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.

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.

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.

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.

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

⊕⊕⊝⊝
low^1,2

Non‐fatal SAE due to asthma

17

2849

10

022

Peto OR 1.09

(95% CI 0.50 to 2.40)

23%

⊕⊕⊝⊝
low^1,2

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%

⊕⊕⊝⊝
low^1,2

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

⊕⊕⊝⊝
low^1,3

Non‐fatal SAE all‐cause

28

554

36

662

Peto OR 0.77

(95% CI 0.46 to 1.28)

0%

⊕⊕⊝⊝
low^1,3

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%

⊕⊕⊝⊝
low^1,3

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

⊕⊕⊝⊝
low^1,2

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%

⊕⊕⊝⊝
low^1,2

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

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

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

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

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

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

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

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.

 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

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)

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)