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Tratamiento por inhalación de acción prolongada (agonistas beta, anticolinérgicos y esteroides) para la EPOC: un metanálisis de redes

Appendices

Appendix 1. The Cochrane Library search strategy

#1           MeSH descriptor: [Pulmonary Disease, Chronic Obstructive] explode all trees

#2           MeSH descriptor: [Lung Diseases, Obstructive] this term only

#3           COPD:ti

#4           (obstruct*) near/3 (pulmonary or lung* or airway* or airflow* or bronch* or respirat*):ti

#5           #1 or #2 or #3 or #4

#6           indacaterol

#7           salmeterol

#8           *formoterol

#9           long* near (beta* near agonist*)

#10         budesonide

#11         fluticasone

#12         mometasone

#13         inhal* near (corticosteroid* or steroid*)

#14         tiotropium

#15         aclidinium

#16         Glycopyrronium

#17         long* near muscarinic*

#18         umeclidinium

#19         vilanterol

#20         (LABA or LAMA or ICS):ti,ab

#21         {or #6‐#20}

#22         #5 and #21

Appendix 2. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

Electronic searches: core databases

Database

Frequency of search

CENTRAL (The Cochrane Library)

Monthly

MEDLINE (Ovid)

Weekly

EMBASE (Ovid)

Weekly

PsycINFO (Ovid)

Monthly

CINAHL (EBSCO)

Monthly

AMED (EBSCO)

Monthly

 

Handsearches: core respiratory conference abstracts

Conference

Years searched

American Academy of Allergy, Asthma and Immunology (AAAAI)

2001 onwards

American Thoracic Society (ATS)

2001 onwards

Asia Pacific Society of Respirology (APSR)

2004 onwards

British Thoracic Society Winter Meeting (BTS)

2000 onwards

Chest Meeting

2003 onwards

European Respiratory Society (ERS)

1992, 1994, 2000 onwards

International Primary Care Respiratory Group Congress (IPCRG)

2002 onwards

Thoracic Society of Australia and New Zealand (TSANZ)

1999 onwards

 

MEDLINE search strategy used to identify trials for the CAGR

COPD  search

1. Lung Diseases, Obstructive/

2. exp Pulmonary Disease, Chronic Obstructive/

3. emphysema$.mp.

4. (chronic$ adj3 bronchiti$).mp.

5. (obstruct$ adj3 (pulmonary or lung$ or airway$ or airflow$ or bronch$ or respirat$)).mp.

6. COPD.mp.

7. COAD.mp.

8. COBD.mp.

9. AECB.mp.

10. or/1‐9

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1‐7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and the RCT filter are adapted to identify trials in other electronic databases

Appendix 3. Search to retrieve relevant trials from the CAGR

#1 MeSH DESCRIPTOR Pulmonary Disease, Chronic Obstructive Explode All

#2 MeSH DESCRIPTOR Bronchitis, Chronic

#3 (obstruct*) near3 (pulmonary or lung* or airway* or airflow* or bronch* or respirat*)

#4 COPD:MISC1

#5 (COPD OR COAD OR COBD):TI,AB,KW

#6 #1 OR #2 OR #3 OR #4 OR #5

#7 indacaterol or QAB149

#8 salmeterol

#9 *formoterol

#10 long* near (beta* near agonist*)

#11 budesonide

#12 fluticasone

#13 mometasone

#14 inhal* near (corticosteroid* or steroid*)

#15 tiotropium

#16 aclidinium or LAS34273

#17 Glycopyrronium or NVA237

#18 long* near muscarinic*

#19 umeclidinium or GSK573719

#20 vilanterol or GW642444

#21 (LABA or LAMA or ICS):TI,AB

#22 #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21

#23 #6 and #22

[Note: in search line #4, MISC1 refers to the field in which the record has been coded for condition, in this case, COPD]

Appendix 4. SGRQ class effects versus placebo (12 months)a

Effect vs placebo
Class NWMA

Effect vs placebo
Sensitivity analysis

Rank

Class

Median

95% CrI

Median

95% CrI

Mean

Median

95% CrI

Pr (best)

LABA/ICS

‐3.60

(‐4.63 to ‐2.34)

‐3.53

(‐4.69 to ‐2.15)

1.2

1

(1 to 3)

0.86

LAMA

‐2.50

(‐3.30 to ‐1.68)

‐2.56

(‐3.49 to ‐1.69)

2.9

3

(1 to 4)

0.04

LABA

‐2.55

(‐3.68 to ‐1.70)

‐2.61

(‐3.82 to ‐1.68)

2.8

3

(1 to 4)

0.07

ICS

‐2.34

(‐3.45 to ‐1.27)

‐2.34

(‐3.58 to ‐1.16)

3.2

3

(1 to 4)

0.03

aFor effects versus placebo, smaller values indicate larger benefits of the active treatment

Crl = credible interval.

SGRQ = St George's Respiratory Questionnaire.

ICS = inhaled corticosteroid.

LABA = long‐acting beta2‐agonist.

LABA/ICS = long‐acting beta2‐agonist/inhaled corticosteroid.

LAMA = long‐acting antimuscarinic antagonist.

NWMA = network meta‐analysis.

Pr = probability.

Appendix 5. SGRQ individual treatment effects versus placebo (12 months)a

Effect vs placebo
Class NWMA

Rank

Class

Treatment

Median

95% CrI

Mean

Median

95% CrI

Pr (best)

LABA

Form 12 (2)

‐2.51

(‐3.39 to ‐1.73)

10.7

11

(4 to 17)

0.00

Form 24 (2)

‐2.71

(‐4.43 to ‐1.60)

8.8

8

(1 to 18)

0.05

Ind 300 (1)

‐2.85

(‐4.44 to ‐1.77)

7.8

7

(1 to 17)

0.06

Ind 6000 (1)

‐2.81

(‐4.38 to ‐1.74)

8.1

7

(1 to 17)

0.05

Salm 50 (2)

‐1.81

(‐2.62 to ‐0.92)

16.0

17

(9 to 18)

0.00

LAMA

Tio 5 (1)

‐2.77

(‐3.50 to ‐2.08)

8.1

8

(3 to 15)

0.00

Tio 10 (1)

‐2.83

(‐4.04 to ‐1.92)

7.6

7

(1 to 16)

0.03

Tio 18 (1)

‐2.15

(‐2.88 to ‐1.33)

13.6

14

(6 to 18)

0.00

Acl 200 (1)

‐2.33

(‐3.28 to ‐1.16)

12.0

12

(4 to 18)

0.00

Acl 200 (2)

‐2.52

(‐3.94 to ‐1.08)

10.3

10

(2 to 18)

0.02

Acl 400 (2)

‐2.49

(‐3.89 to ‐1.04)

10.5

11

(2 to 18)

0.02

Gly 50 (1)

‐2.42

(‐3.31 to ‐1.40)

11.2

11

(4 to 18)

0.00

ICS

Bud 400 (2)

‐2.33

(‐3.48 to ‐1.21)

12.0

12

(4 to 18)

0.00

Flut 500 (2)

‐2.16

(‐2.89 to ‐1.41)

13.5

14

(6 to 18)

0.00

Mom 400 (2)

‐2.51

(‐3.97 to ‐1.31)

10.4

11

(2 to 18)

0.02

LABA/ICS

Form‐bud 12/160 (2)

‐3.45

(‐4.75 to ‐1.62)

4.9

3

(1 to 16)

0.19

Form‐bud 12/320 (2)

‐3.74

(‐4.80 to ‐2.70)

2.6

2

(1 to 8)

0.35

Salm‐flut 50/500 (2)

‐3.58

(‐4.29 to ‐2.85)

3.1

3

(1 to 8)

0.21

aFor effects versus placebo, smaller values indicate larger benefits of the active treatment. All doses are in micrograms

Crl = credible interval.

SGRQ = St George's Respiratory Questionnaire.

ICS = inhaled corticosteroid.

LABA = long‐acting beta2‐agonist.

LABA/ICS = long‐acting beta2‐agonist/inhaled corticosteroid.

LAMA = long‐acting antimuscarinic antagonist.

NWMA = network meta‐analysis.

Pr = probability.

Appendix 6. FEV1 class effects versus placebo (12 months)a

Effect vs placebo
Class NWMA

Effect vs placebo
Sensitivity analysis

Rank

Class

Median

95% CrI

Median

95% CrI

Mean

Median

95% CrI

Pr (best)

LABA/ICS

100.80

(55.50 to 140.10)

100.00

(53.77 to 141.50)

1.7

1

(1 to 3)

0.5

LAMA

92.64

(56.23 to 129.60)

94.23

(56.08 to 134.30)

2.0

2

(1 to 3)

0.3

LABA

87.05

(47.28 to 130.50)

86.88

(46.12 to 132.00)

2.3

2

(1 to 3)

0.2

ICS

28.36

(‐11.93 to 65.70)

28.00

(‐13.34 to 66.90)

4.1

4

(4 to 5)

0.0

aFor effects versus placebo, smaller values indicate larger benefits of the active treatment.

Crl = credible interval.

FEV1 = forced expiratory volume in one second.

ICS = inhaled corticosteroid.

LABA = long‐acting beta2‐agonist.

LABA/ICS = long‐acting beta2‐agonist/inhaled corticosteroid.

LAMA = long‐acting antimuscarinic antagonist.

NWMA = network meta‐analysis.

Pr = probability.

Appendix 7. FEV1 individual treatment effects versus placebo (12 months)a

Effect vs placebo
Class NWMA

Rank

Class

Treatment

Median

95% CrI

Mean

Median

95% CrI

Pr (best)

LABA

Form 12 (2)

69.96

(33.27 to 105.40)

12.2

13

(6 to 16)

0.00

Ind 300 (1)

102.20

(52.85 to 169.30)

6.2

6

(1 to 14)

0.15

Ind 600 (1)

99.22

(51.43 to 162.50)

6.7

6

(1 to 14)

0.10

Salm 50 (2)

78.73

(36.65 to 118.20)

10.6

11

(4 to 15)

0.00

LAMA

Tio 5 (1)

96.90

(59.78 to 136.30)

7.0

7

(1 to 14)

0.04

Tio 10 (1)

103.00

(61.53 to 157.10)

5.8

5

(1 to 13)

0.13

Tio 18 (1)

82.37

(50.63 to 114.10)

9.9

10

(3 to 15)

0.01

Acl 200 (2)

87.55

(28.91 to 138.30)

8.9

9

(1 to 16)

0.03

Acl 400 (2)

97.26

(48.15 to 159.00)

6.8

6

(1 to 14)

0.10

Gly 50 (1)

91.43

(51.93 to 130.90)

8.0

8

(1 to 14)

0.03

ICS

Bud 400 (2)

25.02

(‐23.30 to 66.78)

16.7

17

(13 to 19)

0.00

Bud 750+ (2)

24.02

(‐31.55 to 68.90)

16.8

17

(13 to 19)

0.00

Flut 500 (2)

27.04

(‐9.27 to 61.93)

16.5

17

(14 to 19)

0.00

Mom 400 (2)

38.89

(‐3.13 to 87.00)

15.2

15

(9 to 18)

0.00

LABA/ICS

Form‐bud 12/160 (2)

99.60

(56.01 to 139.80)

6.4

6

(1 to 14)

0.07

Form‐bud 12/320 (2)

105.00

(66.88 to 141.80)

5.3

5

(1 to 12)

0.11

Salm‐flut 50/250 (2)

102.10

(35.97 to 158.80)

6.3

5

(1 to 15)

0.14

Salm‐flut 50/500 (2)

100.50

(59.29 to 138.70)

6.2

6

(1 to 13)

0.08

aFor effects versus placebo, smaller values indicate larger benefits of the active treatment. All doses are in micrograms.

Crl = credible interval.

FEV1 = forced expiratory volume in one second.

ICS = inhaled corticosteroid.

LABA = long‐acting beta2‐agonist.

LABA/ICS = long‐acting beta2‐agonist/inhaled corticosteroid.

LAMA = long‐acting antimuscarinic antagonist.

NWMA = network meta‐analysis.

Pr = probability.

Study flow diagram.
 aAll 58 studies identified in the review search were also identified in the electronic database search.
 Abbreviations: CDSR = Cochrane Database of Systematic Reviews.
Figuras y tablas -
Figure 1

Study flow diagram.
aAll 58 studies identified in the review search were also identified in the electronic database search.
Abbreviations: CDSR = Cochrane Database of Systematic Reviews.

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Network structures for both outcomes at six months.
Figuras y tablas -
Figure 2

Network structures for both outcomes at six months.

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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St George's Respiratory Questionnaire (SGRQ) change from baseline—six‐month and 12‐month class results.
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Figure 4

St George's Respiratory Questionnaire (SGRQ) change from baseline—six‐month and 12‐month class results.

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Trough forced expiratory volume in one second (FEV1) change from baseline—six‐month and 12‐month class results.
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Figure 5

Trough forced expiratory volume in one second (FEV1) change from baseline—six‐month and 12‐month class results.

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St George's Respiratory Questionnaire (SGRQ) probability ranking diagrams—six months and 12 months.
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Figure 6

St George's Respiratory Questionnaire (SGRQ) probability ranking diagrams—six months and 12 months.

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Forced expiratory volume in one second (FEV1) probability ranking diagrams—six months and 12 months.
Figuras y tablas -
Figure 7

Forced expiratory volume in one second (FEV1) probability ranking diagrams—six months and 12 months.

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Table 1. All included studies—summary characteristics

Study ID

Weeks

Arms includeda

N

Ageb

% male

% pred FEV1b

Pack‐yearsb

Abrahams 2013

24

tiotropium, placebo

856

64.2

64.9

43.3

46.9

ACCLAIM 2009

52

aclidinium, placebo

843

62.4

78.6

53.9

39.9

ACCLAIM II 2009

52

aclidinium, placebo

804

65.1

63.0

50.3

57.9

Anzueto 2009

52

salmeterol, salmeterol/fluticasone

797

65.4

54

34.0

57.2

ATTAIN 2011

24

aclidinium (2), placebo

828

62.4

67.4

52.5

40.2

Bateman 2010a

48

tiotropium, placebo

3991

64.8

77.6

39.9

46

Bateman 2010b

48

tiotropium (2), placebo

1990

65.0

74.2

37.7

nr

Bateman 2013 [SHINE]

26

indacaterol, tiotropium, glycopyrronium, placebo

1667

64.0

74.9

55.0

nr

Bourbeau 1998

26

budesonide, placebo

79

66

78.6

36.5

51

Brusasco 2003

26

salmeterol, tiotropium, placebo

1207

64.2

76.3

38.5

43.8

Burge 2000 [ISOLDE]

156

fluticasone, placebo

751

63.8

74.6

50.2

44

Calverley 2003a

52

formoterol, budesonide, formoterol/budesonide, placebo

1122

64

76

36

39

Calverley 2003 [TRISTAN]

52

salmeterol, fluticasone, salmeterol/fluticasone, placebo

1466

63.2

72.5

44.7

42.3

Calverley 2003b

52

mometasone, placebo

631

nr

nr

47

nr

Calverley 2007 [TORCH]

156

salmeterol, fluticasone, salmeterol/fluticasone, placebo

6185

65.0

75.8

44.0

48.5

Calverley 2008

52

mometasone (2), placebo

911

65.1

68.3

42.3

nr

Calverley 2010

48

formoterol, formoterol/budesonide

718

63.9

81.3

42.4

38.8

Campbell 2005

26

formoterol, placebo

432

55

67

53.6

37

Casaburi 2002

52

tiotropium, placebo

921

65

65.0

38.7

61.4

Chan 2007

48

tiotropium, placebo

913

66.8

59.7

39.4

50.6

Cooper 2010

104

tiotropium, placebo

519

64.6

77.3

38.2

51.7

Dahl 2010

52

formoterol, placebo

867

63.5

31.9

51.7

40.8

Dal Negro 2003

52

salmeterol, salmeterol/fluticasone, placebo

18

nr

83.3

50.0

41.4

Doherty 2012

26

formoterol, mometasone, formoterol/mometasone (2), placebo

1196

59.7

75.2

38.6

45.1

Donohue 2010 [INHANCE]

26

indacaterol (2), tiotropium, placebo

1683

63.6

62.8

55.6

49.7

Dusser 2006

48

tiotropium, placebo

1010

64.7

88

47.9

nr

Fang 2008

52

tiotropium, salmeterol/fluticasone

126

62.5

73.8

nr

nr

Ferguson 2008

52

salmeterol, salmeterol/fluticasone

782

64.9

55

32.8

56.5

FLTA3025

26

fluticasone (2), placebo

640

64.4

68.8

nr

nr

Gelb 2012

52

aclidinium (2)

605

nr

nr

46.5

nr

GLOW1 2011

26

glycopyrronium, placebo

822

63.9

81.8

54.6

44.8

GLOW2 2012

52

glycopyrronium, tiotropium, placebo

1066

63.6

64.2

56.0

49.1

Hanania 2003

26

salmeterol, fluticasone, salmeterol/fluticasone, placebo

723

63.9

63.1

42

56.5

Kardos 2007

43

salmeterol, salmeterol/fluticasone

994

63.9

75.8

40.4

36.9

Kornmann 2011

26

salmeterol, placebo

339

63.3

74.7

53.3

40.3

Lapperre 2009

130

fluticasone (2), salmeterol/fluticasone, placebo

114

61

86.6

55.3

44.3

Laptseva 2002

26

budesonide, placebo

49

nr

nr

nr

nr

Mahler 2002

26

salmeterol, fluticasone, salmeterol/fluticasone, placebo

674

63.5

65.8

41

40.8

Mahmud 2007

26

salmeterol, tiotropium

90

nr

91

nr

nr

Niewoehner 2005

26

tiotropium, placebo

1829

67.9

98.5

35.6

68.4

Ohar 2013

26

salmeterol, salmeterol/fluticasone

639

nr

nr

nr

nr

Ozol 2005

26

budesonide, placebo

26

65.4

69.2

59.2

45.0

Paggiaro 1998

26

fluticasone, placebo

281

63

74

57

nr

Pauwels 1999

156

budesonide, placebo

1277

52.5

72.9

76.9

39.3

Powrie 2007

52

tiotropium, placebo

142

66.4

62.9

50.0

55.2

Renkema 1996

104

budesonide, placebo

39

55

100

63.5

nr

Rennard 2009

52

formoterol, budesonide, formoterol/budesonide, placebo

1964

63.2

63.9

39.6

40 (med)

Rossi 2002

52

formoterol (2), placebo

645

62.7

83.3

nr

nr

Schermer 2009

156

fluticasone, placebo

190

59.0

70.5

64.5

28.3

SCO100470

26

salmeterol, salmeterol/fluticasone

1050

63.6

77.8

nr

nr

SCO30002

52

salmeterol/fluticasone, fluticasone, placebo

387

64.8

82

nr

nr

SCO40041

156

salmeterol, salmeterol/fluticasone

186

65.7

61.3

nr

nr

Senderovitz 1999

26

budesonide, placebo

26

60.5

53.5

nr

nr

Shaker 2009

104+

budesonide, placebo

254

63.6

58.3

52

56

Sharafkhaneh 2012

52

formoterol, budesonide/formoterol (2)

1219

63.0

62.0

37.7

44.3

SLMF4010

26

salmeterol, placebo

34

63.8

88.3

nr

nr

SPARK 2013

64

tiotropium (OL), glycopyrronium

1483

63.4

74.1

nr

nr

Szafranski 2003

52

formoterol, budesonide, formoterol/budesonide, placebo

812

64

78.8

36.2

44.5

Tashkin 2008 [SHINE]

26

formoterol, budesonide, formoterol/budesonide (3), placebo

1704

63.4

66.9

39.9

40 (med)

Tashkin 2008a [UPLIFT]

208

tiotropium, placebo

5993

64.5

74.7

39.4

48.7

Tashkin 2012

26

formoterol, mometasone, formoterol/mometasone (2), placebo

1055

59.8

77.5

nr

40.4

To 2011

52

salmeterol, indacaterol

186

69.1

nr

53

nr

Tonnel 2008 [TIPHON]

39

tiotropium, placebo

554

64.2

86.1

46.9

43.7

Trooster 2011

24

tiotropium, placebo

457

61.8

68.4

nr

nr

Verhoeven 2002

26

fluticasone, placebo

23

55

82.3

63.5

25.5

Vestbo 1999

156

budesonide, placebo

290

59.1

87.5

86.6

nr

Vogelmeier 2008

26

formoterol, tiotropium, placebo

640

62.6

77.5

51.4

38.0

Vogelmeier 2011 [POET]

52

salmeterol, tiotropium

7384

62.9

74.7

49.3

38.3

Wedzicha 2008 [INSPIRE]

104

tiotropium, salmeterol/fluticasone

1323

64.5

82.5

39.3

40.4

Zheng 2006

24

salmeterol/fluticasone, placebo

448

66.3

88.6

nr

nr

Zhong 2012

24

budesonide, formoterol/budesonide

308

65.2

95.1

32.7

nr

aNumbers in parentheses indicate multiple doses of the same treatment.

bAge, % predicted FEV1 and pack‐years smoked are reported as means unless otherwise stated.

bid = twice daily.

FEV1 = forced expiratory volume in one second.

ICS = inhaled corticosteroid.

LABA = long‐acting beta2‐agonist.

LABA/ICS = long‐acting beta2‐agonist/inhaled corticosteroid combination therapy.

LAMA = long‐acting muscarinic antagonist.

nr = not reported.

PBO = placebo inhaler.

qd = once daily.
Figuras y tablas -
Table 1. All included studies—summary characteristics
Ir a la tabla de la revisión
Table 2. SGRQ network composition and transitivity assessmenta

Comparison

Comparisons

N

Ageb

% male

% FEV1c

Packsd

LABA vs placebo

16

13,808

62.9

74.7

46.2

42.5

LAMA vs placebo

15

22,406

64.2

71.3

47.1

47.5

ICS vs placebo

10

8153

63.4

74.9

41.7

42.7

LABA/ICS vs placebo

10

9097

63.1

75.3

39.7

42.4

LABA vs LAMA

2

2680

63.7

69.5

55.2

49.7

LABA vs ICS

7

6226

62.7

73.8

40.0

42.7

LABA vs LABA/ICS

13

12,505

63.1

71.0

38.8

43.9

LAMA vs ICS

0

‐

‐

‐

‐

‐

LAMA vs LABA/ICS

1

1323

64.5

82.5

39.3

40.4

ICS vs LABA/ICS

10

8721

62.9

75.3

38.8

42.9

aSummary population data are for all study comparisons excluding those made in the 29 studies that could not be included in either the six‐month or the 12‐month SGRQ network.

bAge = mean years.

c% FEV1 = mean percentage predicted FEV1.

dPacks = mean pack‐years.

FEV1 = forced expiratory volume in one second.

ICS = inhaled corticosteroid.

LABA = long‐acting beta2‐agonist.

LABA/ICS = long‐acting beta2‐agonist/inhaled corticosteroid combination therapy.

LAMA = long‐acting muscarinic antagonist.

SGRQ = St George's Respiratory Questionnaire.
Figuras y tablas -
Table 2. SGRQ network composition and transitivity assessmenta
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Table 3. FEV1 network composition and transitivity assessmenta

Comparison

Comparisons

N

Ageb

% male

%FEV1c

Packsd

LABA vs Placebo

13

8680

63.3

73.2

47.7

43.9

LAMA vs Placebo

16

23,111

64.3

72.2

47.6

48.9

ICS vs Placebo

12

4574

63.6

71.9

46.2

45.2

LABA/ICS vs Placebo

9

4978

63.9

73.5

41.6

44.4

LABA vs LAMA

2

2680

63.7

69.5

55.2

49.7

LABA vs ICS

5

2506

63.6

67.1

40.6

46.7

LABA vs LABA/ICS

12

8005

63.7

68.8

39.9

45.8

LAMA vs ICS

0

‐

‐

‐

‐

‐

LAMA vs LABA/ICS

0

‐

‐

‐

‐

‐

ICS vs LABA/ICS

8

4560

63.6

71.7

39.0

45.5

aSummary population data are for all study comparisons excluding those made in the 23 studies that could not be included in either the six‐month or the 12‐month FEV1 network; all doses are given in micrograms.

bAge = mean years.

c% FEV1 = mean percentage predicted FEV1.

dPacks = mean pack‐years.

FEV1 = forced expiratory volume in one second.

ICS = inhaled corticosteroid.

LABA = long‐acting beta2‐agonist.

LABA/ICS = long‐acting beta2‐agonist/inhaled corticosteroid combination therapy.

LAMA = long‐acting muscarinic antagonist.
Figuras y tablas -
Table 3. FEV1 network composition and transitivity assessmenta
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Table 4. Distribution of studies by individual treatment node

Class

Treatment node mcg

Studies

LABA

Formoterol 12 bid

Calverley 2003a; Calverley 2003 [TRISTAN]; Calverley 2010;

Campbell 2005; Dahl 2010; Doherty 2012; Rennard 2009; Rossi 2002;

Sharafkhaneh 2012; Szafranski 2003; Tashkin 2008 [SHINE]; Tashkin 2012;

Vogelmeier 2008a

Formoterol 24 bid

Rossi 2002

Indacaterol 300 qd

Dahl 2010; Donohue 2010 [INHANCE]

Indacaterol 600 qd

Dahl 2010

Indacaterol 150 qd

Bateman 2013 [SHINE]; Donohue 2010 [INHANCE]

Salmeterol 50 bid

Anzueto 2009; Brusasco 2003; Dal Negro 2003a; Calverley 2007 [TORCH];

Ferguson 2008; Hanania 2003a; Kardos 2007; Kornmann 2011; Mahler 2002a;

Mahmud 2007a; Ohar 2013a; SCO100470; SCO40041a; SLMF4010;

Vogelmeier 2011 [POET]a

LAMA

Tiotropium 5 qd

Abrahams 2013; Bateman 2010a; Bateman 2010b

Tiotropium 10 qd

Bateman 2010b

Tiotropium 18 qd

Bateman 2013 [SHINE]; Brusasco 2003; Casaburi 2002; Chan 2007;
Cooper 2010a; Donohue 2010 [INHANCE]; Dusser 2006a; Fang 2008a;
GLOW2 2012; Mahmud 2007a; Niewoehner 2005a; Powrie 2007a; SPARK 2013;
Tashkin 2008a [UPLIFT]; Tonnel 2008 [TIPHON]; Trooster 2011a;
Vogelmeier 2008a; Vogelmeier 2011 [POET]a; Wedzicha 2008 [INSPIRE]

Aclidinium bromide 200 qd

ACCLAIM 2009; ACCLAIM II 2009

Aclidinium bromide 200 bid

ATTAIN 2011; GLOW1 2011

Aclidinium bromide 400 bid

ATTAIN 2011; Gelb 2012

Glycopyrronium bromide 50 qd

Bateman 2013 [SHINE]; GLOW1 2011; GLOW2 2012; SPARK 2013

ICS

Budesonide 320‐400 bid

Calverley 2003a; Laptseva 2002a; Ozol 2005a; Pauwels 1999a;

Senderovitz 1999a; Shaker 2009a; Szafranski 2003; Tashkin 2008 [SHINE];

Zhong 2012

Budesonide 750‐1000 bid

Bourbeau 1998; Renkema 1996a; Vestbo 1999

Fluticasone 250 bid

FLTA3025; Hanania 2003

Fluticasone 500 bid

Burge 2000 [ISOLDE]; Calverley 2003 [TRISTAN]; Calverley 2007 [TORCH];
FLTA3025; Lapperre 2009a; Mahler 2002; Paggiaro 1998; Schermer 2009;
SCO30002a; Verhoeven 2002a

Mometasone 400 bid or 800 qd

Calverley 2003b; Calverley 2008; Doherty 2012; Tashkin 2012

LABA/ICS

Formoterol/bud 12/160 bid

Rennard 2009; Sharafkhaneh 2012; Tashkin 2008 [SHINE]; Zhong 2012

Formoterol/bud 12/320 bid

Calverley 2003a; Calverley 2010; Rennard 2009; Sharafkhaneh 2012;

Szafranski 2003; Tashkin 2008 [SHINE]

Formoterol/mom 12/200 bid

Doherty 2012; Tashkin 2012

Formoterol/mom 12/400 bid

Doherty 2012; Tashkin 2012

Salmeterol/flut 50/250 bid

Anzueto 2009; Dal Negro 2003; Fang 2008a; Hanania 2003; Ohar 2013

Salmeterol/flut 50/500 bid

Calverley 2003 [TRISTAN]; Calverley 2007 [TORCH];

Ferguson 2008; Lapperre 2009a; Mahler 2002; SCO100470; SCO30002a;

SCO40041a; Wedzicha 2008 [INSPIRE]; Zheng 2006

PBO

Placebo inhaler

Abrahams 2013; ACCLAIM 2009; ACCLAIM II 2009; ATTAIN 2011;

Bateman 2010a; Bateman 2010b; Bateman 2013 [SHINE]; Bourbeau 1998;

Brusasco 2003; Burge 2000 [ISOLDE]; Calverley 2003a; Calverley 2003 [TRISTAN];

Calverley 2003b; Calverley 2007 [TORCH]; Calverley 2008; Calverley 2010;

Campbell 2005; Casaburi 2002; Chan 2007; Cooper 2010a; Dahl 2010;

Dal Negro 2003; Doherty 2012; Donohue 2010 [INHANCE]; Dusser 2006a; FLTA3025;

GLOW1 2011; GLOW2 2012; Hanania 2003; Kornmann 2011; Lapperre 2009a;

Laptseva 2002a; Mahler 2002; Niewoehner 2005a; Ozol 2005; Paggiaro 1998;

Pauwels 1999a; Powrie 2007; Renkema 1996a; Rennard 2009; Rossi 2002; Schermer 2009;

SCO30002; Senderovitz 1999; Shaker 2009; Sharafkhaneh 2012; SLMF4010;

SPARK 2013; Szafranski 2003; Tashkin 2008 [SHINE]; Tashkin 2008a [UPLIFT];

Tashkin 2012; To 2011a; Tonnel 2008 [TIPHON]; Trooster 2011; Verhoeven 2002a;

Vestbo 1999; Vogelmeier 2008a; Zheng 2006

aStudies not contributing data to either outcome.

bid = twice daily.

ICS = inhaled corticosteroid.

LABA = long‐acting beta2‐agonist.

LABA/ICS = long‐acting beta2‐agonist/inhaled corticosteroid combination therapy.

LAMA = long‐acting muscarinic antagonist.

PBO = placebo inhaler.

qd = once daily.
Figuras y tablas -
Table 4. Distribution of studies by individual treatment node
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Table 5. Sensitivity analysis—blinding

Study ID

Arm removed

Analyses affected

Bateman 2013 [SHINE]

Tiotropium 18 mcg

SGRQ6m, FEV6m

Donohue 2010 [INHANCE]

Tiotropium 18 mcg

SGRQ6m, FEV6m

GLOW2 2012

Tiotropium 18 mcg

SGRQ6m, FEV6m, SGRQ12m, FEV12m

SPARK 2013

Whole study (2 arms)

SGRQ6m, FEV6m, SGRQ12m, FEV12m

Vogelmeier 2008

Tiotropium 18 mcg

Did not appear in analyses

FEV = forced expiratory volume in one second

SGRQ = St George's Respiratory Questionnaire

6m = six month analysis

12m = 12 month analysis
Figuras y tablas -
Table 5. Sensitivity analysis—blinding
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Table 6. SGRQ class effects versus placebo (six months)a

Effect vs placebo
Class NWMA

Effect vs placebo
Sensitivity analysis

Rank

Class

Median

95% CrI

Median

95% CrI

Mean

Median

95% CrI

Pr (best)

LABA/ICS

‐3.89

(‐4.70 to ‐2.97)

‐3.89

(‐4.66 to ‐3.05)

1.0

1

(1 to 2)

0.96

LAMA

‐2.63

(‐3.53 to ‐1.97)

‐2.78

(‐3.58 to ‐2.13)

2.4

2

(1 to 4)

0.03

LABA

‐2.29

(‐3.18 to ‐1.53)

‐2.09

(‐2.93 to ‐1.36)

3.1

3

(2 to 4)

0.01

ICS

‐2.00

(‐3.06 to ‐0.87)

‐1.96

(‐2.99 to ‐0.91)

3.5

4

(2 to 4)

0.00

aFor effects versus placebo, smaller values indicate larger benefits of the active treatment; all doses are given in micrograms.

Crl = credible interval.

SGRQ = St George's Respiratory Questionnaire.

ICS = inhaled corticosteroid.

LABA = long‐acting beta2‐agonist.

LABA/ICS = long‐acting beta2‐agonist/inhaled corticosteroid.

LAMA = long‐acting antimuscarinic antagonist.

NWMA = network meta‐analysis.

Pr = probability.
Figuras y tablas -
Table 6. SGRQ class effects versus placebo (six months)a
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Table 7. SGRQ individual treatment effects versus placebo (six months)a

Rank (from class NWMA)

Effect vs placebo
Class NWMA

Effect vs placebo
NWMA no class

Rank (from class NWMA)

Class

Treatment (number daily doses)

Median

95% CrI

Median

95% CrI

Mean

Median

95% CrI

Pr (best)

LABA

Form 12 (2)

‐1.84

(‐2.60 to ‐0.94)

‐1.20

(‐2.10 to ‐0.30)

14.9

15

(10 to 17)

0.00

Ind 300 (1)

‐2.38

(‐3.63 to ‐1.44)

‐3.10

(‐4.86 to ‐1.36)

11.3

12

(5 to 17)

0.00

Ind 150 (1)

‐2.75

(‐3.95 to ‐1.85)

‐3.67

(‐4.76 to ‐2.58)

8.7

8

(3 to 16)

0.01

Salm 50 (2)

‐2.20

(‐2.98 to ‐1.43)

‐2.27

(‐3.27 to ‐1.27)

12.9

13

(7 to 17)

0.00

LAMA

Tio 5 (1)

‐2.50

(‐3.16 to ‐1.86)

‐2.42

(‐3.20 to ‐1.63)

10.5

10

(6 to 16)

0.00

Tio 18 (1)

‐2.53

(‐3.12 to ‐1.97)

‐2.66

(‐3.33 to ‐1.99)

10.3

10

(6 to 15)

0.00

Acl 200 (2)

‐2.66

(‐4.04 to ‐1.70)

‐3.79

(‐6.14 to ‐1.45)

9.1

9

(2 to 16)

0.01

Acl 400 (2)

‐2.81

(‐4.40 to ‐1.90)

‐4.59

(‐6.94 to ‐2.23)

7.9

7

(1 to 15)

0.03

Gly 50 (1)

‐2.63

(‐3.42 to ‐1.94)

‐2.83

(‐3.74 to ‐1.91)

9.5

9

(5 to 15)

0.00

ICS

Bud 400 (2)

‐1.76

(‐2.82 to ‐0.55)

‐0.97

(‐2.32 to 0.38)

14.9

16

(7 to 17)

0.00

Flut 500 (2)

‐1.95

(‐3.07 to ‐0.74)

‐1.71

(‐3.40 to ‐0.01)

13.9

15

(6 to 17)

0.00

Mom 400 (2)

‐2.28

(‐3.51 to ‐1.19)

‐2.77

(‐4.47 to ‐1.09)

11.9

13

(5 to 17)

0.00

LABA/ICS

Form‐bud 12/160 (2)

‐4.04

(‐4.91 to ‐3.15)

‐3.85

(‐4.99 to ‐2.70)

2.6

2

(1 to 6)

0.29

Form‐bud 12/320 (2)

‐3.80

(‐4.63 to ‐2.84)

‐3.31

(‐4.39 to ‐2.22)

3.9

4

(1 to 9)

0.10

Form‐mom 12/200 (2)

‐3.85

(‐4.82 to ‐2.66)

‐3.45

(‐5.17 to ‐1.74)

3.7

4

(1 to 10)

0.15

Form‐mom 12/400 (2)

‐3.75

(‐4.72 to ‐2.48)

‐3.09

(‐4.81 to ‐1.37)

4.3

4

(1 to 11)

0.10

Salm‐flut 50/500 (2)

‐4.05

(‐4.97 to ‐3.18)

‐4.36

(‐5.60 to ‐3.12)

2.6

2

(1 to 6)

0.31

aFor effects versus placebo, smaller values indicate larger benefits of the active treatment; all doses are given in micrograms.

Crl = credible interval.

SGRQ = St George's Respiratory Questionnaire.

ICS = inhaled corticosteroid.

LABA = long‐acting beta2‐agonist.

LABA/ICS = long‐acting beta2‐agonist/inhaled corticosteroid.

LAMA = long‐acting antimuscarinic antagonist.

NWMA = network meta‐analysis.

Pr = probability.
Figuras y tablas -
Table 7. SGRQ individual treatment effects versus placebo (six months)a
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Table 8. FEV1 class effects versus placebo (six months)a

Effect vs placebo
Class NWMA

Effect vs placebo
Sensitivity analysis

Rank

Class

Median

95% CrI

Median

95% CrI

Mean

Median

95% CrI

Pr (best)

LABA/ICS

133.30

(100.60 to 164.00)

132.80

(98.93 to 165.60)

1.1

1

(1 to 2)

0.9

LAMA

103.50

(81.78,124.90)

103.60

(79.01 to 126.60)

2.4

2

(1 to 3)

0.1

LABA

99.44

(71.98,127.80)

99.86

(70.41 to 130.50)

2.6

3

(1 to 4)

0.0

ICS

65.36

(33.06,96.91)

65.52

(31.23 to 97.16)

3.9

4

(3 to 4)

0.0

aFor effects versus placebo, smaller values indicate larger benefits of the active treatment; all doses are given in micrograms.

Crl = credible interval.

FEV1 = forced expiratory volume in one second.

ICS = inhaled corticosteroid.

LABA = long‐acting beta2‐agonist.

LABA/ICS = long‐acting beta2‐agonist/inhaled corticosteroid.

LAMA = long‐acting antimuscarinic antagonist.

NWMA = network meta‐analysis.

Pr = probability.
Figuras y tablas -
Table 8. FEV1 class effects versus placebo (six months)a
Ir a la tabla de la revisión
Table 9. FEV1 individual treatment effects versus placebo (six months)a

Effect vs placebo
Class NWMA

Effect vs placebo
NWMA no class

Rank (from class NWMA)

Class

Treatment (number daily doses)

Median

95% CrI

Median

95% CrI

Mean

Median

95% CrI

Pr (best)

LABA

Form 12 (2)

94.88

(60.70 to 122.80)

53.92

(13.00 to 94.07)

12.0

13

(5 to 18)

0.00

Ind 300 (1)

103.30

(71.95 to 150.10)

137.90

(63.69 to 209.90)

9.5

10

(2 to 16)

0.02

Ind 150 (1)

99.53

(72.32 to 127.20)

100.70

(65.74 to 133.80)

10.8

12

(4 to 16)

0.00

Salm 50 (2)

101.00

(73.39 to 130.70)

114.70

(75.96 to 149.30)

10.3

11

(4 to 16)

0.00

LAMA

Tio 5 (1)

105.40

(81.87 to 131.80)

110.50

(73.82 to 145.40)

8.9

9

(3 to 15)

0.01

Tio 10 (1)

106.40

(79.80 to 142.00)

121.00

(62.88 to 175.20)

8.6

8

(2 to 15)

0.02

Tio 18 (1)

105.20

(85.54 to 125.50)

107.00

(82.93 to 129.50)

9.0

9

(4 to 15)

0.00

Acl 200 (1)

98.83

(59.06 to 123.20)

59.31

(9.47 to 107.90)

11.3

11

(5 to 18)

0.00

Acl 200 (2)

100.60

(65.20 to 127.10)

74.82

(11.81 to 134.20)

10.7

11

(4 to 17)

0.00

Acl 400 (2)

107.30

(80.93 to 143.50)

108.80

(45.06 to 168.30)

8.2

8

(2 to 15)

0.02

Gly 50 (1)

103.60

(79.83 to 127.50)

101.50

(67.86 to 133.40)

9.5

10

(3 to 15)

0.00

ICS

Bud 400 (2)

61.89

(23.86 to 94.06)

14.59

(‐29.22 to 58.25)

17.6

18

(14 to 19)

0.00

Bud 750+ (2)

63.10

(14.75 to 99.65)

‐2.26

(‐95.77 to 91.34)

17.3

18

(12 to 19)

0.00

Flut 250 (2)

66.78

(34.19 to 101.10)

76.18

(29.36 to 122.30)

16.9

17

(11 to 19)

0.00

Flut 500 (2)

72.16

(40.20 to 109.80)

97.04

(54.90 to 138.40)

15.9

16

(8 to 19)

0.00

LABA/ICS

Form‐bud 12/160 (2)

131.10

(91.65 to 164.00)

80.84

(26.99 to 132.70)

3.9

3

(1 to 13)

0.16

Form‐bud 12/320 (2)

127.30

(85.14 to 159.50)

72.77

(28.75 to 116.70)

4.7

4

(1 to 14)

0.11

Salm‐flut 50/250 (2)

139.70

(106.20 to 182.90)

173.00

(116.20 to 226.40)

2.4

2

(1 to 8)

0.39

Salm‐flut 50/500 (2)

137.10

(104.40 to 172.10)

152.40

(104.10 to 197.80)

2.8

2

(1 to 9)

0.26

aFor effects versus placebo, bigger values indicate larger benefits of the active treatment; all doses are given in micrograms.

Crl = credible interval.

FEV1 = forced expiratory volume in one second.

ICS = inhaled corticosteroid.

LABA = long‐acting beta2‐agonist.

LABA/ICS = long‐acting beta2‐agonist/inhaled corticosteroid.

LAMA = long‐acting antimuscarinic antagonist.

NWMA = network meta‐analysis.

Pr = probability.
Figuras y tablas -
Table 9. FEV1 individual treatment effects versus placebo (six months)a
Ir a la tabla de la revisión