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Resumen de la seguridad del formoterol o salmeterol habitual en adultos con asma: una revisión global de revisiones Cochrane

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References

References to included reviews

Cates 2008

Cates CJ, Cates MJ. Regular treatment with salmeterol for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews 2008, Issue 3. [DOI: 10.1002/14651858.CD006363.pub2]

Cates 2010

Cates CJ, Lasserson TJ. Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/14651858.CD007694.pub2]

Cates 2012a

Cates CJ, Cates MJ. Regular treatment with formoterol for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews 2012, Issue 4. [DOI: 10.1002/14651858.CD006923.pub3]

Cates 2012b

Cates CJ, Lasserson TJ. Regular treatment with formoterol versus regular treatment with salmeterol for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews 2012, Issue 3. [DOI: 10.1002/14651858.CD007695.pub3]

Cates 2013a

Cates CJ, Lasserson TJ, Jaeschke R. Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews 2013, Issue 3. [DOI: 10.1002/14651858.CD006922.pub3]

Cates 2013b

Cates CJ, Jaeschke R, Schmidt S, Ferrer M. Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews 2013, Issue 6. [DOI: 10.1002/14651858.CD006924.pub3]

Additional references

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Altman 2003

Altman DG, Bland JM. Statistics notes: interaction revisited: the difference between two estimates. BMJ 2003;326(7382):219.

Anderson 2008

Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 2008;372(9643):1107‐19. [1474‐547X: (Electronic)]

Boushey 1980

Boushey HA, Holtzman MJ, Sheller JR, Nadel JA. Bronchial hyperreactivity. American Review of Respiratory Disease 1980;121(2):389‐413. [(Print)]

Bradburn 2007

Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A. Much ado about nothing: a comparison of the performance of meta‐analytical methods with rare events. Statistics in Medicine 2007;26(1):53‐77. [0277‐6715: (Print)]

Bucher 1997

Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta‐analysis of randomized controlled trials. Journal of Clinical Epidemiology 1997;50(6):683‐91.

Castle 1993

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(6884):1034‐7.

Cates 2011

Cates CJ. Assessing the risks of serious adverse events from regular long‐acting beta‐agonists for adults and children with asthma. MD Thesis, University of Cambridge,2011.

Cates 2012c

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. [DOI: 10.1002/14651858.CD010005]

Chan 2004

Chan A‐W, Hrobjartsson A, Haahr MT, Gotzsche PC, Altman DG. Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA 2004;291(20):2457‐65.

Chan 2004a

Chan A‐W, Krleza‐Jeric K, Schmid I, Altman DG. Outcome reporting bias in randomized trials funded by the Canadian Institutes of Health Research. Canadian Medical Association Journal 2004;171(7):735‐40.

Chowdhury 2011

Chowdhury BA, Seymour SM, Levenson MS. Assessing the safety of adding LABAs to inhaled corticosteroids for treating asthma. The New England Journal of Medicine 2011;364(26):2473‐5.

Cipriani 2013

Cipriani A, Higgins JPT, Geddes JR, Salanti G. Conceptual and technical challenges in network meta‐analysis. Annals of Internal Medicine 2013;159:130‐7.

Cockcroft 2006

Cockcroft D. Airway hyper‐responsiveness as a determinant of the early asthmatic response to inhaled allergen. Journal of Asthma 2006;43(3):175‐8.

Corren 2013

Corren J, Mansfield LE, Pertseva T, Blahzko V, Kaiser K. Efficacy and safety of fluticasone/formoterol combination therapy in patients with moderate‐to‐severe asthma. Respiratory Medicine 2013;107:180‐95.

GINA 2012

GINA. Global strategy for asthma management and prevention. http://www.ginasthma.org/local/uploads/files/GINA_Report_March13.pdf (accessed 9 February 2013).

Ioannidis 2001

Ioannidis JP, Lau J. Completeness of safety reporting in randomized trials: an evaluation of 7 medical areas. JAMA 2001;285(4):437‐43. [0098‐7484: (Print)]

Ioannidis 2004

Ioannidis JPA, Evans SJW, Gotzsche PC, O'Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Annals of Internal Medicine 2004;141(10):781‐8.

Lougheed 2010

Lougheed MD, Lemiere C, Dell SD, Ducharme FM, Fitzgerald JM, Leigh R, et al. Canadian Thoracic Society Asthma Committee commentary on long‐acting beta‐2 agonist use for asthma in Canada. Canadian Respiratory Journal 2010;17(2):57‐8.

Matsunaga 2013

Matsunaga K, Kawabata H, Hirano T, Sugiura H, Minakata Y, Ichinose M. Difference in time‐course of improvement in asthma control measures between budesonide and budesonide/formoterol. Pulmonary Pharmacology & Therapeutics 2013;26:189‐94.

McMahon 2011

McMahon AW, Levenson MS, McEvoy BW, Mosholder AD, Murphy D. Age and risks of FDA–approved long‐acting β2‐adrenergic receptor agonists. Pediatrics 2011;128(5):e1147‐54.

Nathan 2012

Nathan R A, D'Urzo A, Blazhko V, Kaiser K. Safety and efficacy of fluticasone/formoterol combination therapy in adolescent and adult patients with mild‐to‐moderate asthma: a randomised controlled trial. BMC Pulmonary Medicine 2012;12:67.

NCT01444430

AstraZeneca. A 6 Month Safety Study Comparing Symbicort With Inhaled Corticosteroid Only in Asthmatic Adults and Adolescents. http://clinicaltrials.gov/show/NCT01444430(accessed June 2012).

NCT01462344

GlaxoSmithKline. 6‐Month Safety and Benefit Study of ADVAIR in Children 4‐11 Years Old (VESTRI). http://clinicaltrials.gov/show/NCT01462344 (accessed 29 June 2012).

NCT01471340

Merck. A Serious Asthma Outcome Study With Mometasone Furoate/Formoterol Versus Mometasone Furoate in Asthmatics 12 Years and Over (P06241 AM3) (SPIRO). http://clinicaltrials.gov/ct2/show/NCT01471340(accessed June 2012).

NCT01475721

GlaxoSmithKline. SAS115359: A 6‐Month Study to Assess the Safety and Benefit of Inhaled Fluticasone Propionate/Salmeterol Combination Compared With Inhaled Fluticasone Propionate in the Treatment of Adolescents and Adults (12 Years of Age and Older) With Asthma. (AUSTRI). http://clinicaltrials.gov/show/NCT01475721(accessed June 2012).

Pearlman 2013

Pearlman DS, LaForce CF, Kaiser K. Fluticasone/Formoterol combination therapy compared with monotherapy in adolescent and adult patients with mild to moderate asthma. Clinical Therapeutics 2013;35:950‐66.

Phillips 1990

Phillips GD, Finnerty JP, Holgate ST. Comparative protective effect of the inhaled beta‐2‐agonist salbutamol (albuterol) on bronchoconstriction provoked by histamine, methacholine, and adenosine 5'‐monophosphate in asthma. Journal of Allergy and Clinical Immunology 1990;85(4):755‐62.

RevMan 5.2 [Computer program]

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan) 5.2. Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.

Salpeter 2006

Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta‐analysis: effect of long‐acting beta‐agonists on severe asthma exacerbations and asthma‐related deaths. Annals of Internal Medicine 2006;144(12):904‐12.

Sears 2013

Sears MR, Radner F. Safety of formoterol in asthma clinical trials: an update. European Respiratory Journal Epub 30 May 2013. [DOI: 10.1183/09031936.00004713]

Shea 2007

Shea B, Grimshaw J, Wells G, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology 2007;7:10. [DOI: 10.1186/1471‐2288‐7‐10]

SIGN/BTS 2012

Scottish Intercollegiate Guidelines Network/British Thoracic Society. British guideline on the management of asthma: a national clinical guideline 2008 (revised January 2012). http://www.sign.ac.uk/guidelines/fulltext/101/. Edinburgh: Scottish Intercollegiate Guidelines Network, (accessed 9 February 2013).

SMART 2006

Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM, SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129(1):15‐26.

Stirbulov 2012

Stirbulov R, Fritscher CC, Pizzichini E, Pizzichini MMM. Evaluation of the efficacy and safety of a fixed‐dose, single‐capsule budesonide‐formoterol combination in uncontrolled asthma: a randomized, double‐blind, multicenter, controlled clinical trial. Jornal Brasileiro de Pneumologia 2012;38:431‐7.

Tattersfield 2006

Tattersfield AE. Current issues with beta2‐adrenoceptor agonists: historical background. Clinical Reviews in Allergy and Immunology 2006;31(2‐3):107‐18.

Van Noord 1996

Van Noord JA, Smeets JJ, Raaijmakers JAM, Bommer AM, Maesen FPV. Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action. European Respiratory Journal 1996;9(8):1684‐8.

Visual Rx 2012

Cates CJ. Visual Rx 3.0. www.nntonline.net/visualrx/(September 2008).

Weinberger 2006

Weinberger M, Abu‐Hasan M. Life threatening asthma during treatment with salmeterol. New England Journal of Medicine 2006;355:852‐3.

Whittington 2004

Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363(9418):1341‐5.

Network of comparisons of serious adverse events from reviews of regular formoterol and salmeterol. Figure 1A shows the numbers of trials and adults on monotherapy versus placebo. Figure 1B shows the numbers of trials and adults on combination therapy versus the same dose of ICS. Adults randomly assigned to other arms in the included trials have not been counted.
Figures and Tables -
Figure 1

Network of comparisons of serious adverse events from reviews of regular formoterol and salmeterol. Figure 1A shows the numbers of trials and adults on monotherapy versus placebo. Figure 1B shows the numbers of trials and adults on combination therapy versus the same dose of ICS. Adults randomly assigned to other arms in the included trials have not been counted.

Review selection flow diagram.
Figures and Tables -
Figure 2

Review selection flow diagram.

Formoterol or salmeterol monotherapy versus placebo (with variable background use of ICS).
Figures and Tables -
Figure 3

Formoterol or salmeterol monotherapy versus placebo (with variable background use of ICS).

Formoterol monotherapy versus salmeterol monotherapy.
Figures and Tables -
Figure 4

Formoterol monotherapy versus salmeterol monotherapy.

Formoterol or salmeterol combination therapy versus the same dose of ICS.
Figures and Tables -
Figure 5

Formoterol or salmeterol combination therapy versus the same dose of ICS.

Formoterol combination therapy versus salmeterol combination therapy.
Figures and Tables -
Figure 6

Formoterol combination therapy versus salmeterol combination therapy.

Table 1. Summary of Findings 1 ‐ LABA monotherapy v placebo with variable background ICS use

Comparison

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Regular LABA (salmeterol or formoterol)

Adults who died of any cause

Formoterol monotherapy v placebo

Follow‐up: mean 14 weeks

0 per 10000

not estimable

(see comment)

OR 4.49 (0.24 to 84.80)

4824

(13 studies)

⊕⊕⊝⊝
low1

No deaths on placebo, two deaths on formoterol

Salmeterol monotherapy v placebo

Follow‐up: mean 27 weeks

23 per 10000

31 per 10000

(20 to 48)

OR 1.33 (0.85 to 2.08)

29,128

(10 studies)

⊕⊕⊕⊝
moderate2

LABA monotherapy v placebo

Follow‐up: mean 26 weeks

20 per 10000

27 per 10000

(18 to 43)

OR 1.37 (0.88 to 2.13)

33,952
(23 studies)

⊕⊕⊕⊝
moderate2

Adults with a non‐fatal serious adverse event of any cause

Formoterol monotherapy v placebo

Follow‐up: mean 14 weeks

106 per 10000

133 per 10000

(83 to 214)

OR 1.26 (0.78 to 2.04)

5758

(17 studies)

⊕⊕⊕⊝
moderate2

Salmeterol monotherapy v placebo

Follow‐up: mean 27 weeks

345 per 10000

391 per 10000

(348 to 437)

OR 1.14 (1.01 to 1.28)

30,196

(13 studies)

⊕⊕⊕⊕
high

LABA monotherapy v placebo

Follow‐up: mean 26 weeks

316 per 10000

359 per 10000

(322 to 401)

OR 1.14 (1.02 to 1.29)

35,954
(30 studies)

⊕⊕⊕⊕
high

*The basis for the assumed risk (was the mean control group risk across all studies, including those with no events in either arm of the trial). 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 are very wide, as only two deaths occurred (‐2 points)

2. Confidence intervals are wide enough to include important harm and benefit (‐1 for imprecision)

Figures and Tables -
Table 1. Summary of Findings 1 ‐ LABA monotherapy v placebo with variable background ICS use
Table 2. Summary of Findings 2 ‐ formoterol monotherapy versus salmeterol monotherapy for adults with asthma

Comparison

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Salmeterol monotherapy

Formoterol monotherapy

Adults who died of any cause

Formoterol monotherapy v salmeterol monotherapy

Follow‐up: mean 24 weeks

18 per 10000

2 per 10000

(0 to 115)

OR 0.14 (0.00 to 6.82)

1116
(3 studies)

⊕⊝⊝⊝
very low1

Adults with a non‐fatal serious adverse event of any cause

Formoterol monotherapy v salmeterol monotherapy

Follow‐up: mean 24 weeks

641 per 10000

501 per 10000

(305 to 806)

OR 0.77 (0.46 to 1.28)

1116
(3 studies)

⊕⊕⊝⊝
low2

*The basis for the assumed risk (was the mean control group risk across all 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. Open studies (‐1 point) and confidence intervals are very wide indeed, as only one death occurred (‐2 points)

2. Open studies and wide confidence intervals (‐1 point each)

Figures and Tables -
Table 2. Summary of Findings 2 ‐ formoterol monotherapy versus salmeterol monotherapy for adults with asthma
Table 3. Summary of Findings 3 ‐ LABA combination therapy v ICS

Comparison

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Regular LABA (salmeterol or formoterol)

Adults who died of any cause

Formoterol combination therapy v ICS

Follow‐up: mean 29 weeks

2 per 10000

7 per 10000

(2 to 32)

OR 3.56

(0.79 to 16.03)

11,271
(25 studies)

⊕⊕⊕⊝
moderate1

Salmeterol combination therapy v ICS

Follow‐up: mean 34 weeks

11 per 10000

10 per 10000

(3 to 29)

OR 0.90

(0.31 to 2.60)

13,447
(35 studies)

⊕⊕⊕⊝
moderate1

LABA combination therapy v ICS

Follow‐up: mean 32 weeks

7 per 10000

10 per 10000

(4 to 24)

OR 1.42

(0.60 to 3.38)

24,718
(60 studies)

⊕⊕⊕⊝
moderate1

Adults with a non‐fatal serious adverse event of any cause

Formoterol combination therapy v ICS

Follow‐up: mean 29 weeks

241 per 10000

239 per 10000

(187 to 304)

OR 0.99

(0.77 to 1.27)

11,271
(25 studies)

⊕⊕⊕⊝
moderate1

Salmeterol combination therapy v ICS

Follow‐up: mean 34 weeks

209 per 10000

240 per 10000

(191 to 298)

OR 1.15

(0.91 to 1.44)

13,447
(35 studies)

⊕⊕⊕⊝
moderate1

LABA combination therapy v ICS

Follow‐up: mean 32 weeks

228 per 10000

244 per 10000

(206 to 288)

OR 1.07

(0.90 to 1.27)

24,718
(60 studies)

⊕⊕⊕⊝
moderate1

*The basis for the assumed risk (was the mean control group risk across all studies, including those with no events in either arm of the trial). 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 are wide and include important harm and benefit (‐1 for imprecision)

Figures and Tables -
Table 3. Summary of Findings 3 ‐ LABA combination therapy v ICS
Table 4. Summary of Findings 4 ‐ formoterol combination therapy versus salmeterol combination therapy for adults with asthma

Comparison

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Salmeterol combination therapy

Formoterol combination therapy

Adults who died of any cause

Direct comparisons of formoterol combination therapy v salmeterol combination therapy

Follow‐up: mean 23 weeks

3 per 10000

8 per 10000

(1 to 48)

OR 2.68
(0.44 to 16.14)

6769
(10 studies)

⊕⊕⊝⊝
low1

Based on data from all formoterol combination trials

Adults with a non‐fatal serious adverse event of any cause

Direct comparisons of formoterol combination therapy v salmeterol combination therapy

Follow‐up: mean 23 weeks

226 per 10000

252 per 10000

(186 to 342)

OR 1.12
(0.82 to 1.53)

6769
(10 studies)

⊕⊕⊕⊝
moderate2

*The basis for the assumed risk (was the mean control group risk across all 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 are very wide, as only five deaths occurred (‐2 points)

2. Confidence intervals are wide and include important harm and benefit (‐1 point)

Figures and Tables -
Table 4. Summary of Findings 4 ‐ formoterol combination therapy versus salmeterol combination therapy for adults with asthma
Table 5. Summary of results of included Cochrane reviews

Comparison

Cates 2012a

(with additional data from two new trials)

Formoterol Monotherapy

Placebo

Pooled Effect Size

(95% Confidence Interval)

Quality of the evidence
(GRADE)

Outcome

(mean duration 14 weeks)

Events

Total

Events

Total

Peto Odds Ratio

I2

Mortality all‐cause

2

2924

0

1900

Peto OR 4.49

(95% CI 0.24 to 84.80)

0%

⊕⊕⊕⊝
moderate1

Non‐fatal SAE all‐cause

48

3401

25

2357

Peto OR 1.26

(95% CI 0.78 to 2.04)

15%

⊕⊕⊕⊝
moderate1

Mortality due to asthma

1

2495

0

1690

Peto OR 4.54

(95% CI 0.07 to 285.25)

Data from single trial

⊕⊕⊝⊝
low1,2

Non‐fatal SAE due to asthma

17

2849

10

022

Peto OR 1.09

(95% CI 0.50 to 2.40)

23%

⊕⊕⊝⊝
low1,2

Comparison

Cates 2008

Salmeterol Monotherapy

Placebo

Pooled Effect Size

(95% Confidence Interval)

Outcome

(mean duration 27 weeks)

Events

Total

Events

Total

Peto Odds Ratio

I2

Mortality all‐cause

44

14648

33

14480

Peto OR 1.33

(95% CI 0.85 to 2.08)

0%

⊕⊕⊕⊝
moderate1

Non‐fatal SAE all‐cause

587

15170

518

15026

Peto OR 1.14

(95% CI 1.01 to 1.28)

0%

⊕⊕⊕⊕
high

Mortality due to asthma

13

14648

3

14480

Peto OR 3.49

(95% CI 1.31 to 9.31)

Data from single trial

⊕⊕⊕⊕
high

Non‐fatal SAE due to asthma

23

1994

16

1847

Peto OR 1.43

(95% CI 0.75 to 2.71)

0%

⊕⊕⊝⊝
low1,2

Comparison

Cates 2012b

Formoterol Monotherapy

Salmeterol Monotherapy

Pooled Effect Size

(95% Confidence Interval)

Outcome

(mean duration 26 weeks)

Events

Total

Events

Total

Peto Odds Ratio

I2

Mortality all‐cause

0

554

1

662

Peto OR 0.14

(95% CI 0.00 to 6.82)

Data from single trial

⊕⊕⊝⊝
low1,3

Non‐fatal SAE all‐cause

28

554

36

662

Peto OR 0.77

(95% CI 0.46 to 1.28)

0%

⊕⊕⊝⊝
low1,3

Mortality due to asthma

0

554

0

662

Not estimable

Not applicable

Non‐fatal SAE due to asthma

6

554

7

662

Peto OR 0.86

(95% CI 0.29 to 2.57)

0%

⊕⊕⊝⊝
low1,3

Comparison

Cates 2013b

(with additional data from three new trials)

Formoterol Combination Therapy

Inhaled Corticosteroids

Pooled Effect Size

(95% Confidence Interval)

Outcome

(mean duration 29 weeks)

Events

Total

Events

Total

Peto Odds Ratio

I2

Mortality all‐cause

6

6507

1

4764

Peto OR 3.56

(95% CI 0.79 to 16.03)

0%

⊕⊕⊕⊝
moderate1

Non‐fatal SAE all‐cause

145

6507

115

4764

Peto OR 0.99

(95% CI 0.77 to 1.27)

0%

⊕⊕⊕⊝
moderate1

Mortality due to asthma

1

6507

0

4764

Peto OR 7.34

(95% CI 0.15 to 369.72)

Data from single trial

⊕⊕⊝⊝
low1,2

Non‐fatal SAE due to asthma

17

6325

30

4576

Peto OR 0.49

(95% CI 0.28 to 0.88)

0%

⊕⊕⊕⊝
moderate2

Comparison

Cates 2013a

Salmeterol Combination Therapy

Inhaled Corticosteroids

Pooled Effect Size

(95% Confidence Interval)

Outcome

(mean duration 34 weeks)

Events

Total

Events

Total

Peto Odds Ratio

I2

Mortality all‐cause

7

6986

7

6461

Peto OR 0.90

(95% CI 0.31 to 2.60)

0%

⊕⊕⊕⊝
moderate1

Non‐fatal SAE all‐cause

167

6986

135

6461

Peto OR 1.15

(95% CI 0.91 to 1.44)

0%

⊕⊕⊕⊝
moderate1

Mortality due to asthma

0

6986

0

6461

Not estimable

Not applicable

Non‐fatal SAE due to asthma

29

6986

23

6461

Peto OR 1.12

(95% CI 0.65 to 1.94)

5%

⊕⊕⊕⊝
moderate1

Comparison

Cates 2010

Formoterol Combination Therapy

Salmeterol Combination Therapy

Pooled Effect Size

(95% Confidence Interval)

Outcome

(mean duration 24 weeks)

Events

Total

Events

Total

Peto Odds Ratio

I2

Mortality all‐cause

4

3453

1

3316

Peto OR 2.68

(95% CI 0.44 to 16.14)

0%

⊕⊕⊕⊝
moderate1

Non‐fatal SAE all‐cause

90

3453

75

3316

Peto OR 1.12

(95% CI 0.82 to 1.53)

13%

⊕⊕⊕⊝
moderate1

Mortality due to asthma

0

3453

0

3316

Not estimable

Not applicable

Non‐fatal SAE due to asthma

17

3081

25

3082

Peto OR 0.69

(95% CI 0.37 to 1.26)

33%

⊕⊕⊝⊝
low1,2

1. Few events were observed leading to wide CIs (including the possibilities of no effect and appreciable harm)

2.There was no independent assessment of the cause of serious adverse events, leading to possible ascertainment bias for disease‐specific outcomes

3. Open studies

Figures and Tables -
Table 5. Summary of results of included Cochrane reviews
Table 6. Characteristics of included reviews

Review title

Inclusion criteria

Date of search

No. included studies (all versus placebo or ICS)

No. included studies (adults only versus placebo or ICS)

Studies

(Randomised trials only)

Participants

(Diagnosis of asthma; any age group)

Intervention

Comparison

Primary outcome measures

(All‐cause mortality & non‐fatal SAEs)

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

Cates 2012a

Yes

Yes

Inhaled formoterol twice/day; at least 12 weeks duration; any dose; any delivery device

Placebo or SABA

Yes

January 2012

20 (versus placebo)

15 (versus placebo)

2. Regular treatment with salmeterol for chronic asthma: serious adverse events Cates 2008

Yes

Yes

Inhaled salmeterol twice/day; at least 12 weeks duration; any dose; any delivery device

Placebo or SABA

Yes

August 2011

24 (versus placebo)

19 (versus placebo)

3. Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events Cates 2013b

Yes

Yes

ICS and formoterol once or twice/day; at least 12 weeks duration; any dose; any single or separate device

Same dose and type of ICS

Yes

August 2012

27

20

4. Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events Cates 2013a

Yes

Yes

ICS and salmeterol once or twice/day; at least 12 weeks duration; any dose; any single or separate device

Same dose and type of ICS

Yes

August 2012

40

35

5. Regular treatment with formoterol versus regular treatment with salmeterol for chronic asthma: serious adverse events Cates 2012b

Yes

Yes

Inhaled formoterol; at least 12 weeks duration; not randomised with ICS

Inhaled salmeterol; at least 12 weeks duration; not randomised with ICS

Yes

January 2012

4

3

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 2010

Yes

Yes

Inhaled formoterol with an ICS; at least 12 weeks duration; any dose; any single or separate delivery device

Inhaled salmeterol with an ICS; at least 12 weeks duration; any dose; any single or separate delivery device

Yes

August 2011

10

10

Figures and Tables -
Table 6. Characteristics of included reviews
Table 7. Characteristics of adult trials comparing formoterol monotherapy to placebo

Study ID from adults in Cates 2012a

% patients on background ICS

 (N)

 (N)

(N)

Placebo

(N)

Mortality data (all‐cause)

Duration (weeks)

Formoterol Dose

48 mcg/day

24 mcg/day

12 mcg/day

 

 

Bensch 2001

51

135

136

136

12

Busse 2004

64

80

80

12

Corren 2007

0

123

131

12

Corren 2013

0

111

109

12

Ekstrom 1998

86

135

129

 

12

Ekstrom 1998a

89

114

113

 

12

Fitzgerald 1999

100

89

91

24

LaForce 2005

67

86

91

12

Molimard 2001

100

130

129

12

Nathan 2012

0

116

111

12

Noonan 2006

100

123

125

12

Pleskow 2003

44

136

139

141

12

SD‐037‐0344

100

429

210

12

Steffensen 1995

87

103

101

 

12

van der Molen 1997

100

125

114

 

24

van Schayck 2002

95

46

41

12

Wolfe 2006

62

525

527

514

16

mean duration

14 weeks

All trials contributed data for non‐fatal serious adverse events of any cause. Corren 2013 and Nathan 2012 have been added to the trials already included in the Cochrane review.

Figures and Tables -
Table 7. Characteristics of adult trials comparing formoterol monotherapy to placebo
Table 8. Characteristics of adult trials comparing salmeterol monotherapy with placebo

Study ID from adults Cates 2008

% patients on background ICS

Number on salmeterol

**Dose of salmeterol (mcg/bd)

Number on placebo

Data found on mortality (all‐cause)

Data found on non‐fatal SAE (all‐cause)

Duration (weeks)

Adinoff 1998

64

142

50

244

 

 

36

Boyd 1995

100

55

100

64

 

12

Busse 1998

67

263

50

275

 

12

Chervinsky 1999

51

176

50

176

 

52

D'Alonso 1994a

21

106

50

108

 

 

12

D'Urso 2001

93

455

50

456

24

Kavuru 2000

0*

92

50

82

12

Kemp 1998a

43

149

50

152

 

 

12

Kemp 1998b

100

252

50

254

 

12

Lazarus 2001

0*

54

50

56

16

Nathan 1999

0*

128

50

129

26

Nathan 2006

0*

91

50

89

 

12

Pearlman 1992

25

78

50

79

 

12

Pearlman 2004

0*

92

50

87

 

12

Rosenthal 1999

0

202

50

206

 

 

24

Shapiro 2000

0*

88

50

93

12

SLMF4002

100

93

100

95

26

SMART 2006

47

13,176

50

13,179

28

Wolfe 2000

33

331

50

167

12

mean duration

27 weeks

* background ICS treatment was withdrawn from all participants

** 50 micrograms is the ex‐actuator dose, but in some studies this is reported as the equivalent delivered dose of 42 micrograms

Figures and Tables -
Table 8. Characteristics of adult trials comparing salmeterol monotherapy with placebo
Table 9. Characteristics of adult trials comparing formoterol monotherapy to salmeterol monotherapy (with background ICS)

Study ID from adults in Cates 2012b

N

Age

Formoterol  Device

Salmeterol Device

Location

Sponsor

Duration (weeks)

Condemi  2001

528

18+

Foradil Aerolizer

Serevent Diskus

USA

Novartis

26

Gabbay 1998

127

18+

Foradil Aerolizer

Serevent Diskus

UK

Novartis

12

Vervolet 1998

482

18+

Foradil Aerolizer

Serevent Diskus

Europe

Novartis

26

Total

1137

mean duration 24 weeks

All the above trials compared formoterol (Foradil) 12 mcg twice daily with salmeterol 50 mcg twice daily and all participants were taking a background inhaled corticosteroid.

Figures and Tables -
Table 9. Characteristics of adult trials comparing formoterol monotherapy to salmeterol monotherapy (with background ICS)
Table 10. Characteristics of adult trials comparing formoterol combination therapy versus same dose ICS

Study ID from adults in Cates 2013b

Age (Years

N on F&ICS

N on ICS Alone

Daily dose of budesonide or other ICS (mcg metered dose)

Daily Dose of Formoterol (mcg metered dose)

Once daily

Twice daily

Combined inhalers

Separate inhalers

DPI

pMDI

Duration weeks

Brown 2012

12+

377

364

800

24

52

Buhl 2003

18+

352

171

400

12

12

Chuchalin 2002

18+

111

114

400

24

12

Corren 2007

12+

123

121

400

24

12

Corren 2013

12+

110

113

250 (fluticasone)

12

12

D5896C00001

12+

312

153

400

12/24

12

Jenkins 2006

12+

341

115

1600

48

24

Kuna 2006

18+

409

207

200

12

12

Meltzer 2012

12+

182

188

200 (mometasone)

20

26

Morice 2007

12+

462

217

800

24

12

Nathan 2010

12+

191

192

400 (mometasone)

20

26

Nathan 2012

12+

115

117

100 (fluticasone)

12

12

Noonan 2006

12+

239

109

400

24

12

O'Byrne 2001

18+

554

550

400

12

52

O'Byrne 2001a

18+

315

312

800

12

52

Pauwels 1997

18+

210

213

200

24

52

Pauwels 1997a

18+

215

214

800

24

52

Pearlman 2012

12+

119

119

100 (fluticasone)

12

12

Peters 2008

12+

443

133

1600

48

52

Price 2002

12+

250

255

800

24

24

SD‐039‐0726

16+

301

145

200

12/24

12

Spector 2012

12+

156

155

800

24

12

Weinstein 2010

12+

255

240

800 (mometasone)

20

12

Zangrilli 2011

12+

127

123

800

24

12

Zetterstrom 2001

18+

238

124

800

24

12

mean duration

29 weeks

All trials of combination salmeterol and ICS contributed data on fatal and non‐fatal serious adverse events of any cause. Corren 2013, Nathan 2012 and Pearlman 2012 have been added to the trials already included in the Cochrane review.

Figures and Tables -
Table 10. Characteristics of adult trials comparing formoterol combination therapy versus same dose ICS
Table 11. Characteristics of adult trials comparing salmeterol combination therapy versus ICS

Study ID from adults in Cates 2013a

Age of Participants (Years)

N on FSC

N on ICS

Daily dose of fluticasone (mcg)

Daily dose of salmeterol (mcg)

Combined Inhaler

Separate Inhalers

Duration (weeks)

Aubier 1999

12+

338

165

1000

100

28

Bailey 2008

12+

239

236

200

100

52

Bateman 2001

12+

1709

1707

200

100

52

GOAL 2004

12+

333

165

200/500/1000

100

12

Godard 2008

18+

159

159

500

100

24

Ind 2003

16+

336

160

500

100

28

Katial 2011

12+

306

315

500

100

52

Kavuru 2000

12+

310

318

200

100

52

Kerwin 2011

12+

92

90

500

100

12

Koenig 2008

12+

156

156

200/500/1000

100

40

Koopmans 2006

18+

173

177

500

100

12

Lundback 2006

18+

101

102

500

100

12

Murray 2004

12+

94

91

200

100

12

Nathan 2006

12+

171

168

220

100

16

Nelson 2003

12+

95

97

200

100

12

Pearlman 2004

12+

92

89

200

100

12

Renzi 2010

12+

262

270

200

100

24

Rojas 2007

12+

180

182

500

100

12

SAM30007

18+

29

32

200/500/1000

100

30

SAM40004

18+

42

21

200

100

52

SAM40008

18+

93

93

1000

100

26

SAM40031

18+

41

41

200/500/1000

100

52

SAM40065

12+

150

150

200/500/1000

100

40

SAS30022

12+

210

212

500

50

12

SAS30023

12+

151

155

100

50

12

SAS40036

15+

172

159

200

100

16

SAS40037

15+

161

161

200

100

16

SAS40068

12+

262

270

200

100

24

SFA103153

12+

239

236

200

100

52

SFCF4026

18+

159

159

500

100

24

Shapiro 2000

12+

84

84

500

100

12

SLGF75

16+

14

17

200

100

12

Strand 2004

18+

78

72

200

100

12

van Noord 2001

12+

337

172

1000

100

12

Wallin 2003

12+

18

19

400

100

12

mean duration

34 weeks

All trials of combination salmeterol and ICS contributed data on fatal and non‐fatal serious adverse events of any cause

Figures and Tables -
Table 11. Characteristics of adult trials comparing salmeterol combination therapy versus ICS
Table 12. Characteristics of adult trials comparing formoterol combination therapy to salmeterol combination therapy

Study ID from adults in Cates 2010

N

Duration (weeks)

Formoterol device

Formoterol dose

ICS type and dose

Salmeterol device

Salmeterol dose

ICS type and dose

Duration (weeks)

Aalbers 2004

439

26

DPI

12 µg bd

Budesonide 400 µg bd

DPI

50 µg bd

Fluticasone 250 µg bd

26

Bodzenta‐Lukaszyk 2011

202

12

HFA pMDI with AeroChamber

10 µg bd

Fluticasone 100 µg or 250 µg bd

HFA pMDI with AeroChamber

50 µg bd

Fluticasone 100 µg or 250 µg bd

12

Busse 2008

833

30

pMDI

12 µg bd

Budesonide 400 µg bd

DPI

50 µg bd

Fluticasone 250 µg bd

30

Dahl 2006

1397

24

DPI

12 µg bd

Budesonide 400 µg bd

DPI

50 µg bd

Fluticasone 250 µg bd

24

Kuna 2007

2218

24

DPI

12 µg bd

Budesonide 400 µg bd

pMDI

50 µg bd

Fluticasone 250 µg bd

24

Maspero 2010

404

52

pMDI

10 µg bd

Mometasone 200 µg or 400 µg bd

pMDI

50 µg bd

Fluticasone 250 µg or 500 µg bd

52

Papi 2007

228

12

pMDI

12 µg bd

Beclomethasone extra fine 200 µg bd

pMDI

50 µg bd

Fluticasone 250 µg bd

12

Ringdal 2002

428

12

DPI two separate inhalers

12 µg bd

Budesonide 800 µg bd

DPI

50 µg bd

Fluticasone 250 µg bd

12

SAM 40010

373

12

DPI

6 µg bd

Budesonide 200 µg bd

DPI

50 µg bd

Fluticasone 100 µg bd

12

SAM 40048

247

12

DPI

6 µg bd

Budesonide 200 µg bd

DPI

50 µg bd

Fluticasone 250 µg bd

12

mean duration 23 weeks

All trials of combination salmeterol and ICS contributed data on fatal and non‐fatal serious adverse events of any cause

Figures and Tables -
Table 12. Characteristics of adult trials comparing formoterol combination therapy to salmeterol combination therapy
Table 13. AMSTAR ratings

AMSTAR Criteria

Cates 2012a

Cates 2008

Cates 2013b

Cates 2013a

Cates 2012b

Cates 2010

1. Was an 'a priori' design provided? 

Yes

Yes

Yes

Yes

Yes

Yes

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

Yes

Yes

Yes

Yes

Yes

No

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

No

No

Yes

Yes

Yes

No

3. Was a comprehensive literature search performed?

Yes

Yes

Yes

Yes

Yes

Yes

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

No

No

No

No

No

No

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

Yes

Yes

Yes

Yes

Yes

Yes

6. Were the characteristics of the included studies provided?

Yes

Yes

Yes

Yes

Yes

Yes

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

Yes

Yes

Yes

Yes

Yes

Yes

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

Yes

Yes

Yes

Yes

Yes

Yes

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

Yes

Yes

Yes

Yes

Yes

Yes

10. Was the likelihood of publication bias assessed?

Yes

Yes

Yes

Yes

Not applicable

Not applicable

11. Was the conflict of interest stated?

Yes

Yes

Yes

Yes

Yes

Yes

Total criteria met:

10.5

10.5

11

11

10

9

Note: item 4 is met with the assessment 'NO', all others 'YES'. 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.

Figures and Tables -
Table 13. AMSTAR ratings
Table 14. Mean rate of serious adverse events in control arms of included trials

 Comparison

Adults with an event on control (n)

Total number of adults on control (N)

SAE per 10,000 adults (95% CI)

Mean duration of trials (weeks)

SAE per 10,000 adults per week

Formoterol v Placebo

25

2357

106 (65 to 147)

14

7.6

Salmeterol v Placebo

518

15026

345 (317 to 375)

27

12.8

Formoterol & ICS v ICS

115

4764

241 (197 to 285)

29

8.3

Salmeterol & ICS v ICS

135

6461

209 (177 to 247)

34

6.1

Figures and Tables -
Table 14. Mean rate of serious adverse events in control arms of included trials
Table 15. Mortality by cause of death in combination formoterol trials

Study ID

Treatment arm

Cause of death

Buhl 2003

Formoterol and budesonide

Cardiac arrest

O'Byrne 2001

Formoterol and budesonide (separate inhalers)

Status asthmaticus, followed by septic shock

Pauwels 1997a

Formoterol and budesonide (separate inhalers)

Suicide

Zetterstrom 2001

Formoterol and budesonide

Suicide

Brown 2012

Formoterol and budesonide

Cerebro‐vascular accident

Brown 2012

Budesonide

Homicide

Nathan 2010

Formoterol and mometasone

Uterine Leiomyosarcoma

Jenkins 2006

Formoterol and budesonide

Pulmonary embolus (but the death occurred after the control budesonide arm was discontinued so was not included in the meta‐analysis)

Figures and Tables -
Table 15. Mortality by cause of death in combination formoterol trials
Table 16. Mortality by cause of death on combination therapy with salmeterol

Study ID

Treatment arm

Cause of death

Aubier 1999

salmeterol and fluticasone

(separate inhalers)

Bronchial carcinoma (one death)

GOAL 2004

salmeterol/fluticasone

Myocardial infarction (two deaths) and pneumonia (one death)

GOAL 2004

fluticasone

Myocardial infarction (two deaths)

Ind 2003

salmeterol and fluticasone

(separate inhalers)

Pneumothorax (one death)

Kerwin 2011

salmeterol/fluticasone

Cardiac disease (one death)

Kerwin 2011

fluticasone

Breast cancer (one death)

Koenig 2008

fluticasone

Cardiac arrest and deep vein thrombosis (one death)

Renzi 2010

fluticasone

Cardiac arrest (one death)

SAS40068

fluticasone

Ventricular hypertrophy and aortic hypoplasia (one death)

Strand 2004

fluticasone

Unknown cause (one death)

van Noord 2001

salmeterol/fluticasone

Leukaemia (one death)

Figures and Tables -
Table 16. Mortality by cause of death on combination therapy with salmeterol