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#16 Long-Acting Beta-Agonist Inhalers in Asthma: Breathing Evidence Into the Debate?


CLINICAL QUESTION
QUESTION CLINIQUE
 Are the serious adverse events associated with long-acting beta-agonists (LABAs) in asthma important enough to limit their use?

BOTTOM LINE
RÉSULTAT FINAL
 In asthmatics, LABA should not be used without inhaled steroids. LABAs increase serious adverse events when used alone, but not when combined with an inhaled steroid (at least in patients >12 years-old). LABA monotherapy does not increase adverse events in COPD patients.


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EVIDENCE
DONNÉES PROBANTES
 FDA meta-analysis1 (and related publications2,3) of 110 Randomized Controlled Trials (RCTs) of 60,954 patients including 11% adolescents and 6% children with a median follow-up of 24 weeks. 
  • LABA statistically significant increased risk of serious asthma-related event (asthma-related death, intubation or hospitalization): 
    • 2.8 extra events per 1,000 asthmatics treated with LABA, Number Needed to Harm (NNH)=358. 
  • Examining risk +/- inhaled steroid. 
    • LABA alone versus no therapy: Statistically significant increase of 3.63 extra events per 1,000 asthmatics, NNH=276. 
    • LABA + inhaled steroid versus inhaled steroid: Non-statistically significant 0.25 extra events per 1,000 asthmatics. 
  • The risk increases with decreasing age (2/1,000 in adults age 18-64 and 15/1,000 in children 4-11). 
Three RCTs4-6 of 29,580 asthmatics (mean ages 43.5 years4,5, 7.6 years6) comparing LABA + steroid combination inhaler versus inhaled steroid alone over 6 months, in author-pooled analyses: 
  • No significant difference in serious asthma-related event: LABA/steroid 0.7%, steroid 0.64%. 
  • Statistically significant reduction in severe asthma exacerbations: LABA/steroid 8.7%, steroid 10.4%, Number Needed to Treat (NNT)=59. 
Context:  
  • These findings are supported by four Cochrane reviews7-10 and four other meta-analyses11-14 of LABA safety in asthma: 
    • Statistically significant increase in non-fatal serious adverse events versus placebo with formoterol (NNH=149 over 16 weeks)7 and salmeterol (NNH=188 over 28 weeks).8  
    • LABA + inhaled steroid: No statistically significant increase in serious adverse events with formoterol/steroid9 or salmeterol/steroid10 versus steroid alone. 
    • In one meta-analysis of LABA + inhaled steroid,14 statistical significance reached, but actual difference was very small (NNH>3,334). 
  • Serious adverse events with LABA are not increased in COPD. LABA alone does not increase mortality in COPD patients, and statistically significantly reduces the risk of COPD exacerbations requiring hospitalization (NNT=56).14 
updated by ricky aug 22 2016

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Author(s)
Auteur(s)
  • G. Michael Allan MD CCFP
  • James McCormack BSc(Pharm) PharmD

1. Meta-analysis prepared for Drug Safety and Risk Management Advisory Committee and Pediatric Advisory Committee, December 10-11, 2008. Available at: www.fda.gov/ohrms/dockets/ac/08/slides/2008-4398s1-04-Levensosn.pdf. Last accessed August 25, 2016.

2. Kramer JM. N Engl J Med. 2009; 360:1592-5.

3. Sears MR. Chest. 2009; 136:604-7.

4. Stempel DA, Raphiou IH, Kral KM, et al. N Engl J Med. 2016; 374:1822-30.

5. Peters SP, Bleecker ER, Canonica GW, et al. N Engl J Med. 2016; 375:850-60.

6. Stempel DA, Szefler SJ, Pederson S, et al. N Enl J Med. 2016; 375:840-9.

7. Cates CJ, Cates MJ. Cochrane Database Syst Rev. 2012; 4:CD006923.

8. Cates CJ, Cates MJ. Cochrane Database Syst Rev. 2008; 3:CD006363.

9. Cates CJ, Jaeschke R, Schmidt S, et al. Cochrane Database Syst Rev. 2013; 6:CD006924.

10. Cates CJ, Jaeschke R, Schmidt S, et al. Cochrane Database Syst Rev. 2013; 3:CD006922.

11. Sears MR, Radner F. Eur Respir J. 2014; 43:103-14.

12. Weatherall M, Wijesinghe M, Perrin K, et al. Thorax. 2010; 65:39-43.

13. Wijesinghe M, Weatherall M, Perrin K, et al. Eur Respir J. 2009; 34:803-11.

14. Salpeter SR, Wall AJ, Buckley NS. Am J Med. 2010; 123:322-8.

15. Kew KM, Mavergames C, Walters JAE. Cochrane Database Syst Rev. 2013; 10:CD010177.

Authors do not have any conflicts of interest to declare.

Les auteurs n’ont aucun conflit d’intérêts à déclarer.

Most recent review: 22/08/2016

By: Ricky D. Turgeon BSc(Pharm) ACPR PharmD

Comments:

Evidence Updated: Large trial of LABA + inhaled steroid versus inhaled steroid alone; Bottom Line: Strengthened conclusion of safety of LABA + inhaled steroid.
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