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Safety of regular formoterol or salmeterol in children with asthma: an overview of Cochrane reviews

  1. Christopher J Cates1,*,
  2. Marta Oleszczuk2,
  3. Elizabeth Stovold1,
  4. L. Susan Wieland3

Editorial Group: Cochrane Airways Group

Published Online: 17 OCT 2012

DOI: 10.1002/14651858.CD010005.pub2


How to Cite

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, Issue 10. Art. No.: CD010005. DOI: 10.1002/14651858.CD010005.pub2.

Author Information

  1. 1

    St George's, University of London, Population Health Research Institute, London, UK

  2. 2

    University of Alberta, Department of Oncology, Edmonton, AB, Canada

  3. 3

    Brown University Public Health Program, Center for Evidence-based Medicine, Providence, Rhode Island, USA

*Christopher J Cates, Population Health Research Institute, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK. ccates@sgul.ac.uk.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 17 OCT 2012

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Table 1. Summary of findings - children with a serious adverse event

ComparisonIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlRegular LABA (salmeterol or formoterol)

Children with a fatal serious adverse event of any cause

All comparisonssee commentsee commentsee commentsee commentsee commentThere was only a single child who died in all the studies so mortality could not be assessed.

Children with a non-fatal serious adverse event of any cause

Regular formoterol versus placebo Cates 2012a
Follow-up: mean 27 weeks
12 per 100030 per 1000
(15 to 56)
OR 2.48
(1.27 to 4.83)
1335
(5 studies)
⊕⊕⊕⊕
high

Regular salmeterol versus placebo Cates 2008
Follow-up: mean 31 weeks
56 per 100072 per 1000
(46 to 108)
OR 1.3
(0.82 to 2.05)
1333
(5 studies)
⊕⊕⊕⊝
moderate1

Regular formoterol & ICS versus ICS Cates 2009b

Follow-up: mean 13 weeks
8 per 100014 per 1000
(7 to 27)
OR 1.62 (0.80 to 3.28)2788

(7 studies)
⊕⊕⊕⊝
moderate1

Regular salmeterol & ICS versus ICS Cates 2009a
Follow-up: mean 15 weeks
5 per 10006 per 1000
(2 to 19)
OR 1.20
(0.37 to 3.91)
1862
(5 studies)
⊕⊕⊕⊝
moderate1

Regular formoterol versus regular salmeterol Cates 2012b
Follow-up: 13 weeks
13 per 1000

(on salmeterol)
12 per 1000
(1 to 168)

(on formoterol)
OR 0.95
(0.06 to 15.33)
156
(1 study)
⊕⊕⊝⊝
low1,2
Formoterol was considered the active treatment and salmeterol the control treatment for this comparison

Children with a non-fatal serious adverse event related to asthma

Regular formoterol versus placebo Cates 2012a
Follow-up: mean 27 weeks
2 per 10008 per 1000
(4 to 18)
OR 4.06
(1.78 to 9.22)
1335
(5 studies)
⊕⊕⊕⊕
high

Regular salmeterol versus placebo Cates 2008
Follow-up: mean 31 weeks
33 per 100055 per 1000
(33 to 92)
OR 1.72
(1 to 2.98)
1333
(5 studies)
⊕⊕⊕⊕
high

Regular formoterol & ICS versus ICS Cates 2009b
Follow-up: mean 13 weeks
4 per 10006 per 1000
(2 to 17)
OR 1.49
(0.48 to 4.61)
2788
(7 studies)
⊕⊕⊝⊝
low1,3

Regular salmeterol & ICS versus ICS Cates 2009a
Follow-up: mean 15 weeks
1 per 10001 per 1000
(0 to 17)
OR 0.99
(0.06 to 15.85)
1862
(5 studies)
⊕⊕⊝⊝
low1,3

*The basis for the assumed risk (was the mean control group risk across studies). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio; SAE: serious adverse event

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1. Confidence intervals include the possibility of an increase and a decrease in SAEs on regular LABA
2. Single unblinded study
3. Considerable heterogeneity between trial results
 
Table 2. Characteristics of included reviews

Inclusion criteria





Review titleStudiesParticipantsInterventionComparisonPrimary outcome measuresDate of searchNo. included studies (all)No. included studies (children only)

1. Regular treatment with formoterol for chronic asthma: serious adverse events

Cates 2012a
Randomised controlled trialsDiagnosis of asthma; any age groupInhaled formoterol twice/day; at least 12 weeks duration; any dose; any delivery devicePlacebo or short-acting beta2-agonistsAll-cause mortality

All-cause non-fatal SAEs
January 2012225

2. Regular treatment with salmeterol for chronic asthma: serious adverse events Cates 2008Randomised controlled trialsDiagnosis of asthma; any age groupInhaled salmeterol twice/day; at least 12 weeks duration; any dose; any delivery devicePlacebo or short-acting beta2-agonistsAll-cause mortality

All-cause non-fatal SAEs
August 2011325

3. Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events Cates 2009bRandomised controlled trialsDiagnosis of asthma; any age groupInhaled corticosteroids and formoterol once or twice/day; at least least 12 weeks duration; any dose; any single or separate deviceSame dose and type of inhaled corticosteroidsAll-cause mortality

All-cause non-fatal SAEs
October 2008217

4. Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events Cates 2009aRandomised controlled trialsDiagnosis of asthma; any age groupInhaled corticosteroids and salmeterol once or twice/day; at least least 12 weeks duration; any dose; any single or separate deviceSame dose and type of inhaled corticosteroidsAll-cause mortality

All-cause non-fatal SAEs
October 2008333 (2 additional studies identified by updated search)

5. Regular treatment with formoterol versus regular treatment with salmeterol for chronic asthma: serious adverse events Cates 2012bRandomised controlled trialsDiagnosis of asthma; any age groupInhaled formoterol; at least 12 weeks duration; not randomised with inhaled corticosteroidsInhaled salmeterol; at least 12 weeks duration; not randomised with inhaled corticosteroidsAll-cause mortality

All-cause non-fatal SAEs
January 201241

6. Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events Cates 2010Randomised controlled trialsDiagnosis of asthma; any age groupInhaled formoterol with an inhaled steroid; at least 12 weeks duration; any dose; any single or separate delivery deviceInhaled salmeterol with an inhaled steroid; at least 12 weeks duration; any dose; any single or separate delivery deviceAll-cause mortality

All-cause non-fatal SAEs
August 201170

 
Table 3. Regular formoterol v placebo trial details

Duration

(weeks)
% children on ICS background Rx Formoterol

48 mcg/day (N)
 Formoterol

24 mcg/day (N)
Formoterol

12 mcg/day (N)
Placebo (N)BrandAge Ranges

Bensch 20025269171171176Foradil5 to 12

Corren 200712099Oxis6 to 11

Levy 20051272127122Foradil5 to 13

Von Berg 20031282838184Oxis6 to 17

Zimmerman 20041210094105101Oxis6 to 11

Totalmean = 27 weeks171475186492

All trials were sponsored by AstraZeneca or Novartis, and contributed data on all-cause mortality and non-fatal serious adverse events, except Levy 2005 for which mortality data was not available.

 
Table 4. Regular salmeterol v placebo trial details

Duration

(weeks)
% children on ICS background RxSalmeterol 100 mcg/day (N)Salmeterol 50 mcg/day (N)Placebo(N)Age Ranges

Russell 199512100991074 to 16

Simons 199752080806 to 14

SLGA301412501091151104 to 11

von Berg 199852522202065 to 15

Weinstein 199812571021054 to 11

TOTAL mean =31 weeks610115608

All trials were sponsored by GSK and contributed data on all-cause mortality and non-fatal serious adverse events

 
Table 5. Regular formoterol & ICS v ICS trial details

Children and AdolescentsDuration (weeks)Formoterol and ICS (N)ICS Alone (N)Daily Dose Budesonide (mcg )Daily Dose Formoterol (mcg )Combined InhalerAge Ranges

Morice 200812415207200246 to 11

Pohunek 200612417213400244 to 11

SD-039-0714121361344001211 to 17

SD-039-071812128145200246 to 15

SD-039-07192612363400246 to 11

SD-039-07251235216920012 or 246 to 15

Tal 200212148138400244 to 17

Totalmean = 13 weeks1,7191,069

All trials were sponsored by AstraZeneca and contributed data on fatal and non-fatal serious adverse events

 
Table 6. Regular salmeterol & ICS v ICS trial details

Duration (Weeks)Salmeterol & ICSICS aloneDose of Fluticasone mcg/dayDose of Salmeterol mcg/dayCombined InhalerAge Ranges

Li 2010121731772001004 to 11

Malone 2005121011022001004 to 11

NCT01192178161711682001004 to 11

SAM40012241811812001004 to 11

SAS3002112304304100504 to 11

Totalmean = 15 weeks930932

All trials were sponsored by GSK and contributed data on all-cause mortality and non-fatal serious adverse events

 
Table 7. Regular formoterol versus regular salmeterol

Duration (Weeks)% children on ICS background RxFormoterol 24 mcg/daySalmeterol 100 mcg/dayFormoterol deviceSalemterol deviceSponsorsAge Ranges

Everden 200412100%8076Oxis TurbohalerSalmeterol AccuhalerAstraZeneca6 to 17

 
Table 8. AMSTAR ratings

AMSTAR CriteriaCates 2008Cates 2012aCates 2009aCates 2009bCates 2012bCates 2010

1. Was an 'a priori' design provided? YesYesYesYesYesYes

2a. Was there duplicate study selection? (0.5 point)YesYesYesYesYesNo

2b. Was there duplicate data extraction? (0.5 point)NoNoYesYesYesNo

3. Was a comprehensive literature search performed?YesYesYesYesYesYes

4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?NoNoNoNoNoNo

5. Was a list of studies (included and excluded) provided?YesYesYesYesYesYes

6. Were the characteristics of the included studies provided?YesYesYesYesYesYes

7. Was the scientific quality of the included studies assessed and documented?YesYesYesYesYesYes

8. Was the scientific quality of the included studies used appropriately in formulating conclusions?YesYesYesYesYesYes

9. Were the methods used to combine the findings of studies appropriate?YesYesYesYesYesYes

10. Was the likelihood of publication bias assessed?YesYesYesYesNot applicableNot applicable

11. Was the conflict of interest stated?YesYesYesYesYesYes

Total criteria met:10.510.51111109

 

(item 4 is met with the assessment 'NO', all others 'YES')

Note: we felt that item 2 was 2 separate questions, so we split it into two parts and awarded half a point for each. This differs from the published version of the tool.

 
Table 9. Risks of Bias for the included trials in each Cochrane review

Cochrane reviewtrial IDsequence generationallocation concealmentblindingincomplete outcome dataselective reporting

"Regular tretatment with formoterol for chronic asthma: SAE" Cates 2012aBensh 2002unclearunclearlowlowlow

Levy 2005unclearunclearlowlowunclear1

von Berg 2003lowunclearlowlowlow

Zimmenman 2004unclearunclearlowunclearlow

Corren 2002lowunclearlowunclearlow

"regular treatment with salmeterol for chronic asthma: SAE" Cates 2008Lenny 1995an/aunclearlown/alow

Lenny 1995bn/aunclearlown/alow

Russel 1995n/aunclearlown/alow

Simons 1997n/aunclearlown/alow

SLGA 3014n/aunclearlown/alow

von Berg 1998n/aunclearlown/alow

Weinstein 1998n/aunclearlown/alow

"Regular treatment with formoterol and ICS for chronic asthma: SAE" Cates 2009bMorice 2008lowunclearlowlowlow

Pohunek 2006unclearunclearlowlowlow

SD-039-0714unclearunclearlowlowlow

SD-039-0718lowunclearlowlowlow

SD-039-0719unclearunclearhighlowlow

SD-039-0725unclearunclearlowlowlow

Tal 2002lowunclearlowlowlow

 

"Regular treatment with salmeterol and ICS for chronic asthma: SAE" Cates 2009a
Li 2010unclearunclearlowlowlow

Malone 2005unclearunclearlowlowlow

NCT01192178unclearunclearlowlowlow

SAM40012unclearunclearlowlowlow

SAS30021unclearunclearlowlowlow

"Regular treatment with formoterol versus regular treatment with satmeterol for chronic asthma: SAE" Cates 2012bEverden 2004lowunclearhighlowlow

 1. No mortality data was available from this trial
 
Table 10. Risk differences for children with SAE of any cause

Children with an all-cause SAE (pooled risk differences, M-H Random)


Formoterol monotherapyPlaceboRisk Difference (95% CI)Heterogeneity (I-squared)




Children with SAETotalChildren with SAETotal

3484364920.0195 (-0.0034, 0.0425)55%


Salmeterol monotherapyPlaceboRisk Difference (95% CI)Heterogeneity (I-squared)




Children with SAETotalChildren with SAETotal

46725346080.0225 (0.0023, 0.0426)0%


Formoterol combination therapyICSRisk Difference (95% CI)Heterogeneity (I-squared)




Children with SAETotalChildren with SAETotal

251719910690.0034 (-0.0062, 0.0131)34%


Salmeterol combination therapyICSRisk Difference (95% CI)Heterogeneity (I-squared)




Children with SAETotalChildren with SAETotal

693059320.0008 (-0.0067, 0.0082)0%

 
Table 11. Mean event rates in control arms of included trials (SAE of any cause)

 ComparisonChildren with an event (n)Total number of children (N)SAE per 10,000 children (95% CI)Mean duration of trials (weeks)SAE per 10,000 children per week (95% CI)

Formoterol v Placebo6492122 (56 to 263)275 (2 to 10)

Salmeterol v Placebo34608559 (403 to 771)3118 (13 to 25)

Formoterol & ICS v ICS9106984 (44 to 159)136 (3 to 12)

Salmeterol & ICS v ICS593254 (23 to 125)154 (2 to 8)

 
Table 12. Monotherapy versus combination therapy risk differences for children with SAE of any cause

Children with an all-cause SAE (pooled risk differences, M-H Random)


LABA monotherapyPlaceboRisk Difference (95% CI)Heterogeneity (I-squared)




Children with SAETotalChildren with SAETotal

8015684011000.0191 (0.0061, 0.0321)15%


LABA combination therapyICSRisk Difference (95% CI)Heterogeneity (I-squared)




Children with SAETotalChildren with SAETotal

3126491420010.0017 (-0.0037, 0.0070)2%

 
Table 13. Risk differences for children with SAE related to asthma

Children with an asthma related SAE (pooled risk differences, M-H Random)


Formoterol monotherapyPlaceboRisk Difference (95% CI)Heterogeneity (I-squared)




Children with SAETotalChildren with SAETotal

2584314920.0196 (-0.0071, 0.0463)75%


Salmeterol monotherapyPlaceboRisk Difference (95% CI)Heterogeneity (I-squared)




Children with SAETotalChildren with SAETotal

35725206080.0185 (0.0027, 0.0343)0%


Formoterol combination therapyICSRisk Difference (95% CI)Heterogeneity (I-squared)




Children with SAETotalChildren with SAETotal

91719410690.0000 (-0.0064, 0.0064)19%


Salmeterol combination therapyICSRisk Difference (95% CI)Heterogeneity (I-squared)




Children with SAETotalChildren with SAETotal

19301932-0.0005 (-0.0058, 0.0048)0%

 
Table 14. Monotherapy versus combination therapy risk differences for children with SAE related to asthma

Children with an asthma related SAE (pooled risk differences, M-H Random)


LABA monotherapyPlaceboRisk Difference (95% CI)Heterogeneity (I-squared)




Children with SAETotalChildren with SAETotal

6015682111000.0197 (0.0055, 0.0339)44%


LABA combination therapyICSRisk Difference (95% CI)Heterogeneity (I-squared)




Children with SAETotalChildren with SAETotal

10264952001-0.0003 (-0.0040, 0.0034)0%

 
Table 15. Mean event rates in control arms of included trials (SAE related to asthma)

 ComparisonChildren with an event (n)Total number of children (N)SAE per 10,000 children (95% CI)Mean duration of trials (weeks)SAE per 10,000 children per week (95% CI)

Formoterol v Placebo149220 (4 to 114)271 (0 to 4)

Salmeterol v Placebo20608329 (214 to 503)3111 (7 to 16)

Formoterol & ICS v ICS4106937 (15 to 96)133 (1 to 7)

Salmeterol & ICS v ICS193211 (2 to 61)151 (0 to 4)