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Clinician Article

Stopping long-acting beta2-agonists (LABA) for adults with asthma well controlled by LABA and inhaled corticosteroids.



  • Ahmad S
  • Kew KM
  • Normansell R
Cochrane Database Syst Rev. 2015 Jun 19;(6):CD011306. doi: 10.1002/14651858.CD011306.pub2. (Review)
PMID: 26089258
Read abstract Read evidence summary
Disciplines
  • Allergy and Immunology
    Relevance - 6/7
    Newsworthiness - 5/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 5/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 5/7
  • Respirology/Pulmonology
    Relevance - 6/7
    Newsworthiness - 4/7
  • Hospital Doctor/Hospitalists
    Relevance - 5/7
    Newsworthiness - 4/7
  • Internal Medicine
    Relevance - 5/7
    Newsworthiness - 4/7
  • Emergency Medicine
    Relevance - 4/7
    Newsworthiness - 4/7

Abstract

BACKGROUND: Poorly controlled asthma often leads to preventable exacerbations that require additional medications, as well as unscheduled hospital and clinic visits.Long-acting beta2-agonists (LABA) are commonly given to adults with asthma whose symptoms are not well controlled by inhaled corticosteroids (ICS). US and UK regulators have issued warnings for LABA in asthma, and now recommend they be used "for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved".

OBJECTIVES: To compare cessation of long-acting beta2-agonists (LABA) versus continued use of LABA/inhaled corticosteroids (LABA/ICS) for adults whose asthma is well controlled, and to determine whether stopping LABA:1. results in loss of asthma control or deterioration in quality of life;2. increases the likelihood of asthma attacks or 'exacerbations'; or3. increases or decreases the likelihood of serious adverse events of any cause.

SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register (CAGR), www.ClinicalTrials.gov, www.who.int/ictrp/en/, reference lists of primary studies and existing reviews and manufacturers' trial registries (GlaxoSmithKline (GSK) and AstraZeneca). We searched all databases from their inception to April 2015, and we imposed no restriction on language of publication.

SELECTION CRITERIA: We looked for parallel randomised controlled trials (RCTs) of at least eight weeks' duration, in which adults whose asthma was well controlled by any dose of ICS+LABA combination therapy were randomly assigned to (1) step-down therapy to ICS alone versus (2) continuation of ICS and LABA.

DATA COLLECTION AND ANALYSIS: Two review authors independently screened all records identified by the search strategy. We used an Excel extraction tool to manage searches, document reasons for inclusion and exclusion and extract descriptive and numerical data from trials meeting inclusion criteria.Prespecified primary outcomes were (1) exacerbations requiring oral steroids, (2) asthma control and (3) all-cause serious adverse events.

MAIN RESULTS: Six randomised, double-blind studies between 12 and 24 weeks' long met the inclusion criteria. Five studies contributed data to the meta-analysis, assigning 2781 people with stable asthma to the comparison of interest. The definition of stable asthma and inclusion criteria varied across studies, and Global Initiative for Asthma (GINA) criteria were not used. Risk of bias across studies was generally low, and most evidence was rated as moderate quality.Stopping LABA might increase the number of people having exacerbations and requiring oral corticosteroids (odds ratio (OR) 1.74, 95% confidence interval (CI) 0.83 to 3.65; participants = 1257; studies = 4), although the confidence intervals did not exclude the possibility that stopping LABA was beneficial; over 17 weeks, 19 people per 1000 who continued their LABA had an exacerbation, compared with 32 per 1000 when LABA were stopped (13 more per 1000, 95% CI 3 fewer to 46 more).People who stopped LABA had worse scores on the Asthma Control Questionnaire (mean difference (MD) 0.24, 95% CI 0.13 to 0.35; participants = 645; studies = 3) and on measures of asthma-related quality of life (standardised mean difference (SMD) 0.36, 95% CI 0.15 to 0.57; participants = 359; studies = 2) than those who continued LABA, but the effects were not clinically relevant.Too few events occurred for investigators to tell whether stopping LABA has a greater effect on serious adverse events compared with continuing LABA+ICS (OR 0.82, 95% CI 0.28 to 2.42; participants = 1342; studies = 5), and no study reported exacerbations requiring an emergency department visit or hospitalisation as a separate outcome. Stopping LABA may result in fewer adverse events of any kind compared with continuing, although the effect was not statistically significant (OR 0.83, 95% CI 0.66 to 1.05; participants = 1339; studies = 5), and stopping LABA made people more likely to withdraw from participation in research studies (OR 1.95, 95% CI 1.47 to 2.58; participants = 1352; studies = 5).

AUTHORS' CONCLUSIONS: This review suggests that stopping LABA in adults who have stable asthma while they are taking a combination of LABA and ICS inhalers may increase the likelihood of asthma exacerbations that require treatment with oral corticosteroids, but this is not certain. Stopping LABA may slightly reduce asthma control and quality of life, but evidence was insufficient to show whether this had an effect on important outcomes such as serious adverse events and exacerbations requiring hospital admission, and longer trials are warranted. Trialists should include patient-important outcomes such as asthma control and quality of life and should use validated measurement tools. Definitions of exacerbations should be provided.


Clinical Comments

Allergy and Immunology

Many practitioners have noted that switching from combination LABA/ICS to ICS increases number of exacerbations, so this review adds little.

Allergy and Immunology

The results are similar to the clinical practice experience. The combined drugs offer better asthma control and no noticeable increase in adverse reactions. I and others remain unclear regarding the agencies' advisory.

General Internal Medicine-Primary Care(US)

A Cochrane review that indicates there may be a problem stopping an LABA in asthma, but more data are needed. I don`t believe this is news.

Hospital Doctor/Hospitalists

Overall the results are not conclusive, limiting their utility and application to clinical cases.

Internal Medicine

Although this review does not give definitive answers about stopping LABA, it is useful information to have.

Respirology/Pulmonology

Stopping LABA needs close monitoring.

Respirology/Pulmonology

This is a clinically relevant and important topic. However, the newsworthiness of the review is limited due to the extremely equivocal nature of the findings. The first line in the conclusion states that, "The review SUGGESTS that stopping...MAY increase....but this is NOT CERTAIN." (wow - not even certain about a suggestion that there may be something). The second sentence in the conclusion also does not go far (e.g., "may slightly", "evidence was insufficient"). This is not a fault with the Cochrane Review. Rather, it reflects the inadequacy of the available evidence to inform clinical practice on this topic. The value of this Cochrane Review is not that it provides much helpful information for the clinician, but that it identifies a gap in knowledge and a need for future clinical trials.

Respirology/Pulmonology

Cochrane meta-analysis of whether asthma patients stable on LABA/ICS deteriorate if LABA is withdrawn. The finding is that the evidence is still inconclusive. Important clinical question but the answer is still not clear.

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