of severe exacerbations was reduced
Asthma Control Questionnaire, 5-item version (ACQ-5) scores, irrespective of baseline eosinophil count [78]. Initial placebo-
forced expiratory volume in 1 second (FEV1) predicted, and controlled trials of the anti-IL-13 antibodies lebrikizumab and
patient-reported outcomes [70]. tralokinumab have produced encouraging results, especially
in patients with high baseline levels of periostin (a proposed
biomarker of increased IL-13 activity) [79]. Lebrikizumab and
4.2. Other pharmacological agents
tralokinumab improved FEV1 in patients with uncontrolled
GINA recommends the addition of tiotropium to medium-/ and moderate-to-severe asthma, respectively, with lebrikizu-
high-dose ICS/LABA as an alternative controller option at mab also reducing the rate of severe exacerbations [79].
Step 4 and as a preferred option at Step 5 in patients with More recently, however, Phase III studies with lebrikizumab
a history of exacerbations [2]. Tiotropium, glycopyrronium, failed to show a consistent reduction in exacerbations among
and umeclidinium are long-acting muscarinic antagonists patients with severe, uncontrolled asthma [80]. Antagonism
that act as bronchodilators. Glycopyrronium plus beclo- of the prostaglandin D2 (PGD2) receptor CRTh2 with BI
methasone has been studied in a Phase II trial of patients 671800 and AZD1981 has shown improvements in FEV1 in
uncontrolled on low-/medium-dose ICS/LABA, and results patients with asthma [81,82], with AZD1981 also improving
are due soon [71]. The addition of umeclidinium to fluti- ACQ-5 scores [82]. In a Phase II study of 61 patients with
casone furoate has demonstrated a modest improvement persistent moderate-to-severe asthma and an elevated spu-
of FEV1 in patients with asthma who were symptomatic tum eosinophil count, antagonism of the DP2 receptor with
despite maintenance with ICS [72]. Ultra-LABAs such as the selective oral antagonist fevipiprant (QAW039) signifi-
indacaterol and vilanterol, so-called due to their once- cantly improved Standardized Asthma Quality of Life
daily dosing, are of interest in the treatment of COPD, in Questionnaire (AQLQ[S]) scores, post-bronchodilator FEV1,
which they may be useful in preventing exacerbations [13]. and functional residual capacity compared with placebo
Their use in asthma is also under investigation. However, without a significant effect on blood eosinophil [83]. A 12-
results of a small proof-of-concept Phase IV study of the week, dose-ranging, placebo-controlled study of fevipiprant
effect on exacerbations of indacaterol in combination with also noted improvements in lung function [84]. Initial Phase
tiotropium in patients with persistent asthma receiving ICS IIa study results have shown that SB010, a novel inhaled
did not suggest that concomitant tiotropium modified the GATA3-specific DNAzyme, is able to attenuate both early-
bronchoprotective tolerance induced by indacaterol [73]. A and late-phase asthmatic responses after allergen provoca-
review of 14 studies of vilanterol in combination with tion in patients with mild asthma [85], as can the anti-thymic
fluticasone furoate in asthma demonstrated advantages in stromal lymphopoietin (TSLP) antibody tezepelumab (AMG
 EXPERT REVIEW OF RESPIRATORY MEDICINE 9

157/MEDI9929) [86]. A recently reported Phase II, dose-ran- were common, with 44% of respondents reporting the use of
ging study of tezepelumab noted significant reductions in oral steroids in the previous year. Furthermore, a quarter of
annualized asthma exacerbation rates of 61–71%, along with respondents had visited an emergency department, with 12%
improvements in lung function and other aspects of asthma ultimately having been hospitalized [92]. Nevertheless, over 80%
control [87]. Interestingly, the findings were independent of of respondents (overall and among those with a history of
baseline eosinophil count or other Type 2 biomarkers, high- exacerbations) considered their asthma to be controlled [92].
lighting the potential benefits of targeting an ‘upstream’ Even among respondents who had experienced an exacerbation
cytokine rather than a single downstream pathway. Further requiring oral steroids, three quarters regarded their asthma as
studies are required to confirm the efficacy and safety of not serious [92]. Similar results were obtained in the REALISE Asia
these therapies, but they may play an increasing role in the online survey of 2467 patients with asthma, with over 90% of
treatment of asthma in the future. patients considering their asthma to be under control despite
half having GINA-defined uncontrolled asthma and one-third
being hospitalized for asthma [93]. These findings, together
5. Conclusion with evidence that approximately half of adults and children on
Over the last 20 years, GINA has continuously reviewed the long-term therapy for asthma fail to take medications as directed
increasing body of evidence on asthma management, taking at least part of the time [94], represent a major obstacle to
into account both pharmacological and non-pharmacologi- achieving asthma control and clearly demonstrate a need for
cal interventions. GINA guidelines recommend a stepwise greater patient education on asthma control and management.
approach to the pharmacological treatment of asthma and However, asthma information alone does not improve outcome
have advocated the use of ICS/LABA delivered in a single [95]; further support such as guided self-management is required
inhaler for maintenance and relief in patients at Step 3 and to effect a positive change in outcome [89]. Depending on the
above since 2006 [15]. Flexibly dosed budesonide/formoterol needs of the patient, the degree of independence in a guided
for maintenance and relief (SMART) is associated with reduc- self-management plan can range from patient-directed self-man-
tions in severe exacerbations, prolonging the time to first agement to physician-directed self-management [15]. To be
exacerbation, and provides greater or equal levels of asthma effective, a guided asthma self-management plan must include
control than higher fixed doses of budesonide/formoterol or self-monitoring of symptoms and/or PEF, a written asthma action
ICS plus SABA as needed with lower overall ICS dose and plan that describes how to recognize and respond to worsening
cost. The benefits of the SMART approach rely on adequate asthma, and regular HCP review of asthma control, treatment,
patient education, and collaborative approaches such as and skills [89]. Evidence supports the use of SMART as part of a
guided self-management plans should be employed wher- guided self-management plan [15,96].
ever possible.
6.2. Uptake of the SMART regimen

6. Expert commentary Despite the benefits of the SMART regimen, two studies of
dosing instructions conducted in the UK identified low levels
Effective asthma management relies on a collaborative approach of SMART prescription [97,98]. Rates of SMART prescribing
between HCPs and patients (or parents/carers), taking into may be low due to a lack of familiarity with SMART among
account the patient’s own treatment goals [15]. All patients primary care physicians [98]. Those physicians who are familiar
with asthma should be given a written asthma plan and be with SMART may be explaining the dosing regimen verbally or
closely monitored [15]. Correct inhaler technique is essential for unclearly without formally writing the prescription as SMART
medications to be effective; inhaler skills training, including a dosing [97,98]. There is also evidence of continued concurrent
physical demonstration, should be provided [88]. Patients should prescribing of SABA [97–99].
be encouraged to adhere to controller medication, even when
symptoms are infrequent [15]. Training in asthma self-manage-
ment (self-monitoring of symptoms and/or PEF, written asthma 7. Five-year view
action plan, and regular medical review) improves symptom Asthma is a heterogeneous disease, and the development of
control and can minimize the risk of exacerbations and need novel therapies requires an understanding of pathophysiolo-
for health-care utilization in adults [89] and children [90]. gic phenotypes. Over the next 5 years, we anticipate that
biomarkers will become increasingly important for stratifying
patient subtypes, developing specific therapies, and informing
6.1. Patient education
treatment choices. Large-scale multidisciplinary studies that
The majority of patients fail to self-manage appropriately during collate data on epidemiology, allergen biochemistry, immu-
the ‘window of opportunity’ preceding an exacerbation and in nology, molecular biology, epigenetics, functional genomics,
some cases fail to respond entirely [23]. Therefore, education is bioinformatics, and computational and systems biology will be
vital to ensure that patients do not miss the ‘window’ [91]. necessary to provide a deeper view of asthma. Initiatives such
The REALISE (REcognise Asthma and LInk to Symptoms and as MeDALL (Mechanisms of the Development of ALLergy),
Experience) online survey of 8000 European patients with which aims to profile asthma and correlate clinical features
asthma found low levels of asthma control, with 45% of respon- and biomarkers with molecular characteristics, will provide a
dents reporting uncontrolled asthma [92]. Acute exacerbations wealth of data in the future [100].
10 J. LIN ET AL.

Key issues •• The GINA Science Committee reviews research on asthma

management and prevention and makes evidence-based
● GINA recommends a stepwise approach to the manage- recommendations for patient care in its yearly report.
ment of asthma and has advocated the use of ICS/LABA 3. GINA. 2002 GINA report: global strategy for asthma management
delivered in a single inhaler for maintenance and relief for and prevention. 2002 [cited 2017 Oct 05]. Available from: http://
[Link] upon request
patients at Step 3 and above since 2006. 4. GINA. 2006 GINA report: global strategy for asthma management
● Flexibly dosed budesonide/formoterol for maintenance and and prevention. 2006 [cited 2017 Oct 05]. Available from: http://
relief (SMART) reduces severe exacerbations, prolongs the [Link] upon request
time to first exacerbation, and provides greater or equal 5. Masoli M, Fabian D, Holt S, et al. The global burden of asthma:
levels of asthma control than higher fixed doses of bude- executive summary of the GINA dissemination committee report.
Allergy. 2004;59:469–478.
sonide/formoterol or ICS plus SABA as needed with lower 6. Castle W, Fuller R, Hall J, et al. Serevent nationwide surveillance
overall ICS dose and cost. study: comparison of salmeterol with salbutamol in asthmatic
● Patient education and support via guided management is patients who require regular bronchodilator treatment. BMJ.
required to achieve the full benefit of the SMART approach. 1993;306:1034–1037.
● Add-on therapy with biologics is the recommended treat- 7. Nelson HS, Weiss ST, Bleecker ER, et al. The salmeterol multicenter
asthma research trial: a comparison of usual pharmacotherapy for
ment option for patients not adequately controlled on GINA asthma or usual pharmacotherapy plus salmeterol. Chest.
Step 4 treatment (ICS/LABA). 2006;129:15–26.
● The use of budesonide/formoterol as needed in patients 8. Mann M, Chowdhury B, Sullivan E, et al. Serious asthma exacerbations in
with mild asthma is the focus of ongoing trials (SYGMA1/2, asthmatics treated with high-dose formoterol. Chest. 2003;124:70–74.
Novel START). 9. Reddel HK, Levy ML. The GINA asthma strategy report: what’s new
for primary care? NPJ Prim Care Respir Med. 2015;25:15050.
● In the future, biomarkers will become increasingly impor- 10. Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic
tant for stratifying patient subtypes and informing treat- Society/European Respiratory Society statement: asthma control and
ment choices. exacerbations: standardizing endpoints for clinical asthma trials and
clinical practice. Am J Respir Crit Care Med. 2009;180:59–99.
11. Basheti IA, Qunaibi E, Bosnic-Anticevich SZ, et al. User error with
Diskus and Turbuhaler by asthma patients and pharmacists in
Acknowledgments Jordan and Australia. Respir Care. 2011;56:1916–1923.
12. Melani AS, Bonavia M, Cilenti V, et al. Inhaler mishandling remains
We would like to acknowledge Dr Tom Priddle and Victoria Fasolino of
common in real life and is associated with reduced disease control.
Nucleus Global for medical writing support and editorial assistance.
Respir Med. 2011;105:930–938.
13. GOLD. Global strategy for the diagnosis, management, and preven-
tion of chronic obstructive pulmonary disease report. 2017 [cited
Funding 2017 Oct 05]. Available from: [Link]
14. Reddel HK, Busse WW, Pedersen S, et al. Should recommendations
This manuscript has received medical writing assistance funded by about starting inhaled corticosteroid treatment for mild asthma be
AstraZeneca China. based on symptom frequency: a post-hoc efficacy analysis of the
START study. Lancet. 2017;389:157–166.
15. GINA. 2016 GINA report: global strategy for asthma management
and prevention. 2016 [cited 2017 Oct 05]. Available from: http://
Declaration of interest [Link] upon request
C Liu reports receiving personal fees from AstraZeneca, Boehringer Ingelheim, 16. Kew KM, Karner C, Mindus SM, et al. Combination formoterol and
and GlaxoSmithKline. The authors have no other relevant affiliations or financial budesonide as maintenance and reliever therapy versus combina-
involvement with any organization or entity with a financial interest in or tion inhaler maintenance for chronic asthma in adults and children.
financial conflict with the subject matter or materials discussed in the manu- Cochrane Database Syst Rev. 2013;12:CD009019.
script apart from those disclosed. Peer reviewers on this manuscript have no 17. Barnes PJ. Scientific rationale for using a single inhaler for asthma
relevant financial or other relationships to disclose. control. Eur Respir J. 2007;29:587–595.
18. Cates CJ, Karner C. Combination formoterol and budesonide as main-
tenance and reliever therapy versus current best practice (including
ORCID inhaled steroid maintenance), for chronic asthma in adults and chil-
dren. Cochrane Database Syst Rev. 2013;4:CD007313.
Jiangtao Lin [Link] 19. Papi A, Corradi M, Pigeon-Francisco C, et al. Beclometasone-formo-
terol as maintenance and reliever treatment in patients with
asthma: a double-blind, randomised controlled trial. Lancet Respir
Med. 2013;1:23–31.
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