Elsevier

The Lancet

Volume 389, Issue 10065, 14–20 January 2017, Pages 157-166
The Lancet

Articles
Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study

https://doi.org/10.1016/S0140-6736(16)31399-XGet rights and content

Summary

Background

Low-dose inhaled corticosteroids (ICS) are highly effective for reducing asthma exacerbations and mortality. Conventionally, ICS treatment is recommended for patients with symptoms on more than 2 days per week, but this criterion has scant evidence. We aimed to assess the validity of the previous symptom-based cutoff for starting ICS by establishing whether there was a differential response to budesonide versus placebo for severe asthma exacerbations, lung function, and asthma symptom control across subgroups identified by baseline asthma symptom frequency.

Methods

We did a post-hoc analysis of the 3 year inhaled Steroid Treatment As Regular Therapy (START) study, done in 32 countries, with clinic visits every 3 months. Patients (aged 4–66 years) with mild asthma diagnosed within the previous 2 years and no previous regular corticosteroids were randomised to receive once daily, inhaled budesonide 400 μg (those aged <11 years 200 μg) or placebo. Coprimary outcomes for this analysis were time to first severe asthma-related event (SARE; hospital admission, emergency treatment, or death) and change from baseline in lung function after bronchodilator. Interaction with baseline symptom frequency was investigated, with patients grouped by more than two symptom days per week and two or fewer symptom days per week (divided into no days to 1 day, and more than 1 day to 2 days). Analysis was done by intention to treat.

Findings

Of 7138 patients (n=3577 budesonide; n=3561 placebo), baseline symptom frequency was 0–1 days per week for 2184 (31%) participants, more than 1 and less than or equal to 2 symptom days per week for 1914 (27%) participants, and more than 2 symptom days per week for 3040 (43%) participants. For budesonide versus placebo, time to first SARE was longer across symptom frequency subgroups (hazard ratios 0·54 [95% CI 0·34–0·86] for 0–1 symptom days per week, 0·60 [0·39–0·93] for >1 to ≤2 symptom days per week, 0·57 [0·41–0·79] >2 symptom days per week, pinteraction=0·94), and the decline in postbronchodilator lung function was less at 3 years' follow-up (pinteraction=0·32). For budesonide versus placebo, severe exacerbations requiring oral or systemic corticosteroids were reduced (rate ratio 0·48 [0·38–0·61] 0–1 symptom days per week, 0·56 [0·44–0·71] >1 to ≤2 symptom days per week, and 0·66 [0·55–0·80] >2 symptom days per week, pinteraction=0·11), prebronchodilator lung function was higher, and symptom-free days were more frequent (p<0·0001 for all three subgroups), with no interaction by symptom frequency (prebronchodilator pinteraction=0·43; symptom-free days pinteraction=0·53). Similar results were noted when participants were classified by any guidelines criterion as so-called persistent versus so-called intermittent asthma.

Interpretation

In mild recent-onset asthma, once daily, low-dose budesonide decreases SARE risk, reduces lung function decline, and improves symptom control similarly across all symptom subgroups. The results do not support restriction of inhaled corticosteroids to patients with symptoms on more than 2 days per week and suggest that treatment recommendations for mild asthma should consider both risk reduction and symptoms.

Funding

AstraZeneca.

Introduction

Chronic airway inflammation is a characteristic feature of asthma, even in patients with infrequent symptoms.1, 2 Inhaled corticosteroids (ICS) have been the mainstay of asthma treatment for many years, with their efficacy and effectiveness confirmed by meta-analyses of high-quality, randomised, placebo-controlled studies3 and population-based analyses of large, linked datasets.4, 5 These studies show that ICS treatment leads to improvement in the two key domains of asthma control;6 the first being improved symptom control, indicated by reduced asthma symptom frequency, waking in the night, need for short-acting β2-agonist (SABA), and activity limitation, and the second being reduced risk of adverse asthma outcomes such as exacerbations, hospital admissions, accelerated decrease in lung function, and death. Most of these benefits are noted at low doses, with a low risk of side-effects.4, 5, 7

For the past 25 years, asthma guidelines have distinguished between so-called persistent and intermittent asthma, with intermittent asthma generally identified by symptom frequency of 2 days or fewer per week.8, 9, 10, 11 For such patients, guidelines have consistently recommended treatment with only as-needed SABA (called Step 1), with regular maintenance ICS treatment (Step 2) reserved for patients with more frequent symptoms.

Research in context

Evidence before this study

For the past 25 years, most asthma guidelines have consistently recommended treatment according to level of baseline symptom frequency; patients with intermittent symptoms, mostly classified as 2 days or fewer per week, are generally prescribed short-acting β2 agonist (SABA) reliever, while only patients with so-called persistent asthma are eligible for inhaled corticosteroids (ICS) therapy. We did a systematic review to identify studies comparing ICS and placebo in patients with mild intermittent asthma, identified by baseline symptoms or SABA use ≤2 days per week. We searched PubMed using the following string: “((Asthma[MeSH Terms]) AND (mild[Title/Abstract] OR intermittent[Title/Abstract]) AND placebo[Title/Abstract]) AND (randomized controlled trial[Publication Type] OR meta-analysis[Publication Type]) AND (*corticosteroid OR corticosteroid* OR budesonide OR fluticasone OR beclometasone OR beclomethasone OR mometasone OR ciclesonide) AND ((‘1990/01/01’[EDAT] : ‘2015/04/20’[EDAT]) OR (‘1990/01/01’[PDAT]: ‘2015/04/20’[PDAT])) AND (‘humans’[MeSH Terms])”. We also searched the most recent Cochrane reviews of each of the above ICS.

A total of six studies comparing ICS and placebo in people with mild asthma remained for evaluation. Only two very small studies restricted enrolment to people with symptoms less than or equal to 2 days per week. None of the other studies included in this literature review assessed treatment efficacy according to the level of baseline symptoms, so it is unclear whether patients with less frequent asthma symptoms at baseline benefit from ICS treatment, or whether there is evidence to support the present symptom-based criteria for initiating ICS. In the present study, we seek to assess these issues.

Added value of this study

To our knowledge, this study is the first to assess the appropriateness of long-standing criteria for initiation of ICS treatment in mild asthma. In this post-hoc investigation of a large pragmatic study of patients with recently diagnosed asthma (within the previous 2 years), we compared the efficacy of low-dose budesonide versus placebo on asthma outcomes, dividing participants by baseline asthma symptom frequency (0–1 symptom days per week, >1 to ≤2 symptom days per week, and >2 symptom days per week). We found that the use of once-daily, low-dose budesonide increases time to first severe asthma-related events (emergency visits, hospital admission, or death), halves the risk of severe exacerbations, reduces lung function decline, and improves asthma symptoms compared with placebo, irrespective of baseline symptom frequency (or any other criterion for so-called persistent asthma). We thus found no evidence to support the past recommendation that patients with asthma should be treated with SABA alone unless their symptoms exceed 2 days per week at presentation.

Implications of all the available evidence

Low-dose ICS leads to substantial risk reduction in mild asthma, both for exacerbations and for decline in lung function, in patients with infrequent baseline symptoms who would not previously have been considered for ICS treatment. The findings challenge long-standing assumptions about the risks of so-called mild asthma, and suggest that decisions about ICS treatment in such patients should be made on the basis of population risk reduction, rather than only on symptom frequency. However, regular daily ICS treatment might not necessarily be appealing to clinicians and patients, because of concerns about adherence and side-effects. Alternative treatment options with an as-needed combination of ICS and β2 agonist might be more acceptable to clinicians and patients, and are being investigated.

However, during preparation of a major revision of the Global Strategy for Asthma Management and Prevention, published by the Global Initiative for Asthma in 2014,12 no evidence was found to support this symptom-based cutoff for initiation of ICS, nor for the long-term safety of treating asthma with SABA alone. In a search for relevant evidence, it was noted that in the inhaled Steroid Treatment As Regular Therapy in early asthma (START) study,13 almost 45% of participants had asthma symptoms on 0–3 days in the 2 weeks before randomisation (≤1·5 days per week), which would not have qualified for ICS treatment by conventional criteria. The study funder (AstraZeneca) was approached by HKR with a proposal for a post-hoc analysis of the START dataset by baseline symptom frequency. We aimed to assess the validity of the previous symptom-based cutoff for starting ICS by establishing whether there was a differential response to budesonide versus placebo for severe asthma exacerbations, lung function, and asthma symptom control across subgroups identified by baseline asthma symptom frequency.

Section snippets

Study design

The methods and outcomes from the START study have been reported previously.13, 14, 15 In brief, the 3-year multinational, randomised, double-blind placebo-controlled study investigated whether treatment with low-dose budesonide in patients with mild asthma diagnosed within the previous 2 years would prevent severe asthma-related events (SAREs) and accelerated reduction in lung function. The study, done in 32 countries, was pragmatic in design, with brief clinic visits every 3 months no daily

Results

Data were available from 7138 participants for this analysis (n=3577 budesonide, n=3561 placebo) as baseline symptoms were missing for 27 patients from the original START cohort (n=20 budesonide, n=7 placebo). Baseline and demographic characteristics are shown in table 1; there were no clinically important differences between randomisation groups. Mean age was 24 (SD 15) years, and 3859 (54%) of 7138 participants were female. At baseline, asthma symptom frequency was 0–1 symptom days per week

Discussion

This post-hoc analysis of the START study showed that, in patients with mild, recently diagnosed asthma, low-dose budesonide halved the long-term risk of serious asthma-related events, reduced the decline in lung function, and improved day-to-day symptom control compared with placebo, even in participants with infrequent baseline symptoms. These findings challenge long-standing recommendations that asthma should be treated with SABA alone if the patient has symptoms on 2 or fewer days per week

Conclusions

This study found that long-term, once-daily, low-dose budesonide treatment reduces the risk of severe asthma exacerbations by half, reduces long-term decline in lung function, and improves asthma symptoms in patients with mild, recent-onset asthma. These beneficial effects were seen even in patients with infrequent baseline symptoms, who would not previously have been considered for ICS treatment. The findings also challenge long-standing assumptions about the risks of mild asthma, and suggest

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