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The safety of regular long-acting beta2-agonists in children with asthma: an overview of Cochrane reviews
Paediatric Respiratory Reviews 14 (2013) 25–26
Contents lists available at SciVerse ScienceDirect
Paediatric Respiratory Reviews
Cochrane Corner
The safety of regular long-acting beta2-agonists in children with asthma: an overview of Cochrane reviews Chris Cates Cochrane Airways Group, Population Health Sciences and Education, St George’s University of London, 6th Floor Hunter Wing, Cranmer Terrace, London, UK, SW17 0RE
WHY DO WE NEED AN OVERVIEW?
WHAT WERE THE FINDINGS ON MORTALITY IN CHILDREN?
Two very large randomised trials (including over 50,000 participants) found an increase in asthma-related deaths in adults who were given regular salmeterol.1,2 Furthermore, individual patient data submitted to the FDA showed that the risks of serious adverse events while on regular formoterol or salmeterol were largest in the younger age-groups. This age-related trend was significant when regular formoterol or salmeterol were used with background inhaled corticosteroids (ICS), but was not found with combination inhalers.3 There are six separate Cochrane reviews looking at the safety of regular salmeterol or regular formoterol (with or without combination inhaled corticosteroids), and we have drawn data together into an overview of Cochrane reviews to summarise data on the serious adverse events in children from the randomised trials in all these reviews.4 We looked at children who suffered fatal and non-fatal (usually involving admission to hospital) serious adverse events of any cause, and also those related to asthma.
There was a single child who died of a sub-arachnoid haemorrhage whilst taking regular formoterol. This meant that we were unable to come to any conclusion about how taking regular formoterol or salmeterol might affect asthma mortality risks in children.
HOW MANY TRIALS DID WE FIND AND WHAT WERE THE RISKS OF BIAS? Two people independently assessed the six Cochrane reviews using the AMSTAR instrument and found the quality of the reviews to be high. We found 22 randomised trials which assessed the safety of regular formoterol or salmeterol in children, and these included 7474 children with asthma. The randomised trials in children were at low risk of bias, and we obtained data on serious adverse events on almost all trials using a combination of published papers, reports on the sponsors’ websites and FDA submissions.
E-mail address: [email protected]. 1526-0542/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.prrv.2012.10.002
WHAT ABOUT NON-FATAL SERIOUS ADVERSE EVENTS? We were unable to detect any significant differences between the safety of regular formoterol and salmeterol in children. However, we sub grouped the trials into those which compared formoterol or salmeterol only (monotherapy) to placebo, and those comparing formoterol or salmeterol in combination with ICS (combination therapy) to the same dose of ICS alone (see Figure 1). The trials of monotherapy showed an increase in serious adverse events which was statistically significant when analysed using Peto Odds Ratios (OR 1.60; 95% CI 1.10 to 2.33). The results for combination therapy had a very similar point estimate, but with fewer events in the trials a wider confidence interval that was not statistically significant (OR 1.50; 95% CI 0.82 to 2.75). DOES THIS MEAN THAT COMBINATION THERAPY IS SAFER THAN MONOTHERAPY? We cannot say categorically that combination therapy is safer, because the statistical test to compare the combination therapy odds ratio to that on monotherapy is negative. The p value of the test for interaction is 0.86 as shown in Figure 1. However, it is striking that there were fewer serious adverse events in both arms of the combination therapy trials. This may be because inhaled corticosteroids were being taken regularly by all children in the combination therapy trials, but could also be due to closer supervision or other factors. We converted the odds ratios into absolute differences by applying them to the overall proportion of
26
C. Cates / Paediatric Respiratory Reviews 14 (2013) 25–26
Figure 1. Non-fatal serious adverse events of any cause in children with asthma treated with a regular long-acting beta2-agonist (LABA). Separate sub-groups are shown for monotherapy (LABA v Placebo) and combination therapy (LABA & ICS v ICS).
children with an event in the control arms of the respective subgroups. This indicates that for every 1000 children treated with monotherapy 21 additional children suffered a serious adverse event over six months (95% CI 4 to 45), whereas on combination therapy only three additional children suffered an event over three months (95% CI minus 1 to 7). WHAT DOES THIS ALL MEAN? We are not in a position to say that regular formoterol or salmeterol are safe in children. Their impact on mortality cannot be assessed from existing evidence from randomised trials. As far as non-fatal events are concerned, there is a relative increase in risk of around 50% found in the trials, with no clear difference between combination therapy and monotherapy trials. However the combination therapy trials had much lower rates of serious adverse events overall, so combination therapy looks to be a better bet. Combination therapy may not be risk free, and the small increase in risk of a serious adverse event of three per thousand over three months has to be balanced against the potential gains in asthma symptom control in each individual child. Moreover,
children on combination therapy should still be carefully monitored and seek help promptly if their asthma gets worse. SOURCES OF SUPPORT The Cochrane overview was funded by the National Institute for Health Research. References 1. Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993;306:1034–7. 2. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM, the SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol. Chest 2006;129:15–26. 3. McMahon AW, Levenson MS, McEvoy BW, Mosholder AD, Murphy D. Age and Risks of FDA–Approved Long-Acting b2-Adrenergic Receptor Agonists. Pediatrics. Published online October 24, 2011 http://dx.doi.org/10.1542/peds.20101720. 4. Cates CJ, Oleszczuk M, Stovold E, Wieland LS. Safety of regular formoterol or salmeterol in children with asthma: an overview of Cochrane reviews. Cochrane Database of Systematic Reviews. 2012(10):Art. No.: CD010005. http:// dx.doi.org/10.1002/14651858.CD010005.pub2.
In collaboration with the Cochrane CF and Genetic Disorders Group’ http://cfgd.cochrane.org/.
Contents lists available at SciVerse ScienceDirect
Paediatric Respiratory Reviews
Cochrane Corner
The safety of regular long-acting beta2-agonists in children with asthma: an overview of Cochrane reviews Chris Cates Cochrane Airways Group, Population Health Sciences and Education, St George’s University of London, 6th Floor Hunter Wing, Cranmer Terrace, London, UK, SW17 0RE
WHY DO WE NEED AN OVERVIEW?
WHAT WERE THE FINDINGS ON MORTALITY IN CHILDREN?
Two very large randomised trials (including over 50,000 participants) found an increase in asthma-related deaths in adults who were given regular salmeterol.1,2 Furthermore, individual patient data submitted to the FDA showed that the risks of serious adverse events while on regular formoterol or salmeterol were largest in the younger age-groups. This age-related trend was significant when regular formoterol or salmeterol were used with background inhaled corticosteroids (ICS), but was not found with combination inhalers.3 There are six separate Cochrane reviews looking at the safety of regular salmeterol or regular formoterol (with or without combination inhaled corticosteroids), and we have drawn data together into an overview of Cochrane reviews to summarise data on the serious adverse events in children from the randomised trials in all these reviews.4 We looked at children who suffered fatal and non-fatal (usually involving admission to hospital) serious adverse events of any cause, and also those related to asthma.
There was a single child who died of a sub-arachnoid haemorrhage whilst taking regular formoterol. This meant that we were unable to come to any conclusion about how taking regular formoterol or salmeterol might affect asthma mortality risks in children.
HOW MANY TRIALS DID WE FIND AND WHAT WERE THE RISKS OF BIAS? Two people independently assessed the six Cochrane reviews using the AMSTAR instrument and found the quality of the reviews to be high. We found 22 randomised trials which assessed the safety of regular formoterol or salmeterol in children, and these included 7474 children with asthma. The randomised trials in children were at low risk of bias, and we obtained data on serious adverse events on almost all trials using a combination of published papers, reports on the sponsors’ websites and FDA submissions.
E-mail address: [email protected]. 1526-0542/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.prrv.2012.10.002
WHAT ABOUT NON-FATAL SERIOUS ADVERSE EVENTS? We were unable to detect any significant differences between the safety of regular formoterol and salmeterol in children. However, we sub grouped the trials into those which compared formoterol or salmeterol only (monotherapy) to placebo, and those comparing formoterol or salmeterol in combination with ICS (combination therapy) to the same dose of ICS alone (see Figure 1). The trials of monotherapy showed an increase in serious adverse events which was statistically significant when analysed using Peto Odds Ratios (OR 1.60; 95% CI 1.10 to 2.33). The results for combination therapy had a very similar point estimate, but with fewer events in the trials a wider confidence interval that was not statistically significant (OR 1.50; 95% CI 0.82 to 2.75). DOES THIS MEAN THAT COMBINATION THERAPY IS SAFER THAN MONOTHERAPY? We cannot say categorically that combination therapy is safer, because the statistical test to compare the combination therapy odds ratio to that on monotherapy is negative. The p value of the test for interaction is 0.86 as shown in Figure 1. However, it is striking that there were fewer serious adverse events in both arms of the combination therapy trials. This may be because inhaled corticosteroids were being taken regularly by all children in the combination therapy trials, but could also be due to closer supervision or other factors. We converted the odds ratios into absolute differences by applying them to the overall proportion of
26
C. Cates / Paediatric Respiratory Reviews 14 (2013) 25–26
Figure 1. Non-fatal serious adverse events of any cause in children with asthma treated with a regular long-acting beta2-agonist (LABA). Separate sub-groups are shown for monotherapy (LABA v Placebo) and combination therapy (LABA & ICS v ICS).
children with an event in the control arms of the respective subgroups. This indicates that for every 1000 children treated with monotherapy 21 additional children suffered a serious adverse event over six months (95% CI 4 to 45), whereas on combination therapy only three additional children suffered an event over three months (95% CI minus 1 to 7). WHAT DOES THIS ALL MEAN? We are not in a position to say that regular formoterol or salmeterol are safe in children. Their impact on mortality cannot be assessed from existing evidence from randomised trials. As far as non-fatal events are concerned, there is a relative increase in risk of around 50% found in the trials, with no clear difference between combination therapy and monotherapy trials. However the combination therapy trials had much lower rates of serious adverse events overall, so combination therapy looks to be a better bet. Combination therapy may not be risk free, and the small increase in risk of a serious adverse event of three per thousand over three months has to be balanced against the potential gains in asthma symptom control in each individual child. Moreover,
children on combination therapy should still be carefully monitored and seek help promptly if their asthma gets worse. SOURCES OF SUPPORT The Cochrane overview was funded by the National Institute for Health Research. References 1. Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993;306:1034–7. 2. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM, the SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol. Chest 2006;129:15–26. 3. McMahon AW, Levenson MS, McEvoy BW, Mosholder AD, Murphy D. Age and Risks of FDA–Approved Long-Acting b2-Adrenergic Receptor Agonists. Pediatrics. Published online October 24, 2011 http://dx.doi.org/10.1542/peds.20101720. 4. Cates CJ, Oleszczuk M, Stovold E, Wieland LS. Safety of regular formoterol or salmeterol in children with asthma: an overview of Cochrane reviews. Cochrane Database of Systematic Reviews. 2012(10):Art. No.: CD010005. http:// dx.doi.org/10.1002/14651858.CD010005.pub2.
In collaboration with the Cochrane CF and Genetic Disorders Group’ http://cfgd.cochrane.org/.