Skip to main content

Main menu

  • Home
  • Articles
    • Current
    • Published Ahead of Print
    • Archive
    • Supplemental Issues
    • Collections - French
    • Collections - English
  • Info for
    • Authors & Reviewers
    • Submit a Manuscript
    • Advertisers
    • Careers & Locums
    • Subscribers
    • Permissions
  • About CFP
    • About CFP
    • About the CFPC
    • Editorial Advisory Board
    • Terms of Use
    • Contact Us
  • Feedback
    • Feedback
    • Rapid Responses
    • Most Read
    • Most Cited
    • Email Alerts
  • Blogs
    • Latest Blogs
    • Blog Guidelines
    • Directives pour les blogues
  • Mainpro+ Credits
    • About Mainpro+
    • Member Login
    • Instructions
  • Other Publications
    • http://www.cfpc.ca/Canadianfamilyphysician/
    • https://www.cfpc.ca/Login/
    • Careers and Locums

User menu

  • My alerts

Search

  • Advanced search
The College of Family Physicians of Canada
  • Other Publications
    • http://www.cfpc.ca/Canadianfamilyphysician/
    • https://www.cfpc.ca/Login/
    • Careers and Locums
  • My alerts
The College of Family Physicians of Canada

Advanced Search

  • Home
  • Articles
    • Current
    • Published Ahead of Print
    • Archive
    • Supplemental Issues
    • Collections - French
    • Collections - English
  • Info for
    • Authors & Reviewers
    • Submit a Manuscript
    • Advertisers
    • Careers & Locums
    • Subscribers
    • Permissions
  • About CFP
    • About CFP
    • About the CFPC
    • Editorial Advisory Board
    • Terms of Use
    • Contact Us
  • Feedback
    • Feedback
    • Rapid Responses
    • Most Read
    • Most Cited
    • Email Alerts
  • Blogs
    • Latest Blogs
    • Blog Guidelines
    • Directives pour les blogues
  • Mainpro+ Credits
    • About Mainpro+
    • Member Login
    • Instructions
  • RSS feeds
  • Follow cfp Template on Twitter
  • LinkedIn
  • Instagram
Article CommentaryCommentary

Safety of long-acting β2-agonists in the management of asthma

A Primary Care Respiratory Alliance of Canada perspective

Anthony D. D’Urzo, Pieter Jugovic, Jacques Bouchard, Reuven Jhirad and Itamar Tamari
Canadian Family Physician February 2010; 56 (2) 119-120;
Anthony D. D’Urzo
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: tonydurzo@sympatico.ca
Pieter Jugovic
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jacques Bouchard
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Reuven Jhirad
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Itamar Tamari
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • eLetters
  • Info & Metrics
  • PDF
Loading

The controversy around the safety of long-acting β2-agonists (LABAs) was revisited by the US Food and Drug Administration (FDA) at a meeting held on December 11, 2008.1 Long-acting β2-agonists have a duration of action of approximately 12 hours, considerably longer than short-acting β2-agonists like salbutamol and terbutaline, which have a duration of action of about 4 hours. In Canada, the LABAs available include salmeterol, formoterol fumarate, and formoterol fumarate dihydrate. At the FDA meeting, a US advisory panel ruled that the 2 available LABA and inhaled corticosteroid (ICS) combination therapies (ie, fluticasone propionate plus salmeterol and budesonide plus formoterol fumarate dihydrate) were safe enough for treating asthma; but asthma-related deaths and serious complications led the expert panel to warn against continued use of salmeterol and formoterol fumarate as monotherapy for adults, adolescents, and children with asthma.

Both LABAs as monotherapy and LABAs in combination with ICSs have been linked by the FDA to adverse outcomes. Recent reviews2–6 on the safety of LABAs in asthma management continue to raise important questions among caregivers. The ongoing debate might confuse some clinicians and patients and interfere with the medical management of this very common respiratory condition. As the use of LABA monotherapy is not contraindicated in patients with chronic obstructive pulmonary disease, distinguishing between asthma and chronic obstructive pulmonary disease represents an important undertaking for family physicians.

Combination therapy

While the number of asthma deaths suspected of being related to LABA use is small, one hopes that a better understanding of LABA use will serve to improve overall asthma control. The possibility that LABAs might have harmful effects in patients with asthma has been suggested by 2 large clinical trials7,8 and a recent meta-analysis,9 which was heavily influenced by a single trial.8 What is important for family physicians to consider is that the trials reporting increased mortality and hospitalization with the use of LABAs included an alarming number of patients who were not taking ICSs. In a large Canadian study,10 salmeterol did not increase serious exacerbations compared with placebo among patients with asthma using ICSs regularly. Although LABAs are extremely effective in improving symptoms and lung function, they do not appear to exert any meaningful clinically relevant anti-inflammatory effects. There are no recently published guidelines that recommend LABA use without concomitant ICS use.11,12 It is very important to emphasize that routine use of LABA monotherapy in asthma should not be considered. Long-acting β2-agonists should preferably be prescribed as LABA-ICS combination inhalers.

To date there are no studies large enough to definitively exclude an increased mortality risk with LABA use in individuals with asthma, even in those patients using ICSs. Therefore, family physicians must consider this potential risk at the population level when developing individual treatment strategies. As LABA use against a background of an inadequate ICS dose might seriously compromise asthma control and lead to death in some patients,8 an important task for family physicians involves selection of appropriate ICS therapy before the addition of LABA therapy—recognizing that in the long-term, airway inflammation might vary and prompt a change in ICS dose in some individuals.

The theoretical possibility that airway inflammation can be masked does exist, and physicians should be aware of these implications.13 A family physician confronted with a patient using only LABA therapy for asthma control should advise the patient of the potential life-threatening risks of this approach. The physician should discontinue the LABA and initiate a course of ICS therapy if asthma control appears suboptimal, including the use of a short-acting β2-agonist for rescue therapy; formoterol has the additional benefit of rapid onset of action as well as being long-acting, which is not the case for salmeterol.14 The addition of LABAs should be as combination inhalers, containing both LABAs and ICSs.6 If the LABA-ICS combination does not result in acceptable asthma control despite adequate inhaler technique and environmental control strategies, a referral for specialty care should be considered.15

Two large, long-term landmark trials, FACET16 (Formoterol and Corticosteroids Establishing Therapy) and GOAL17 (Gaining Optimal Asthma Control), have provided evidence that fixed-dose LABA-ICS combination therapy greatly reduces the future risk of exacerbations and increases the time with improved asthma control compared with ICS therapy alone. The use of a single-inhaler combination (budesonide plus formoterol fumarate dihydrate) for both maintenance and rescue also appears to be safe and effective in asthma management.14

Conclusion

More studies are required to better understand which asthma patients might be at increased risk of death as a result of pharmacotherapeutic interventions. As family physicians involved in the day-to-day care of patients with asthma, we might be well served to recognize that many end points should be considered when evaluating asthma control, acknowledging that some end points will be influenced more by bronchodilator medications and some more by ICS medications. Inhaled corticosteroids should remain first-line therapy for patients with persistent symptoms; LABAs should be added if symptoms are not adequately controlled on low-to-moderate ICS doses. With time, direct measurement of airway inflammation might become more commonplace in primary care. This information might allow us to more fully exploit the proven benefits of LABA-ICS combination therapy in asthma management.

Acknowledgment

We thank Vasant Solanki and Deborah D’Urzo for their assistance in preparing this manuscript.

Footnotes

  • This article has been peer reviewed.

  • Competing interests

    Dr D’Urzo has participated in many clinical trials studying the use of long-acting β2-agonists and inhaled corticosteroids in asthma management that were funded by various pharmaceutical organizations.

  • The opinions expressed in commentaries are those of the authors. Publication does not imply endorsement by the College of Family Physicians of Canada.

  • Cet article a fait l’objet d’une révision par des pairs.

  • Cet article se trouve aussi en français à la page 123.

  • Copyright© the College of Family Physicians of Canada

References

  1. ↵
    US Food and Drug Administration [website]Transcript for December 11, 2008 meetingRockville, MDUS Food and Drug Administration2009Available from: www.fda.gov/ohrms/dockets/ac/08/transcripts/2008-4398t2-day2.pdfAccessed 2009 Dec 16
  2. ↵
    JaeschkeRO’BrynePMMejzaFNairPLesniakNBrozekJThe safety of long-acting β-agonists among patients with asthma using inhaled corticosteroidsAm J Respir Crit Care Med200817810100916Epub 2008 Sep 5
    OpenUrlCrossRefPubMed
  3. SearsMROttossonARadnerFSuissaSLong-acting β-agonists: a review of formoterol safety data from asthma clinical trialsEur Respir J20093312132Epub 2008 Sep 3
    OpenUrlAbstract/FREE Full Text
  4. KramerJMBalancing the benefits and risks of inhaled long-acting beta-agonists—the influence of valuesN Engl J Med20093601615925
    OpenUrlCrossRefPubMed
  5. DrazenJMO’ByrnePMRisks of long-acting beta agonists in achieving asthma controlN Engl J Med20093601616712
    OpenUrlCrossRefPubMed
  6. ↵
    ErnstPMcIvorADucharmeFMBouletLPFitzGeraldMChapmanKRSafety and effectiveness of long-acting inhaled beta-agonist bronchodilators when taken with inhaled corticosteroidsAnn Intern Med200614596924
    OpenUrlPubMed
  7. ↵
    CastleWFullerRHallJPalmerJSerevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatmentBMJ1993306688410347
    OpenUrlAbstract/FREE Full Text
  8. ↵
    NelsonHSWeissSTBleeckerERYanseySWDorinskyPMThe Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterolChest200612911526Erratum in: Chest 2006;129(5):1393
    OpenUrlCrossRefPubMed
  9. ↵
    SalpeterSRBuckleyNSOrminstonTMSalpeterEEMeta-analysis: effect of long-acting β2-agonists on severe asthma exacerbations and asthma-related deathsAnn Intern Med20061441290412Epub 2006 Jun 5
    OpenUrlPubMed
  10. ↵
    D’UrzoADChapmanKRCarterAHargreaveFEFitzgeraldMTesarowskiDEffectiveness and safety of salmeterol in nonspecialist practice settingsChest200111937149
    OpenUrlCrossRefPubMed
  11. ↵
    Global Initiative for Asthma [website]Global strategy for asthma management and preventionBethesda, MDGlobal Initiative for Asthma2008Available from: www.ginasthma.org/Guidelineitem.asp??l1=2&l2=1&intId=1561Accessed 2009 Dec 16
  12. ↵
    National Heart, Lung and Blood Institute [website]Guidelines for the diagnosis and management of asthma (EPR-C)Bethesda, MDNational Heart, Lung and Blood Institute2007Available from: www.nhlbi.nih.gov/guidelines/asthma/Accessed 2008 Dec 22
  13. ↵
    McIvorRAPizzichiniETurnerMOHussackPHargreaveFESearsMRPotential masking effects of salmeterol on airway inflammation in asthmaAm J Respir Crit Care Med1998158392430
    OpenUrlCrossRefPubMed
  14. ↵
    D’UrzoADInhaled glucocorticosteroid and long-acting β2-adrenoceptor agonist single-inhaler combination for both maintenance and rescue therapy: a paradigm shift in asthma managementTreat Respir Med20065638591
    OpenUrlPubMed
  15. ↵
    McIvorRAChapmanKRThe coming of age of asthma guidelinesLancet2008372964310212
    OpenUrlCrossRefPubMed
  16. ↵
    PauwelsRALöfdahlCGPostmaDSTattersfieldAEO’ByrnePMBarnesPJEffect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteriods Establishing Therapy (FACET) International Study GroupN Engl J Med199733720140511
    OpenUrlCrossRefPubMed
  17. ↵
    BatemanEDBousheyHABousquetJBusseWWClarkTJPauwelsRACan guideline-defined asthma control be achieved?The Gaining Optimal Asthma Control Study. Am J Respir Crit Care Med2004170883644Epub 2004 Jul 15
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Canadian Family Physician: 56 (2)
Canadian Family Physician
Vol. 56, Issue 2
1 Feb 2010
  • Table of Contents
  • About the Cover
  • Index by author
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word on The College of Family Physicians of Canada.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Safety of long-acting β2-agonists in the management of asthma
(Your Name) has sent you a message from The College of Family Physicians of Canada
(Your Name) thought you would like to see the The College of Family Physicians of Canada web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Safety of long-acting β2-agonists in the management of asthma
Anthony D. D’Urzo, Pieter Jugovic, Jacques Bouchard, Reuven Jhirad, Itamar Tamari
Canadian Family Physician Feb 2010, 56 (2) 119-120;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Respond to this article
Share
Safety of long-acting β2-agonists in the management of asthma
Anthony D. D’Urzo, Pieter Jugovic, Jacques Bouchard, Reuven Jhirad, Itamar Tamari
Canadian Family Physician Feb 2010, 56 (2) 119-120;
Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Combination therapy
    • Conclusion
    • Acknowledgment
    • Footnotes
    • References
  • eLetters
  • Info & Metrics
  • PDF

Related Articles

  • Innocuité des β2-agonistes dans la prise en charge de l’asthme
  • PubMed
  • Google Scholar

Cited By...

  • Cover concerns
  • Google Scholar

More in this TOC Section

  • Reflections on the value of Canadian multiculturalism in health care delivery
  • The environmental elephant in the office: medications
  • Six-sentence and 3-citation research proposals
Show more Commentary

Similar Articles

Navigate

  • Home
  • Current Issue
  • Archive
  • Collections - English
  • Collections - Française

For Authors

  • Authors and Reviewers
  • Submit a Manuscript
  • Permissions
  • Terms of Use

General Information

  • About CFP
  • About the CFPC
  • Advertisers
  • Careers & Locums
  • Editorial Advisory Board
  • Subscribers

Journal Services

  • Email Alerts
  • Twitter
  • LinkedIn
  • Instagram
  • RSS Feeds

Copyright © 2025 by The College of Family Physicians of Canada

Powered by HighWire