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

Christopher J Cates; Marta Oleszczuk; Elizabeth Stovold; L. Susan Wieland

doi:10.1002/14651858.CD010005.pub2

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Figure 1

Network of comparisons of serious adverse events with regular formoterol and salmeterol (with or without regular inhaled corticosteroids (ICS)). Red lines show direct comparisons between formoterol and salmeterol. Green lines show direct comparisons for each drug with placebo (Figure 1A) or ICS (Figure 1B), and can be compared (horizontally) with each other to make indirect comparisons of formoterol and salmeterol. The placebo comparison results (Figure 1A) can also be compared (vertically) to the ICS comparison results (Figure 1B) to indirectly assess the impact of ICS on the serious adverse events with formoterol and salmeterol.

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Figure 2

Review selection flow diagram.

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Figure 3

Children with all‐cause SAEs compared using Peto ORs

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Figure 4

Children with an all‐cause SAE: formoterol versus placebo subgrouped by brand and dose

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Figure 5

Interaction between randomised use of ICS and children with all‐cause SAE on regular LABA using ORs

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Figure 6

Cates plot of monotherapy versus placebo trials: In the placebo group 36 people out of 1000 had non‐fatal serious adverse events of any cause over 29 weeks, compared to 57 (95% CI 40 to 81) out of 1000 for the LABA monotherapy group. The crossed‐out faces show that there were 21 additional children suffering an SAE for every 1000 treated with LABA monotherapy.

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Figure 7

Cates plot of combination therapy versus ICS trials: In the ICS group 7 people out of 1000 had non‐fatal serious adverse events of any cause over 14 weeks, compared to 10 (95% CI 6 to 19) out of 1000 for the combination therapy group. The crossed‐out faces show that there were 3 additional children suffering an SAE for every 1000 treated with LABA combination therapy.

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Figure 8

Indirect comparison of formoterol and budesonide with salmeterol and fluticasone

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Figure 9

Children with asthma‐related SAE compared using Peto OR

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Figure 10

Interaction between randomised use of ICS and children with asthma‐related SAE on regular LABA using ORs

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

Comparison	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Control	Regular LABA (salmeterol or formoterol)
Children with a fatal serious adverse event of any cause
All comparisons	see comment	see comment	see comment	see comment	see comment	There 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 placeboCates 2012a Follow‐up: mean 27 weeks	12 per 1000	30 per 1000 (15 to 56)	OR 2.48 (1.27 to 4.83)	1335 (5 studies)	⊕⊕⊕⊕ high
Regular salmeterol versus placeboCates 2008 Follow‐up: mean 31 weeks	56 per 1000	72 per 1000 (46 to 108)	OR 1.3 (0.82 to 2.05)	1333 (5 studies)	⊕⊕⊕⊝ moderate¹
Regular formoterol & ICS versus ICSCates 2009b Follow‐up: mean 13 weeks	8 per 1000	14 per 1000 (7 to 27)	OR 1.62 (0.80 to 3.28)	2788 (7 studies)	⊕⊕⊕⊝ moderate¹
Regular salmeterol & ICS versus ICSCates 2009a Follow‐up: mean 15 weeks	5 per 1000	6 per 1000 (2 to 19)	OR 1.20 (0.37 to 3.91)	1862 (5 studies)	⊕⊕⊕⊝ moderate¹
Regular formoterol versus regular salmeterolCates 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)	⊕⊕⊝⊝ low^1,2	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 placeboCates 2012a Follow‐up: mean 27 weeks	2 per 1000	8 per 1000 (4 to 18)	OR 4.06 (1.78 to 9.22)	1335 (5 studies)	⊕⊕⊕⊕ high
Regular salmeterol versus placeboCates 2008 Follow‐up: mean 31 weeks	33 per 1000	55 per 1000 (33 to 92)	OR 1.72 (1 to 2.98)	1333 (5 studies)	⊕⊕⊕⊕ high
Regular formoterol & ICS versus ICSCates 2009b Follow‐up: mean 13 weeks	4 per 1000	6 per 1000 (2 to 17)	OR 1.49 (0.48 to 4.61)	2788 (7 studies)	⊕⊕⊝⊝ low^1,3
Regular salmeterol & ICS versus ICSCates 2009a Follow‐up: mean 15 weeks	1 per 1000	1 per 1000 (0 to 17)	OR 0.99 (0.06 to 15.85)	1862 (5 studies)	⊕⊕⊝⊝ low^1,3
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 1. Summary of findings ‐ children with a serious adverse event

	Inclusion criteria
Review title	Studies	Participants	Intervention	Comparison	Primary outcome measures	Date of search	No. included studies (all)	No. included studies (children only)
1. Regular treatment with formoterol for chronic asthma: serious adverse events Cates 2012a	Randomised controlled trials	Diagnosis of asthma; any age group	Inhaled formoterol twice/day; at least 12 weeks duration; any dose; any delivery device	Placebo or short‐acting beta₂‐agonists	All‐cause mortality All‐cause non‐fatal SAEs	January 2012	22	5
2. Regular treatment with salmeterol for chronic asthma: serious adverse events Cates 2008	Randomised controlled trials	Diagnosis of asthma; any age group	Inhaled salmeterol twice/day; at least 12 weeks duration; any dose; any delivery device	Placebo or short‐acting beta₂‐agonists	All‐cause mortality All‐cause non‐fatal SAEs	August 2011	32	5
3. Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events Cates 2009b	Randomised controlled trials	Diagnosis of asthma; any age group	Inhaled corticosteroids and formoterol once or twice/day; at least least 12 weeks duration; any dose; any single or separate device	Same dose and type of inhaled corticosteroids	All‐cause mortality All‐cause non‐fatal SAEs	October 2008	21	7
4. Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events Cates 2009a	Randomised controlled trials	Diagnosis of asthma; any age group	Inhaled corticosteroids and salmeterol once or twice/day; at least least 12 weeks duration; any dose; any single or separate device	Same dose and type of inhaled corticosteroids	All‐cause mortality All‐cause non‐fatal SAEs	October 2008	33	3 (2 additional studies identified by updated search)
5. Regular treatment with formoterol versus regular treatment with salmeterol for chronic asthma: serious adverse events Cates 2012b	Randomised controlled trials	Diagnosis of asthma; any age group	Inhaled formoterol; at least 12 weeks duration; not randomised with inhaled corticosteroids	Inhaled salmeterol; at least 12 weeks duration; not randomised with inhaled corticosteroids	All‐cause mortality All‐cause non‐fatal SAEs	January 2012	4	1
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	Randomised controlled trials	Diagnosis of asthma; any age group	Inhaled formoterol with an inhaled steroid; at least 12 weeks duration; any dose; any single or separate delivery device	Inhaled salmeterol with an inhaled steroid; at least 12 weeks duration; any dose; any single or separate delivery device	All‐cause mortality All‐cause non‐fatal SAEs	August 2011	7	0

	Duration (weeks)	% children on ICS background Rx	Formoterol 48 mcg/day (N)	Formoterol 24 mcg/day (N)	Formoterol 12 mcg/day (N)	Placebo (N)	Brand	Age Ranges
Bensch 2002	52	69	171	171		176	Foradil	5 to 12
Corren 2007	12	0		9		9	Oxis	6 to 11
Levy 2005	12	72		127		122	Foradil	5 to 13
Von Berg 2003	12	82		83	81	84	Oxis	6 to 17
Zimmerman 2004	12	100		94	105	101	Oxis	6 to 11
Total	mean = 27 weeks		171	475	186	492
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.

	Duration (weeks)	% children on ICS background Rx	Salmeterol 100 mcg/day (N)	Salmeterol 50 mcg/day (N)	Placebo(N)	Age Ranges
Russell 1995	12	100	99		107	4 to 16
Simons 1997	52	0	80		80	6 to 14
SLGA3014	12	50	109	115	110	4 to 11
von Berg 1998	52	52	220		206	5 to 15
Weinstein 1998	12	57	102		105	4 to 11
TOTAL	mean =31 weeks		610	115	608
All trials were sponsored by GSK and contributed data on all‐cause mortality and non‐fatal serious adverse events

Children and Adolescents	Duration (weeks)	Formoterol and ICS (N)	ICS Alone (N)	Daily Dose Budesonide (mcg )	Daily Dose Formoterol (mcg )	Combined Inhaler	Age Ranges
Morice 2008	12	415	207	200	24	✓	6 to 11
Pohunek 2006	12	417	213	400	24	✓	4 to 11
SD‐039‐0714	12	136	134	400	12	✓	11 to 17
SD‐039‐0718	12	128	145	200	24	✓	6 to 15
SD‐039‐0719	26	123	63	400	24	✓	6 to 11
SD‐039‐0725	12	352	169	200	12 or 24	✓	6 to 15
Tal 2002	12	148	138	400	24	✓	4 to 17
Total	mean = 13 weeks	1,719	1,069
All trials were sponsored by AstraZeneca and contributed data on fatal and non‐fatal serious adverse events

	Duration (Weeks)	Salmeterol & ICS	ICS alone	Dose of Fluticasone mcg/day	Dose of Salmeterol mcg/day	Combined Inhaler	Age Ranges
Li 2010	12	173	177	200	100	✓	4 to 11
Malone 2005	12	101	102	200	100	✓	4 to 11
NCT01192178	16	171	168	200	100	✓	4 to 11
SAM40012	24	181	181	200	100	✓	4 to 11
SAS30021	12	304	304	100	50	✓	4 to 11
Total	mean = 15 weeks	930	932
All trials were sponsored by GSK and contributed data on all‐cause mortality and non‐fatal serious adverse events

	Duration (Weeks)	% children on ICS background Rx	Formoterol 24 mcg/day	Salmeterol 100 mcg/day	Formoterol device	Salemterol device	Sponsors	Age Ranges
Everden 2004	12	100%	80	76	Oxis Turbohaler	Salmeterol Accuhaler	AstraZeneca	6 to 17

AMSTAR Criteria	Cates 2008	Cates 2012a	Cates 2009a	Cates 2009b	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
*(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.

Cochrane review	trial ID	sequence generation	allocation concealment	blinding	incomplete outcome data	selective reporting
"Regular tretatment with formoterol for chronic asthma: SAE" Cates 2012a	Bensh 2002	unclear	unclear	low	low	low
	Levy 2005	unclear	unclear	low	low	unclear¹
	von Berg 2003	low	unclear	low	low	low
	Zimmenman 2004	unclear	unclear	low	unclear	low
	Corren 2002	low	unclear	low	unclear	low
"regular treatment with salmeterol for chronic asthma: SAE" Cates 2008	Lenny 1995a	n/a	unclear	low	n/a	low
	Lenny 1995b	n/a	unclear	low	n/a	low
	Russel 1995	n/a	unclear	low	n/a	low
	Simons 1997	n/a	unclear	low	n/a	low
	SLGA 3014	n/a	unclear	low	n/a	low
	von Berg 1998	n/a	unclear	low	n/a	low
	Weinstein 1998	n/a	unclear	low	n/a	low
"Regular treatment with formoterol and ICS for chronic asthma: SAE" Cates 2009b	Morice 2008	low	unclear	low	low	low
	Pohunek 2006	unclear	unclear	low	low	low
	SD‐039‐0714	unclear	unclear	low	low	low
	SD‐039‐0718	low	unclear	low	low	low
	SD‐039‐0719	unclear	unclear	high	low	low
	SD‐039‐0725	unclear	unclear	low	low	low
	Tal 2002	low	unclear	low	low	low
"Regular treatment with salmeterol and ICS for chronic asthma: SAE" Cates 2009a	Li 2010	unclear	unclear	low	low	low
	Malone 2005	unclear	unclear	low	low	low
	NCT01192178	unclear	unclear	low	low	low
	SAM40012	unclear	unclear	low	low	low
	SAS30021	unclear	unclear	low	low	low
"Regular treatment with formoterol versus regular treatment with satmeterol for chronic asthma: SAE" Cates 2012b	Everden 2004	low	unclear	high	low	low
1. No mortality data was available from this trial

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

Formoterol monotherapy		Placebo		Risk Difference (95% CI)	Heterogeneity (I‐squared)
Children with SAE	Total	Children with SAE	Total
34	843	6	492	0.0195 (‐0.0034, 0.0425)	55%

Salmeterol monotherapy		Placebo		Risk Difference (95% CI)	Heterogeneity (I‐squared)
Children with SAE	Total	Children with SAE	Total
46	725	34	608	0.0225 (0.0023, 0.0426)	0%

Formoterol combination therapy		ICS		Risk Difference (95% CI)	Heterogeneity (I‐squared)
Children with SAE	Total	Children with SAE	Total
25	1719	9	1069	0.0034 (‐0.0062, 0.0131)	34%

Salmeterol combination therapy		ICS		Risk Difference (95% CI)	Heterogeneity (I‐squared)
Children with SAE	Total	Children with SAE	Total
6	930	5	932	0.0008 (‐0.0067, 0.0082)	0%

Comparison	Children 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 Placebo	6	492	122 (56 to 263)	27	5 (2 to 10)
Salmeterol v Placebo	34	608	559 (403 to 771)	31	18 (13 to 25)
Formoterol & ICS v ICS	9	1069	84 (44 to 159)	13	6 (3 to 12)
Salmeterol & ICS v ICS	5	932	54 (23 to 125)	15	4 (2 to 8)

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

LABA monotherapy		Placebo		Risk Difference (95% CI)	Heterogeneity (I‐squared)
Children with SAE	Total	Children with SAE	Total
80	1568	40	1100	0.0191 (0.0061, 0.0321)	15%

LABA combination therapy		ICS		Risk Difference (95% CI)	Heterogeneity (I‐squared)
Children with SAE	Total	Children with SAE	Total
31	2649	14	2001	0.0017 (‐0.0037, 0.0070)	2%

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

Formoterol monotherapy		Placebo		Risk Difference (95% CI)	Heterogeneity (I‐squared)
Children with SAE	Total	Children with SAE	Total
25	843	1	492	0.0196 (‐0.0071, 0.0463)	75%

Salmeterol monotherapy		Placebo		Risk Difference (95% CI)	Heterogeneity (I‐squared)
Children with SAE	Total	Children with SAE	Total
35	725	20	608	0.0185 (0.0027, 0.0343)	0%

Formoterol combination therapy		ICS		Risk Difference (95% CI)	Heterogeneity (I‐squared)
Children with SAE	Total	Children with SAE	Total
9	1719	4	1069	0.0000 (‐0.0064, 0.0064)	19%

Salmeterol combination therapy		ICS		Risk Difference (95% CI)	Heterogeneity (I‐squared)
Children with SAE	Total	Children with SAE	Total
1	930	1	932	‐0.0005 (‐0.0058, 0.0048)	0%

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