Background
Two pivotal long-term goals of asthma management are symptom control and risk reduction [
1]. Evaluation of symptom control constitutes the basis of treatment decisions in a continuous asthma management cycle composed of assessment, treatment adjustment, and response review recommended by the Global Initiative for Asthma (GINA) [
1,
2]. Criteria used to assess current clinical control have evolved from a combination of symptoms and lung function (peak expiratory flow [PEF] or forced expiratory volume in 1 s [FEV
1]) endorsed by GINA 2012 [
1] to symptoms alone in GINA 2014 [
3] and subsequent GINA updates [
2]. The removal of lung function from assessment of asthma control is based on the rationale that although still important in predicting risk of exacerbations [
4,
5], lung function testing results, i.e. spirometry, sometimes provide equivocal or even little utility for determining the level of clinical control [
6,
7]. Valid tools that can be used to assess symptom control include simple screening tools (e.g. the 4-item questionnaires endorsed by GINA) [
1], categorical symptom control tools (e.g. Royal College of Physicians Three Questions’ Tool) [
8], and numerical tools (e.g. Asthma Control Questionnaire [ACQ]) [
9].
Inhaled corticosteroids (ICS) with or without long-acting β
2 agonist (LABA) has been recommended by GINA as the mainstay initial controller treatment, and leukotriene receptor antagonist (LTRA) may be considered as an alternative option or add-on medication at step 2 to 4 [
2]. LTRA belongs to anti-leukotrienes and renders anti-inflammatory as well as bronchodilating effects via inhibiting leukotriene receptor or altering leukotriene production. The oral route of administration gives this class of medications an advantage, and they may bring particular benefits for patients with asthma and allergic rhinitis in terms of relieving symptoms and preventing exacerbations [
10]. However, the efficacy of LTRA for asthma control remains controversial, with most evidence so far favouring ICS over LTRA as the preferred maintenance therapy for asthma [
11]. In China, a survey involving two provinces showed that LTRA was frequently prescribed in combination with ICS/LABA for patients with severe asthma (87.5% [49/56]) [
12].
The INITIAL study (NCT02143739) was a 12-week, multicentre, prospective, observational study of patients with asthma comprising 45 centres across Northern and Southern China [
13]. The study aimed to assess asthma severity among newly diagnosed patients as well as their prescribed medications and response to treatment. In the primary analysis of INITIAL data, we observed a high rate of LTRA prescription at baseline (62.1% [2788/4491]), especially in patients with severe asthma (ICS/LABA plus LTRA, 67.4% [1654/2455]; LTRA without ICS/LABA, 35.5% [118/332]) [
13]. The current analysis was conducted to further investigate the medications and medication combinations prescribed at baseline during the INITIAL study, with a focus on ICS/LABA and ICS/LABA plus LTRA, and to determine the impact of the change in asthma control criteria between the Global Initiative for Asthma (GINA) 2012 [
1] and 2018 guidelines [
2].
Methods
This was a post hoc analysis of a 12-week, multicentre, prospective, observational study performed in patients with asthma from 45 centres across Northern and Southern China between June 2014 and September 2016 (INITIAL, NCT02143739). The protocol, full details of the study population and overall results have previously been reported [
13]. Methods specific to this post hoc analysis are briefly described below.
Patients
Eligible patients were aged ≥18 years, had newly diagnosed asthma without exacerbations within 2 weeks and had not used ICS in the 3 months prior to enrolment. Diagnosis of asthma was made based on lung function test (performed for all patients, airflow limitation, reversibility, and variability based on FEV1 or PEF help confirm the diagnosis), the gold standard for asthma diagnosis, and based on symptoms typical of asthma (i.e. recurrent breathlessness, wheezing, cough, and chest tightness, often triggered by allergens, cold, physical or chemical irritations, viral infection, or exercise; wheezing sound and prolonged respiratory phases during flare-ups; alleviation of symptoms spontaneously or upon treatment; exclusion of other possible diseases that have similar symptoms), in accord with criteria recommended by Chinese guidelines for the prevention and management of bronchial asthma (2008, [
14]). Key exclusion criteria were being diagnosed with COPD and having asthma exacerbations within 2 weeks of study inclusion.
Medications
Any medications were prescribed as per routine clinical practice at baseline, Week 4, and Week 8 (with no additional monitoring or diagnostic procedures); treatment decisions were not part of the INITIAL study.
Asthma severity and control
At baseline, patients were screened, and GINA-defined asthma severity [
15] and control were assessed [
1,
2]. Patient-reported outcomes were assessed using the Asthma Control Questionnaire (5-item version; ACQ-5) [
16]. GINA asthma control status and ACQ-5 were assessed at Weeks 4, 8 and 12.
Objectives of this post hoc study
The objectives of the post hoc analysis were to reveal medications prescribed at baseline for asthma, to assess asthma control levels at Week 12 based on GINA 2012 vs GINA 2018 criteria, and to investigate the impact of medications on asthma control.
Statistical analysis
Descriptive statistics were used in this post hoc analysis. Qualitative variables were described by absolute counts and percentages. No inferential statistics were used.
Discussion
Both GINA 2012 criteria, in use at the time of the INITIAL study, and the GINA guidelines in place at the time of this analysis (2018) recommend low and medium−/high-dose ICS/LABA as the preferred option for patients at Step 3 and Step 4 [
1,
2]. The addition of a third controller (LTRA or theophylline) is an option for patients who are not adequately controlled with a medium-dose ICS/LABA after a trial of 2–3 months for patients at Step 4 [
1,
2]. Among ICS/LABA medications, budesonide/formoterol is recommended by GINA 2019 as the preferred formulation of ICS-formoterol at step 1 and 2 based on the evidence of efficacy, and it was also the predominant form used in our population at baseline (88.9%, 3602/4051) [
13], probably because of their availability in one inhaler (e.g. Symbicort) and easy inhaler techniques. Despite these recommendations, ICS/LABA+LTRA (plus others) was the most commonly prescribed initial therapy in 40.8% (1833/4491) of patients, and only 23.5% (1054/4491) of patients were prescribed ICS/LABA only at baseline. Furthermore, there was no numeric difference in the number of patients achieving asthma control at Week 12, irrespective of whether they had been prescribed ICS/LABA and ICS/LABA+LTRA at baseline and regardless of their initial severity level. This suggests that LTRA may have been prescribed unnecessarily in some patients in the INITIAL study. The number of medications prescribed and the cost and complexity of a treatment regimen may also have a negative impact on adherence [
2,
17]. As medication costs form the largest component of direct medical expenditures in asthma [
18], additional medications place further economic burden on patients and healthcare systems. Studies have shown that patients who adhere to their treatment regimen have better control of their asthma [
19].
Despite the lack of clinical benefits with LTRA observed among asthmatic patients in general, it may be a preferred choice for the subset of asthma patients with concomitant allergic rhinitis. Leukotriene plays a critical role in nasal vascular permeability, mucus production, and hypersecretion upon allergen provocation in allergic rhinitis [
20,
21]. By inhibiting the pathogenic process, LTRA is a promising class of medication that can relieve symptoms of rhinitis. Improvement of rhinitis symptoms by LTRA has been demonstrated by a multicentre, placebo-controlled study in patients with symptomatic allergic rhinitis and active asthma (difference between montelukast and placebo in mean change in Daily Rhinitis Symptoms score from baseline, − 0.12 [95% CI, − 0.18 to − 0.06;
p < or = 0.001]) [
10]. The efficacy and benefits of LTRA in allergic rhinitis was also supported by results of a meta-analysis study, in which LTRA reduced mean daily rhinitis symptom scores (by 5% [95% CI, 3–7%]) and improved rhinoconjunctivitis quality of life (by 0.3 [95% CI, 0.24–0.36]) [
22]. LTRA (HDM SLIT in particular) has been recommended by GINA 2019 as an add-on medication for patients with allergic rhinitis and FEV
1 > 70% at step 3 and 4 [
23]. However, in the INITIAL study, patients with an allergic history only comprised 22.1% of the patient population [
13]. Although these patients might derive benefits from LTRA, the majority of asthmatic patients without allergic rhinitis (77.9%) still required more effective medications, such as ICS plus LABA, for symptom control and exacerbation prevention [
2].
Collection of lung function data was at the discretion of the investigator because lung function testing is not a mandatory requirement of the Chinese Thoracic Society Guidelines 2008 [
14]. Therefore, lung function data were not collected for 2942, 2947 and 964 patients at Weeks 4, 8 and 12, respectively, and so GINA 2012 control level could not be determined in these patients. As a result, patient numbers for the comparison of ICS/LABA+LTRA versus ICS/LABA at Week 12 were low, representing only one third (1484) of the FAS. In 2014, GINA criteria underwent a major revision that changed the determination of symptom control by removing lung function testing from the assessment criteria [
3]; these criteria have remained unchanged in subsequent reports including the 2018 version [
2]. Lung function is now considered, along with exacerbations, as a risk factor for poor asthma outcome [
3].
Juniper et al. originally developed the ACQ as a seven-item measure that included forced expiratory volume in 1 s (FEV
1) [
9]. In their 2006 paper, they suggest that while the cut-off point between ‘well-controlled’ and ‘not well-controlled’ asthma is close to 1.00, to be confident that patients are categorised correctly in clinical practice, the optimal cut-offs for well-controlled asthma and inadequately controlled asthma should be 0.75 and 1.50, respectively [
24]. GINA 2006-defined asthma control (that includes lung function) has been shown to have reasonable agreement with the ACQ-5 (that does not include lung function) cut-off points [
25]. GINA 2006 controlled, partly controlled and uncontrolled patients had mean ACQ-5 scores of 0.43, 0.75 and 1.62, respectively [
25]. Another study of the ACQ by Sastre et al. suggested that the cut-off differs depending on whether lung function is included (ACQ without lung function, equivalent to ACQ-5: 0.83) and depending on which test is used (ACQ with FEV
1, equivalent to ACQ-7: 1.14; ACQ with peak expiratory flow [PEF]: 1.28) [
26]. However, a more recent study suggested that the cut-off for uncontrolled asthma was 1.00, despite suggesting a similar cut-off for controlled asthma of 0.50 for both the ACQ-5 (that does not include lung function) and the ACQ-7 (that includes lung function) [
27]. In keeping with these findings, the results of the present post hoc analysis suggest that, in this data set, the removal of lung function test results from the GINA 2014 and later criteria reduces the number of patients considered to have uncontrolled asthma and increases the number considered to have controlled asthma. When baseline severity was taken into account, this difference appeared to be driven by patients with moderate and severe asthma. However, control levels did not differ a great deal between the two classifications, supporting the view that lung function does not correlate strongly with asthma symptoms [
28,
29].
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