appendices...6 appendix 4. patient ratings of relevant outcomes top 3 - most important efficacy...

1

APPENDICES

Appendix 1. Inhalers included in the systematic review ................................................................ 2

Appendix 2. Full list of excluded medications ............................................................................... 4

Appendix 3. All efficacy and safety outcomes considered ............................................................. 5

Appendix 4. Patient ratings of relevant outcomes .......................................................................... 6

Appendix 5. Final MEDLINE Search ............................................................................................. 7

Appendix 6: Included Studies with References for each analysis and sub-group analysis .......... 15

Appendix 7. Characteristics of the randomized controlled trials .................................................. 17

Appendix 8. Patient characteristics ............................................................................................... 26

Appendix 9: Risk of bias results for the included studies ............................................................. 37

Appendix 10. Network Meta-analysis results Outcome ............................................................... 43

Appendix 11. Sensitivity Network Meta-analysis results (only significant) ................................ 78

Appendix 12. SUCRA Values ...................................................................................................... 80

Appendix 13. Forest Plots ............................................................................................................. 83

Appendix 14. Included studies in our review versus previous Cochrane reviews........................ 85

Appendix 15. Characteristics of new studies published since our search date ............................. 90

REFERENCES ............................................................................................................................. 92

2

Appendix 1. Inhalers included in the systematic review

Generic name(s)* Trade name(s)*

Inhaled long-acting beta2-agonists (LABA)

formoterol or eformoterol Foradil, Oxeze, Oxis

indacaterol Arcapta

salmeterol Serevent, SereventDiskus

olodaterol Striverdi

vilanterol or GW642444

AZD3199 (ultra LABA)

Inhaled long-acting muscarinic anticholinergics (LAMA)

aclidinium bromide Tudorza Genuair

glycopyrronium bromide Seebri Breezhaler

tiotropium bromide Spiriva

umeclidinium bromide or GSK573719 Incruse Ellipta

darotropium bromide

Inhaled corticosteroids (ICS)

beclomethasone QVAR, Clenil

budesonide Pulmicort

fluticasone or GW685698 Flovent, FloventDiskus, Flixotide

mometasone Asmanex Twisthaler

triamcinolone acetonide

Combo LABA plus ICS in one inhaler**

formoterol/budesonide Symbicort

formoterol/mometasone Zenhale

salmeterol/fluticasone Advair, AdvairDiskus, Seretide

vilanterol/fluticasone BreoEllipta

beclomethasone/formoterol

Combo LAMA plus ICS in one inhaler**

tiotropium/budesonide

tiotropium/fluticasone

3

Combo LABA plus Short-acting muscarinic anticholinergic (SAMA)

formoterol/ipratropium bromide

Combo LAMA plus LABA in one inhaler**

vilanterol/umeclidinium AnoroEllipta

indacaterol/glycopyrronium QVA149, Ultibro

tiotropium/formoterol

indacterol/tiotropium

tiotropium/salmeterol

Combo LAMA plus LABA in one inhaler (MABA)

GSK961081 (formerly TD5959)

Combo ICS plus LABA plus LAMA in one inhaler

tiotropium/fluticasone/salmeterol

tiotropium/budesonide/formoterol

Combo ICS plus LABA plus SAMA

budesonide/formoterol/ipratropium bromide

Note: *This is not an exhausitve list. **Combination therapy could also be given in multiple

inhalers.

4

Appendix 2. Full list of excluded medications

Generic name(s)* Trade name(s)*

We will exclude the following formulations:

Long-acting beta2-agonists (LABA) in nebulizer and transdermal form

formoterol (when in nebulizer form)

arformoterol

tulobuterol

Inhaled corticosteroids (ICS) in nebulizer form

beclomethasone (when in nebulizer form)

budesonide (when in nebulizer form)

We will exclude ALL of the following agents:

Short-acting beta2-agonists (SABA) (inhaled, nebulizer, oral, injection)

fenoterol

levosalbutamol or levalbuterol Xopenex

salbutamol or albuterol Ventolin

terbutaline Bricanyl

Short-acting muscarinic anticholinergics (SAMA) (inhaler, nebulizer)

ipratropium bromide Combivent, Atrovent

oxitropium bromide

Combo SABA plus anticholinergic in one inhaler (inhaler, nebulizer)

fenoterol/ipratropium

salbutamol/ipratropium

Methylxanthines (oral, injection)

aminophylline

theophylline

Systemic corticosteroids (oral)

prednisone

methyl-prednisolone

Phosphodiesterase-4 (PDE4) inhibitors (oral)

roflumilast

Note: *This is not an exhausitve list.

http://en.wikipedia.org/wiki/Levosalbutamol

http://en.wikipedia.org/wiki/Roflumilast

5

Appendix 3. All efficacy and safety outcomes considered

Efficacy outcomes:

1. Proportion of patients with exacerbations (primary outcome of interest)

2. Number of hospitalizations (overall and due to exacerbations)

3. Number of emergency room visits (overall and due to exacerbations)

4. Function (e.g., 6 minute walk test, paced shuttle walk test)

5. Forced expiratory volume (FEV)

6. Quality of life

7. Mortality

Safety outcomes:

1. All harms

2. Serious harms

3. Withdrawals due to lack of efficacy

4. Treatment-related withdrawals

5. Cardiovascular-related mortality

6. Bone mineral density

7. Dyspnea

8. Ischemic heart disease

9. Heart failure

10. Arrhythmia

11. Pneumonia

12. Cataracts

13. Oral thrush

14. Palpitations

15. Headache

16. Constipation

17. Dry mouth

6

Appendix 4. Patient ratings of relevant outcomes

TOP 3 - MOST important efficacy outcomes:

1. Quality of Life (10/19 rated this outcome in their top 4)

2. Shortness of Breath (9/19 rated this in their top 4)

3. Functional Abilities (8/19 rated this in their top 4)

TOP 3 - LEAST important efficacy outcomes:

1. Mortality (7/19 rated this in their bottom 4)

2. Emergency Room Visits (6/19 rated in bottom 4)

3. Hospitalizations/Exacerbations/FEV (5/19 people rated this in their bottom 4)

TOP 3 - MOST important safety/side effects:

1. & 2. Heart Attack & Heart Failure (12/19 rated this in top 5)

3. Bone Fractures (8/19 rated this in top 5)

TOP 3 - LEAST important safety/side effects:

1. Dry Mouth (13/19 rated this in bottom 5)

2. Headache (9/19 rated this in bottom 5)

3. Constipation & Cataracts (7/19 rated this in bottom 5)

7

Appendix 5. Final MEDLINE Search

1 exp Pulmonary Disease, Chronic Obstructive/

2 exp Emphysema/ or exp Pulmonary Emphysema/

3 ((chronic adj2 obstructi*) and (pulmonary or airway* or air way* or lung$1 or airflow* or

air flow*)).tw.

4 (COPD or COAD).tw.

5 (chronic adj2 bronchitis).tw.

6 emphysema*.tw.

7 or/1-6

8 Formoterol*.tw,rn.

9 (BD 40A or HSDB 7287 or Oxis or UNII-5ZZ84GCW8B).tw.

10 (eformoterol or Foradil).tw.

11 73573-87-2.rn.)

12 Indacaterol.tw,rn.

13 (Arcapta or Onbrez or QAB 149 or QAB149 or UNII-8OR09251MQ).tw.

14 312753-06-3.rn.

15 Salmeterol*.tw,rn.

16 (Aeromax or Astmerole or "GR 33343 X" or "GR 33343X" or HSDB 7315 or SN408D or

UNII-2I4BC502BT).tw.

17 89365-50-4.rn.

18 Salmeterolxinafoate.tw,rn.

19 (Arial or Asmerole or Beglan or Betamican or Dilamax or Inaspir or Salmetedur or

Serevent or Ultrabeta or UNII-6EW8Q962A5).tw.

20 94749-08-3.rn.

21 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or

ultralong-acting) and (beta-agonist* or betaagonist* or beta-adrenergic* or adrenergic beta-

receptor* or beta-receptor agonist* or beta-adrenoceptor agonist*)).tw.


ultralong-acting) and (beta-2-agonist* or beta-2agonist* or beta-2-adrenergic* or adrenergic

beta-2-receptor* or beta-2-receptor agonist* or beta-2-adrenoceptor agonist*)).tw.


ultralong-acting) and (beta2-agonist* or beta2agonist* or beta2-adrenergic* or adrenergic beta2-

receptor* or beta2-receptor agonist* or beta2- adrenoceptor agonist*)).tw.

8

24 ((longacting or long-acting) and ("beta(2)-agonist*" or "beta(2)agonist*" or "beta(2)-

adrenergic*" or "adrenergic beta(2)-receptor*" or "beta(2)-receptor agonist*" or "beta(2)-

adrenoceptor agonist*")).tw.


ultralong-acting) and (B2-agonist* or B2-adrenergic* or adrenergic B2-receptor* or B2-receptor

agonist* or B2-adrenoceptor agonist*)).tw.


ultralong-acting) and (B-2-agonist* or B-2-adrenergic* or adrenergic B-2-receptor* or B-2-

receptor agonist* or B-2-adrenoceptor agonist*)).tw.

27 (LABA or LABAs or Ultra-LABA* or UltraLABA*).tw.


ultralong-acting) and bronchodilator*).tw.


ultralong-acting) and (betamimetic* or beta-mimetic*)).tw.

30 exp Adrenergic beta-Agonists/ or Bronchodilator Agents/

31 (longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or

ultralong-acting).tw.

32 30 and 31

33 or/21-29,32

34 Administration, Inhalation/

35 exp Aerosols/

36 (inhal* or aerosol*).tw.

37 or/34-36

38 33 and 37

39 or/8-20,38 )

40 Beclomethasone/

41 (Aerobec or AeroBec Forte or Aldecin or Apo-Beclomethasone or Ascocortonyl or

AsmabecClickhaler).tw.

42 (Beclamet or Beclazone or BecloAsma or Beclo AZU or Beclocort or Becloforte or

Beclomet or Beclometason* or Beclomethasone or Beclorhinol or Becloturmant or Beclovent or

Becodisk* or Beconase or Becotide or BemedrexEasyhaler or Bronchocort).tw.

43 (Ecobec or Filair or Junik or Nasobec Aqueous or Prolair or Propaderm or Qvar or

Respocort or Sanasthmax or Sanasthmyl or Vancenase or Vanceril or Ventolair or Viarin).tw.

44 (BMJ 5800 or EINECS 224-585-9 or UNII-KGZ1SLC28Z).tw.

45 4419-39-0.rn.

46 Budesonide/

9

47 (Budesonide or Micronyl or Preferid or Pulmicort or Respules or Rhinocort or "S 1320" or

Spirocort or Uceris or UNII-Q3OKS62Q6X).tw.

48 51333-22-3.rn.

49 Fluticasone.tw,rn.

50 (Cutivate or Flixonase or Flixotide or Flonase or Flovent or Fluticason* or HSDB 7740 or

UNII-CUT2W21N7U).tw.

51 Glucocorticoids/

52 glucocorticoid*.tw.

53 Adrenal Cortex Hormones/

54 (corticoid* or corticosteroid* or cortico-steroid*).tw.

55 ((adrenal cortex or adrenal cortical) adj3 hormon*).tw.

56 ((adrenal cortex or adrenal cortical) adj3 steroid*).tw.

57 or/51-56

58 57 and 37

59 or/40-50,58

60 (Fluticasone adj3 salmeterol).tw,rn.

61 (Adoair or Advair or Foxair or "Quikhale SF" or Seretide or Viani).tw.

62 (formoterol adj3 mometasone).tw,rn.

63 (Zenhale or Dulera).tw.

64 (formoterol adj3 budesonide).tw,rn.

65 (Rilast or Symbicord or Symbicort or Vannair).tw.

66 (vilanterol adj3 fluticasone).tw,rn.

67 Breo Ellipta.tw.

68 or/60-67

69 tiotropium.tw,rn.

70 (BA 679 BR or BA 679BR or Spiriva or tiotropium or UNII-0EB439235F or UNII-

XX112XZP0J).tw.

71 aclidiniumbromide.tw,rn.

72 (LAS 34273 or LAS W-330 or BretarisGenuair or EkliraGenuair or TudorzaPressair or

UNII-UQW7UF9N91).tw.

73 glycoyrroniumbromide.tw,rn.

74 (erythro-glycopyrronium bromide or UNII-9SFK0PX55W).tw.


ultralong-acting) and (anticholinergic* or anti-cholinergic* or cholinolytic* or cholinergic-

10

blocking or antimuscarinic* or anti-muscarinic* or ((cholinergic or acetylcholine or muscarinic)

adj3 antagonist*))).tw.

76 (LAMA or LAMAs or Ultra-LAMA* or UltraLAMA*).tw.

77 Muscarinic Antagonists/ or Cholinergic Antagonists/

78 77 and 31

79 75 or 76 or 78

80 79 and 37

81 or/69-74,80

82 39 or 59 or 68 or 81

83 7 and 82

84 randomized controlled trial.pt.

85 controlled clinical trial.pt.

86 randomized.ab.

87 placebo.ab.

88 clinical trials as topic/

89 randomly.ab.

90 trial.ti.

91 or/84-90

92 83 and 91

93 exp Animals/ not (exp Animals/ and Humans/)

94 92 not 93

95 (interview or news).pt.

96 94 not 95

97 96 use mesz

98 96 use prem

99 97 or 98

100 chronic obstructive lung disease/

101 lung emphysema/ or emphysema/

102 ((chronic adj2 obstructi*) and (pulmonary or airway* or air way* or lung$1 or airflow* or

air flow*)).tw.

103 (COPD or COAD).tw.

104 (chronic adj2 bronchitis).tw.

105 emphysema*.tw.

11

106 or/100-105

107 formoterol/ or formoterolfumarate/

108 (BD 40A or HSDB 7287 or Oxis or UNII-5ZZ84GCW8B).tw.

109 (eformoterol or Foradil or formoterol).tw.

110 (73573-87-2 or 183814-30-4).rn.

111 indacaterol/

112 (Arcapta or Onbrez or indacaterol or QAB 149 or QAB149 or UNII-8OR09251MQ).tw.

113 312753-06-3.rn.

114 salmeterol/

115 (Aeromax or Astmerole or "GR 33343 X" or "GR 33343X" or HSDB 7315 or Salmeterol

or SN408D or UNII-2I4BC502BT).tw.

116 89365-50-4.rn.

117 salmeterolxinafoate/

118 (Arial or Asmerole or Beglan or Betamican or Dilamax or Inaspir or Salmetedur or

Salmeterolxinafoate or Serevent or Ultrabeta or UNII-6EW8Q962A5).tw.

119 94749-08-3.rn.


ultralong-acting) and (beta-agonist* or betaagonist* or beta-adrenergic* or adrenergic beta-

receptor* or beta-receptor agonist* or beta-adrenoceptor agonist*)).tw.


ultralong-acting) and (beta-2-agonist* or beta-2agonist* or beta-2-adrenergic* or adrenergic

beta-2-receptor* or beta-2-receptor agonist* or beta-2-adrenoceptor agonist*)).tw.


ultralong-acting) and (beta2-agonist* or beta2agonist* or beta2-adrenergic* or adrenergic beta2-

receptor* or beta2-receptor agonist* or beta2- adrenoceptor agonist*)).tw.

123 ((longacting or long-acting) and ("beta(2)-agonist*" or "beta(2)-agonist*" or "beta(2)-

adrenergic*" or "adrenergic beta(2)-receptor*" or "beta(2)-receptor agonist*" or "beta(2)-

adrenoceptor agonist*")).tw.


ultralong-acting) and (B2-agonist* or B2-adrenergic* or adrenergic B2-receptor* or B2-receptor

agonist* or B2-adrenoceptor agonist*)).tw.


ultralong-acting) and (B-2-agonist* or B-2-adrenergic* or adrenergic B-2-receptor* or B-2-

receptor agonist* or B-2-adrenoceptor agonist*)).tw.

126 (LABA or LABAs or Ultra-LABA* or UltraLABA*).tw.


ultralong-acting) and bronchodilator*).tw.

12


ultralong-acting) and (betamimetic* or beta-mimetic*)).tw.

129 exp beta adrenergic receptor stimulating agent/ or brochodilating agent/

130 (longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or

ultralong-acting).tw.

131 129 and 130

132 or/120-128,131

133 inhalational drug administration/

134 aerosol/

135 (inhal* or aerosol*).tw.

136 or/133-135

137 132 and 136

138 or/107-119,137

139 beclometasone/

140 (Aerobec or AeroBec Forte or Aldecin or Apo-Beclomethasone or Ascocortonyl or

AsmabecClickhaler).tw.

141 (Beclamet or Beclazone or BecloAsma or Beclo AZU or Beclocort or Becloforte or

Beclomet or Beclometason* or Beclomethasone or Beclorhinol or Becloturmant or Beclovent or

Becodisk* or Beconase or Becotide or BemedrexEasyhaler or Bronchocort).tw.

142 (Ecobec or Filair or Junik or Nasobec Aqueous or Prolair or Propaderm or Qvar or

Respocort or Sanasthmax or Sanasthmyl or Vancenase or Vanceril or Ventolair or Viarin).tw.

143 (BMJ 5800 or EINECS 224-585-9 or UNII-KGZ1SLC28Z).tw.

144 4419-39-0.rn.

145 budesonide/

146 (Budesonide or Micronyl or Preferid or Pulmicort or Respules or Rhinocort or "S 1320"

or Spirocort or Uceris or UNII-Q3OKS62Q6X).tw.

147 51333-22-3.rn.

148 fluticasone/ or fluticasone propionate/

149 (Cutivate or Flixonase or Flixotide or Flonase or Flovent or Fluticason* or HSDB 7740 or

UNII-CUT2W21N7U).tw.

150 (90566-53-3 or 80474-14-2).rn.

151 glucocorticoid/

152 glucocorticoid*.tw.

153 corticosteroid/

154 (corticoid* or corticosteroid* or cortico-steroid*).tw.

13

155 ((adrenal cortex or adrenal cortical) adj3 (hormon* or steroid*)).tw.

156 or/151-155

157 156 and 136

158 or/139-150,157

159 fluticasone propionate plus salmeterol/

160 (Adoair or Advair or Foxair or "Quikhale SF" or Seretide or Viani).tw.

161 (fluticasone adj3 salmeterol).tw.

162 136112-01-1.rn.

163 formoterolfumarate plus mometasonefuroate/

164 (formoterol adj3 mometasone).tw.

165 (Zenhale or Dulera).tw.

166 budesonide plus formoterol/

167 (formoterol adj3 budesonide).tw.

168 (Rilast or Symbicord or Symbicort or Vannair).tw.

169 150693-37-1.rn.

170 fluticasone furoate plus vilanterol/

171 (vilanterol adj3 fluticasone).tw.

172 Breo Ellipta.tw.

173 or/159-172

174 tiotropium bromide/

175 (BA 679 BR or BA 679BR or Spiriva or tiotropium or UNII-0EB439235F or UNII-

XX112XZP0J).tw.

176 (186691-13-4 or 136310-93-5).rn.

177 aclidinium bromide/

178 (LAS 34273 or LAS W-330 or BretarisGenuair or EkliraGenuair or TudorzaPressair or

UNII-UQW7UF9N91).tw.

179 320345-99-1.rn.

180 glycoyrronium bromide.tw.

181 (erythro-glycopyrronium bromide or UNII-9SFK0PX55W).tw.


ultralong-acting) and (anticholinergic* or anti-cholinergic* or cholinolytic* or cholinergic-

blocking or antimuscarinic* or anti-muscarinic* or ((cholinergic or acetylcholine or muscarinic)

adj3 antagonist*))).tw.

183 (LAMA or LAMAs or Ultra-LAMA* or UltraLAMA*).tw.

14

184 muscarinic receptor blocking agent/

185 cholinergic receptor blocking agent/

186 (184 or 185) and 130

187 182 or 183 or 186

188 187 and 136

189 or/174-181,188

190 138 or 158 or 173 or 189

191 106 and 190

192 randomized controlled trial/

193 controlled clinical trial/

194 randomized.ab.

195 placebo.ab.

196 "clinical trial (topic)"/

197 randomly.ab.

198 trial.ti.

199 or/192-198

200 191 and 199

201 exp animals/ or exp animal experimentation/ or exp models animal/ or exp animal

experiment/ or nonhuman/ or exp vertebrate/

202 exp humans/ or exp human experimentation/ or exp human experiment/

203 201 not 202

204 200 not 203

205 204 use emcz

206 99 or 205

207 remove duplicates from 206

15

Appendix 6: Included Studies with References for each analysis and sub-group analysis

Literature Search

183 primary publications reporting on 188 studies [1-183] and 20 unpublished studies [184-203] were

included in the review. A total of 203 full-text articles were included [1-203] plus 58 companion reports

[204-261].

Exacerbations

1. Network meta-analysis for Exacerbations included 112 studies, 26 treatments with a total of 77749

patients [1-4, 6, 7, 10, 12-17, 19, 21-23, 25-29, 31-33, 37-39, 42-44, 46, 48, 53, 55, 56, 63, 65, 69, 71,

75-80, 84, 86, 88, 91, 92, 94-97, 101, 102, 104, 105, 108, 112, 116, 119, 120, 122-124, 126, 128, 129,

131, 133, 135, 136, 147, 149, 151, 154, 156, 157, 162, 164, 165, 167, 169, 171, 172, 174-178, 180-

184, 186, 188, 192-197, 199, 203]

2. A Sensitivity analysis for Exacerabtions included 25 studies, 20 treatments, 33211 patients [1, 2, 16,

22, 25, 42, 69, 80, 94, 108, 122, 156, 162, 167, 169, 175, 177, 178, 180, 181, 183].

3. Network meta-analysis including only patients with exacerbations in past year or more, included 20

studies, 17 treatments, with 26141 patients [16, 22, 25, 31, 42, 46, 86, 101, 119, 120, 122, 154, 162,

167, 169, 172, 178, 180, 199].

Mortality

1. Network meta-analysis for Mortality included 88 studies, 28 treatments, 97526 patients in total [2, 3,

7, 10, 11, 16, 19, 22, 24, 25, 27, 31, 37, 38, 42, 43, 45, 46, 51, 54, 56, 63, 68, 69, 71-74, 76, 79, 81,

85-88, 92, 94, 97, 101-104, 106, 108, 114, 115, 117, 119, 122-124, 126, 129, 131, 133, 138, 141, 151,

157, 159, 162, 165, 167-171, 173-178, 180, 183-185, 188, 191-194, 197, 199].

2. A Sensitivity analysis for Mortality included, 23 studies, 22 treatments, 33624 patients [2, 16, 22, 25,

42, 69, 81, 94, 108, 114, 122, 162, 167, 169-171, 173, 175, 177, 178, 180, 182, 183].

Cardiovascular related mortality (CVM)

1. Network meta- analysis for CVM included 37 studies, 20 treatments, 55156 patients [3, 7, 10, 22, 27,

51, 54, 71, 72, 76, 79-81, 85, 88, 94, 106, 108, 115, 117, 123, 126, 129, 138, 168-170, 184, 185, 191-

197, 203].

2. A sensitivity analysis for CVM included 11 studies, 12 treatments, 16443 patients [22, 80, 81, 94,

108, 169, 175, 177, 178, 183].

Pneumonia

1. Network meta-analysis for Pneumonia included 54 studies, 21 treatments, 61551 patients [7, 10, 22,

25, 26, 28, 31, 39, 42, 45, 46, 53, 55, 60, 63, 69, 72, 75, 77-80, 86, 87, 94, 101, 114, 115, 122, 124,

131, 138, 162, 169, 174, 176-178, 180, 181, 183-185, 192-194, 196, 197, 199, 203].

16

2. A sensitivity analysis for Pnemonia included 19 studies, 18 treatments, 28763 patients [2, 22, 25, 42,

69, 80, 94, 114, 122, 162, 169, 177, 178, 180, 181, 183].

Arrhythmia

1. Network meta-analysis for Arrhythmia included 26 studies, 12 treatments, 27407 patients [2, 13, 32,

38, 42, 72, 79, 80, 87, 96, 111, 122, 126, 147, 162, 171, 174, 176, 178, 181, 184, 187, 193, 196, 197,

199].

2. A sensitivity analysis for Arrhythmia included 6 studies, 7 treatments, 13060 patients [2, 80, 122,

162, 178, 181].

17

Appendix 7. Characteristics of the randomized controlled trials

Author, year Country of conduct Setting Study

conduct

period

(weeks)

Treatme

nt

duration

(weeks)

# of

treatme

nt

groups

Overall

Sample

size

Aalbers, 2002[96] Australia, Belgium,

Denmark, Germany,

Hungary, The Netherlands,

Norway, Poland, UK

multi-center 12 12 4 687

Aaron, 2007[167] Canada multi-center 52 52 3 449

Abrahams,

2013[133]

10 countries multi-center 24 24 2 856

Agusti, 2014[178] Europe, Asia (not specified) multi-center 12 12 2 528

Ambrosino,

2008[164]

Italy multi-center 25 25 2 234

Anzueto, 2009[46] USA, Canada multi-center 52 52 2 797

Auffarth, 1991[61] Netherlands NR 8 8 2 24

Barnes, 2006[23] NR multi-center 13 13 2 140

Bateman, 2008[36] South Africa multi-center 6 6 2 107

Bateman, 2010[7]

CR:[210]


Bateman, 2012[83] NR multi-center 4 4 6 576

Bateman, 2013[174] NR multi-center 30 26 5 2144

Bedard, 2012[166] Canada single center 3 3 2 36

Beier, 2007[136] Belgium, Germany, France,

the Netherlands, Slovakia


Beier, 2013[70] Czech Republic, Germany,

Hungary, Poland


Bogdan, 2011[77] Japan, Romania, Russia,

Ukraine


Bolukbas, 2011[142] Germany multi-center 12 1 2 46

Bourbeau,

1998[128]

Canada single center 26 26 2 79

Bourbeau, 2007[52] Canada multi-center 12 12 3 60

Boyd, 1997[19] 18 countries multi-center 18 16 3 674

Briggs, 2005[102] Finland, Greece, Italy,

Portugal, Sweden, Turkey,

UK, USA


Buhl, 2011[27] USA, Austria, Belgium,

Canada, Columbia,

Denmark, Finland, France,

Germany, Greece, Hungary,

Israel, Italy, Mexico,

Norway, Poland, Russia,

Slovakia, Spain,

Switzerland, Turkey, UK


Burge, 2000 [129]

CR:[204-208]

UK multi-center 156.53 156.53 2 751

Caillaud, 2007[4] France multi-center 3 3 8 202

18

Calverley, 2003[34]

CR:[214-216, 261]


Calverly, 2003[53] NR multi-center 6 6 3 121

Calverly, 2003[119] NR (15 countries) multi-center 52 52 4 1022

Calverley,

2007[138] CR: [234-

242]

42 countries (not specified) multi-center 158 156 4 6112

Calverly, 2008[124] 11 countries multi-center 52 52 3 911

Calverley, 2010[25] 8 countries across Europe multi-center 48 48 3 718

Campbell, 2007[32] USA multi-center 8 8 2 204

Casaburi, 2005[103]

CR:[243]

USA multi-center 25 25 2 108

Cazzola, 2000[17] Italy NR 12 12 3 69

Cazzola, 2007[8] Italy NR 12 12 3 90

Celli, 2003[146] USA NR 5 4 2 81

Celli, 2003[104] 15 countries (not specified) multi-center 16 12 2 824

Chan, 2007[11] Canada multi-center 48 48 2 913

Chanez, 2010[15] Europe and Russia multi-center 4 4 7 460

Chapman,

2002[147]

Canada, Denmark, The

Netherlands, Russia,

Sweden, UK


Chapman,

2011[115] CR: [249-

251]

USA, Argentina, Canada,

Germany, India, Italy,

Spain, Sweden, Turkey


Choudhury,

2007[173]

UK multi-center 52 52 2 260

Cooper, 2013[170] 11 countries multi-center 96 96 2 519

Cote, 2009[93] USA multi-center 4 4 2 266

Covelli, 2005[13] USA multi-center 12 12 2 196

Criner, 2008[92] USA multi-center 8 8 2 166

D’Urzo, 2011[79] NR NR 30.29 26 2 822

Dahl, 2001[111] 8 countries multi-center 12 12 3 586

Dahl, 2010[88] Argentina, Chile, Columbia,

Czech, Denmark, Ecuador,

Egypt, Estonia, France,

Germany, Hungary, Israel,

Italy, Korea, Latvia,

Lithuania, Netherlands,

Peru, Romania, Russia,

Slovakia, Spain,

Switzerland, Turkey, UK


Dahl, 2013[82] Denmark multi-center 4 4 2 193

Dahl, 2013[131] Europe (not specified),

Canada, India, Korea, South

Africa


Dal Negro,

2003[137]

Italy single center 52 52 3 18

Decramer,

2013[122]

Argentina, Australia,

Austria, Belgium, Brazil,

Canada, China, Columbia,


19

Costa Rica, Czech,

Denmark, Estonia, Finland,

France, Germany, Hungary,

Iceland, India, Israel, Italy,

Latvia, Lithuania, Mexico,

the Netherlands, Peru,

Philippines, Poland,

Portugal, Romania, Russia,

Slovakia, South Africa,

Spain, Sweden, Switzerland,

Taiwan, Thailand, Turkey,

UK, Venzuela

Decramer,

2014[183]a

Germany, Italy, Mexico,

Peru, Poland, Romania,

Russia, Ukraine, USA

multi-centre 25 24 4 843

Decramer,

2014[183]b


Canada, Chile, Germany,

Mexico, Romania, South

Africa, South Korea, USA

multi-centre 25 24 4 869

Doherty, 2012 North, Central and South

America, Europe, Africa,

Asia (not specified)


Donohue, 2002[3]

CR:[257, 258]


Donohue, 2013[81] USA, Bulgaria, Canada,

Chile, Czech Republic,

Greece, Japan, Mexico,

Poland, Russia, South

Africa, Spain, Thailand


Dransfield, 2011[47] USA multi-center 16 16 2 249

Dransfield,

2013[180]a


Dransfield,

2013[180]b


Dusser, 2006[154] France multi-center 50 48 2 1010

Engel, 1989[12] Denmark single center 12 12 2 18

Feldman, 2010[76] USA, New Zealand,

Belgium


Feldman, 2012[1] USA multi-center 5 4 2 51

Ferguson, 2008[45] USA, Canada multi-center 52 52 2 782

Freeman, 2007[84] UK multi-center 12 12 2 374

Fukuchi, 2013[31] Japan, Korea, Taiwan,

Philippines, Vietnam, India,

Russia, Poland, Ukraine


Gelb, 2013[179] USA, Canada multi-center 54 52 2 602

Gupta, 2002[20] India single center 8 8 2 33

Hagedorn,

2013[109]

Germany multi-center 52 52 2 212

Hanania, 2003[160] USA multi-center 24 24 4 723

Hanania, 2012[26] USA multi-center 24 24 2 342

Hanania, 2012[161] NR multi-center 4 4 6 602

Hasani, 2004[153] UK single center 3 3 2 34

20

Hattotuwa,

2002[157] CR:[260]

UK single center 12 12 2 37

Hoshino, 2011[66] Japan NR 12 12 2 30

Hoshino, 2013[64] Japan NR 16 16 4 60

Johansson, 2008[28] Sweden multi-center 12 12 2 224

Jones, 1997[127] 17 countries including: UK,

Belgium, France, Germany,

Italy, The Netherlands, New

Zealand


Jones, 2011[176]a

NR - 16 European countries multi-center 52 52 2 843

Jones, 2011[176]b NR - 7 mostly North

American countries


Jones, 2012[85] 9 European countries (not

specified), South Africa


Jung, 2012[39] Republic of Korea multi-center 24 24 2 479

Kardos, 2007[101] Germany multi-center 44 44 2 994

Kaushik, 1999[57] India NR 1 1 2 30

Kerwin, 2011[177]a


Kerwin, 2011[177]b


Kerwin, 2012[68]

CR:[244]

USA, Canada multi-center 12 12 3 560

Kerwin, 2012[78] USA, Argentina, Canada,

Chile, France, Germany,

Hungary, Israel, Italy,

Korea, Mexico,

Netherlands, New Zealand,

Peru, Poland, Russia


Kerwin, 2013[10] Chile, Estonia, Germany,

Japan, Korea, Philippines,

Poland, Russian Federation,

USA


Kinoshita, 2012[75]

CR: [253]

Hong Kong, India, Japan,

Korea, Singapore, Taiwan


Korn, 2011[108] USA, Czech, Germany,

Hungary, India, Slovakia,

Spain, Turkey


Kornmann,

2011[123]

15 countries (not specified) multi-center 27 26 3 998

Koser, 2010[132] USA multi-center 12 12 2 247

Kuna, 2013[71] Bulgaria, Canada, Japan,

Poland, Russia


Lapperre, 2009[49]

CR:[252]

The Netherlands multi-center 120 (24

weeks

for one

group)

120 (24

weeks

for one

group)

4 75

Littner, 2000[112] USA multi-center 7.14 4.14 5 169

Llewellyn-Jones,

1996[44]

UK NR 14 8 2 16

Lomas, 2012[21] Estonia, Finland, Germany,

South Korea, Latvia,

Lithuania, The Netherlands,

New Zealand, Russia,


21

Slovenia, South Africa, UK

Lötvall, 2012[67] Norway, Sweden multi-center 4 4 2 60

Magnussen,

2008[106]

Belgium, Canada, Germany,

Denmark, France, Italy, the

Netherlands, South Africa


Mahler, 1999[91] USA multi-center 12 12 2 278

Mahler, 2002[56] Lebanon multi-center 24 24 4 645

Mahler, 2012[175]a


Colombia, Denmark,

Germany, Greece,

Guatemala, Mexico, Peru,

Philippines, South Africa,

Spain, Turkey, USA


Mahler, 2012[175]b Argentina, Canada,

Colombia, Czech Republic,

Hungary, India,

Netherlands, Philippines,

Slovakia, Spain, USA


Maltais, 2005[105] NR multi-center 6 6 2 261

Maltais, 2011[14] Canada, USA multi-center 6 6 2 181

Mansori, 2010[152] Iran single center 24 12 2 40

Martinez, 2013[94] Czech Republic, Germany,

Japan, Poland, Romania,

Russian Federation,

Ukraine, USA


Mathioudakis,

2013[100]

Greece single center 208 208 5 564

McNicholas,

2004[113]

UK, Ireland, The

Netherlands


Mirici, 2001[50] Turkey single center 12 12 2 50

Moita, 2008[165] Portugal multi-center 12 12 2 304

Mroz, 2013[107] Poland single center 12 12 2 34

Nicolini, 2012[140] Italy single center 0.14 0.14 2 100

Niewoehner,

2005[126] CR:[211,

212]


O'Donnell, 2004[65] Canada, USA, Germany multi-center 6 6 2 187

O'Donnell, 2006[48] USA, Canada multi-center 8 8 3 185

Ozol, 2005[150] Turkey NR 24 24 2 26

Paggiaro, 1998[120] 13 European countries (not

specified), New Zealand,

South Africa


Pasqua, 2010[35] Italy NR 4 4 2 22

Pauwels, 1999[117]

CR:[245, 246]

Belgium, Denmark, Finland,

Italy, the Netherlands,

Norway, Spain, Sweden,

UK


Perng, 2009[24] Taiwan multi-center 12 12 3 99

Powrie, 2007[55] UK single center 52 52 2 142

Pukhta, 2010[9] India single center 2 2 2 60

22

Rabe, 2008[37] Austria, Belgium, Denmark,

France, Germany,

Netherlands, South Africa,

Sweden


Reid, 2008[29] Australia NR 24 24 2 34

Renkema, 1996[62] The Netherlands NR 104 104 2 39

Rennard, 2001[171] USA multi-center 12 12 2 267

Rennard, 2009[87] USA, Mexico, Europe (not

specified)


Rossi, 2002[38] Austria, Belgium, Czech

Republic, France, Germany,

Greece, Hungary, Italy,

Slovakia, South Africa,

Spain, USA


Rubin, 2008[99] Brazil single center 0.14 0.003

(30

minutes)

2 40

Rutgers, 1998[143] The Netherlands single center 6 6 2 44

Rutten-van,

1999[18]

The Netherlands multi-center 12 12 2 97

Santus, 2012[30] Italy NR 4 4 2 24

Schermer,

2007[118]


Scherr, 2012[130] Switzerland single center 12 12 2 68

Sechaud, 2012[125] Germany, Denmark multi-center 2 2 5 41

Senderovitz,

1999[144]

Denmark multi-center 24 24 2 26

Shaker, 2009[151]

CR:[256]

Denmark single center 208 104 -208 2 254

Sharafkhaneh,

2012[42]

USA, Central and South

America, South Africa


Sin, 2008[156] Canada multi-center 4 4 3 224

Sposato, 2008[139] Italy single center 0.05 0.34 2 37

Sridevi, 2012[134] India single center 14 14 2 60

Stahl, 2001[98] Sweden multi-center 12 12 2 121

Stockley, 2006[16] Austria, Bulgaria, Belgium,

Croatia, Czech Republic,

Denmark, Ireland, Estonia,

France, Germany, Holland,

Hungary, Latvia, Poland,

Spain, Slovak Republic,

Slovenia, Ukraine, UK


Struijs, 1997[158] The Netherlands NR 52 52 2 33

Sugiura, 2003[40] Japan single center 4 4 2 18

Suzuki, 2010[90] Japan single center 52 52 2 20

Szafranski, 2003[73]

CR:[259]

Argentina, Brazil, Denmark,

Finland, UK, Italy, Mexico,

Poland, Portugal, South

Africa, Spain


Tashkin, 2008 [2]

CR: [217-224, 227-


23

232]

Tashkin, 2008[72] USA, Czech Republic, The

Netherlands, Poland, South

Africa


Tashkin, 2009[95] USA multi-center 12 12 2 255

Tashkin, 2012[69] South America, Asia,

Africa, Europe, North

America (not specified)


The Lung Health

Study Research

Group, 2000 [51]

CR: [209]

NR multi-center 208 mean

160

2 1116

Tonnel, 2008 France multi-center 36 36 2 554

Troosters, 2014[182] Belgium, Canada, Czech

Republic, Germany, Great

Britain, Greece, the

Netherlands, Portugal,

Ukraine, USA


Tzani, 2011[58] Italy multi-center 12 12 2 18

Ulubay, 2005[163] Turkey single center 4 4 2 25

Um, 2007[148] Korea single center 6 6 2 81

Van de Maele,

2010[33]

Belgium multi-center 2 2 5 255

van Den Boom,

2001[149] CR: [247,

248]

The Netherlands single center 52 52 2 74

van den Broek,

2008[89]

Netherlands single center 104 0.006 2 77

van der Valk,

2002[43]


van Noord,

2000[116]


Verhoeven,

2002[59] CR: [254,

255]

The Netherlands NR 24 24 2 23

Verkindre,

2006[155]

France multi-center 14 12 2 100

Vestbo, 1999[114] Denmark single center 144 144 2 290

Vogelmeier,

2008[97]


Vogelmeier,

2010[135]

Germany, France, the

Netherland, Spain, Turkey,

USA


Vogelmeier,

2011[169] CR: [213]


Vogelmeier,

2013[80]

Belgium, Czech, Estonia,

Germany, Hungary, Korea,

Lithuania, Norway, Spain,

South Africa

multi-center 26

efficacy,

30 safety

26 2 523

Wadbo, 2002[60] Sweden multi-center 12 12 2 121

Watkins, 2013[141] USA single center 6 6 3 365

Wedzicha, 2008[22]

CR:[233]

Austria, Belgium, Czech

Republic, Denmark,


24

Estonia, Germany, Greece,

Italy, Latvia, Lithuania, the

Netherlands, Norway,

Romania, Russia, Slovakia,

Slovenia, Spain, Sweden,

Ukraine, UK

Wedzicha,

2013[162]

27 countries (not specified) multi-center 80 64 - 76 3 2206

Weir, 1999[5] UK multi-center 104 104 2 98

Welte, 2008[121] Germany multi-center 13 12 2 321

Welte, 2009[86] 9 countries multi-center 12 12 2 660

Wesseling,

1991[110]


Wielders, 2013[6] 9 countries multi-center 5 4 8 436

Wise, 2013[168] USA, UK, France,

Denmark, Germany and

other countries not specified

multi-center mean

119.6

median

119.28

3 17135

Woolhouse,

2001[145]

UK NR 2 2 2 23

Wouters, 2005[172] The Netherlands multi-center 52 52 2 373

Yao, 2014[181] China, Australia, India multi-center 26 26 3 561

Yildiz, 2004[41] Turkey single center 12 12 2 38

Zheng, 2007[159] China multi-center 26 24 2 445

Zhong, 2012[74] China multi-center 24 24 2 308

Unpublished Studies (n= 20)

Calverley,

2003†[186] USA NR 52 52 2 631

Cheng, 2012†[198] Taiwan NR 52 52 2 78

da Fonseca Reis,

2010†[200] NR NR 12 12 2 18

Dawber, 2005†[189] NR single center 3 3 2 59

GlaxoSmithKline,

2005

(SCO100470)†[193]

Australia, Bulgaria, Croatia,

Czech Republic, France,

Germany, Greece, Italy,

Latvia, Lithuania,

Netherlands, Philippines,

Poland, Romania, Russian

Federation, Slovakia,

Slovenia, Sweden, Thailand,

UK multi-center

24 24 2 1050

GlaxoSmithKline,

2005

(SCO40034)†[195] The Netherlands multi-center

12 12 2 125

GlaxoSmithKline,

2005 (SLMF

4010)†[187] France multi-center

24 24 2 34

GlaxoSmithKline,

2005

(SMS40298)†[197] Canada multi-center

16 16 2 347

GlaxoSmithKline,

2005 USA multi-center 4 8 2 316

25

(SMS40315)†[196]

GlaxoSmithKline,

2005 ,SFCT01

(SCO30002)†[192] Italy, Poland multi-center

54 52 3 387

GlaxoSmithKline,

2006

(SCO100540)†[194] China multi-center

24 24 2 445

GlaxoSmithKline,

2007

(SCO104925)†[185]

Russian Federation, USA,

Chile, Estonia multi-center

12 12 4 161

GlaxoSmithKline,

2008

(SCO40041)†[184] USA multi-center

156 156 2 186

Kelleher,

2011†[201] NR NR 1 1 3 38

Maltais, 2010†[202]

Canada, Germany, USA,

France NR 4 4 4 360

Novartis, 2006

(CQAB149B2205)†

[191]

Belgium, Canada, Denmark,

France, Germany, Italy, the

Netherlands, Norway, Peru,

Russia, Sweden,

Switzerland, USA multi-center

2 2 6 635

Ohar, 2013†[199] USA multi-center 26 26 2 639

Sekiya, 2012†[203] Japan multi-center 52 52 2 163

Sricharoenchai,

2008†[190] Thailand NR NR 0.012 2 15

To, 2011†[188] Japan NR 52 52 2 186

Note: †Unpublished data (n=20 studies)

Abbreviations: NR, not reported; CR: Companion Report; UK, United Kingdom; USA, United States of America

26

Appendix 8. Patient characteristics

Author, year Age category % Female COPD Definition Diagnosis of

COPD (GOLD

criteria)

COPD Severity COPD

duration

range

(mos)

Aalbers, 2002 Adult & elderly (≥18) 3.2 COPD NR moderate to severe† NR

Aaron, 2007 Adult & elderly (≥18) 43.69 non-asthmatic COPD NR moderate to very severe† NR

Abrahams, 2013 Adult & elderly (≥18) 35.53 COPD NR moderate to very severe† NR

Agusti, 2014 Adult & elderly (≥18) 17.99 COPD NR moderate to very severe† NR

Ambrosino, 2008 Adult & elderly (≥18) 16.24 non-asthmatic COPD NR moderate to very severe† NR

Anzueto, 2009 Adult & elderly (≥18) 45.97 chronic bronchitis and/or

emphysema

NA moderate to very severe† NR

Auffarth, 1991 Adult & elderly (≥18) 4.17 COPD NR NR NR

Barnes, 2006 Adult & elderly (≥18) 22.17 COPD NA moderate to severe† NR

Bateman, 2008 Adult & elderly (≥18) 28.97 COPD NR moderate to very severe NR

Bateman,

2010[7]CR:[210]

Adult & elderly (≥18) 22.45 COPD NR moderate to severe† NR

Bateman, 2012 Adult & elderly (≥18) 40.8 COPD NR moderate to severe NR

Bateman, 2013 Adult & elderly (≥18) 24.59 COPD II or III moderate to severe† NR

Bedard, 2012 Adult & elderly (≥18) 32.35 COPD NR moderate to severe NR

Beier, 2007 Adult & elderly (≥18) 22.09 COPD I-IV moderate† NR

Beier, 2013 Adult & elderly (≥18) 32.85 COPD II, III moderate to severe NR

Bogdan, 2011 Adult & elderly (≥18) 12.07 COPD NR moderate to severe† NR

Bolukbas, 2010 Adult & elderly (≥18) NR COPD I-IV NR newely

diagnosed

patients

Bourbeau, 1998 Adult & elderly (≥18) 21.52 NR NA moderate to very severe† NR

Bourbeau, 2007 Adult & elderly (≥18) 15 non-asthmatic COPD I-IV NR NR

Boyd, 1997 Adult & elderly (≥18) 21.07 COPD NA moderate to very severe† NR

Briggs, 2005 Adult & elderly (≥18) 33.51 non-asthmatic COPD NR moderate to severe† NR

Buhl, 2011 Adult & elderly (≥18) 31.5 post-bronchodilator

(salbutamol 400 mg)

No moderate to severe† NR

27

forced expiratory volume

in 1 s (FEV1) ,<80% and

≥30% predicted,

FEV1/forced vital

capacity (FVC),<70%)

Burge, 2000[129]

CR: [204-208]

Adult & elderly (≥18) 25.43 COPD NR mild to very severe† NR

Caillaud, 2007 Adult & elderly (≥18) 14.4 COPD NR moderate to severe† NR

Calverley, 2003[34]

CR:[214-216, 261]

Adult & elderly (≥18) 27.65 COPD NR moderate to very severe† NR

Calverly, 2003[53] Adult & elderly (≥18) 38 non-asthmatic COPD NR severe† NR

Calverly, 2003[119] Adult & elderly (≥18) 24.51 COPD III and IV moderate to very severe† > 24

Calverley,

2007[138] CR:

[234-242]


Calverly, 2008 Adult & elderly (≥18) 31.72 COPD I-IV mild to very severe† NR

Calverley, 2010 Adult & elderly (≥18) 19.35 COPD severe stable COPD

according to the

GOLD guidelines

severe† >24

Campbell, 2007 Adult & elderly (≥18) 48.04 COPD NR moderate to very severe† NR

Casaburi, 2005[103]

CR:[243]


Cazzola, 2000 Adult & elderly (≥18) 8.75 COPD NR mild to very severe† NR

Cazzola, 2007 Adult & elderly (≥18) 11.11 COPD a baseline FEV1 of

less than 50% of

predicted, and a

post-bronchodilator

FEV1/ FVC<70%

following

salbutamol 400 mg

according with the

GOLD criteria of

severity

severe to very severe NR

Celli, 2003[146] Adult & elderly (≥18) 38.27 COPD NR NR NR

Celli, 2003[104] Adult & elderly (≥18) 25.02 COPD NR moderate to very severe† > 24

Chan , 2007 Adult & elderly (≥18) 40.33 COPD NR moderate to very severe† NR

28

Chanez, 2010 Adult & elderly (≥18) 19.34 COPD NR moderate to severe† NR

Chapman, 2002 NR 36.03 COPD NR mild to very severe† NR

Chapman,

2011[115] CR:

[249-251]

Adult & elderly (≥18) 39 COPD Yes moderate to severe† NR

Choudhury, 2007 Adult & elderly (≥18) 47.69 COPD NR moderate to very severe† NR

Cooper, 2013 Adult & elderly (≥18) 23 COPD II/III/IV moderate to very severe† NR

Cote, 2009 Adult & elderly (≥18) 35.34 COPD NR NR NR

Covelli, 2005 Adult & elderly (≥18) 42.3 COPD NR moderate to very severe† NR

Criner, 2008 Adult & elderly (≥18) 32.51 COPD NR moderate to very severe† NR

D’ Urzo, 2011 Adult & elderly (≥18) 18.12 COPD 2008 GOLD

guidelines

moderate to severe† NR

Dahl, 2001 Adult & elderly (≥18) 25 COPD NR NR NR

Dahl, 2010 Adult & elderly (≥18) 19.9 non-asthmatic COPD NR moderate to very severe† NR

Dahl, 2013[82] Adult & elderly (≥18) 39.4 COPD II-III moderate to severe NR

Dahl, 2013[131] Adult & elderly (≥18) 23.1 COPD II-III moderate to severe† NR

Dal Negro, 2003 Adult & elderly (≥18) 11.11 COPD II moderate NR

Decramer, 2013 Adult & elderly (≥18) 23 COPD and severe

airflow limitations

Yes severe† NR

Decramer, 2014a Adult & elderly (≥18) 30.96 non-asthmatic COPD B or D (II-IV) moderate to very severe† NR

Decramer, 2014b Adult & elderly (≥18) 32.22 non-asthmatic COPD B or D (II-IV) moderate to very severe† NR

Doherty, 2012 Adult & elderly (≥18) 24.75 COPD GOLD criteria

diagnoses

moderate to very severe† NR

Donohue, 2002[3]

CR:[257, 258]

Adult & elderly (≥18) 25 COPD NR moderate† NR

Donohue, 2013 Adult & elderly (≥18) 29.31 COPD II, III, IV mod to very severe† NR

Dransfield, 2011 Adult & elderly (≥18) 42.98 COPD NR moderate to severe NR

Dransfield, 2013a Adult & elderly (≥18) 40.57 COPD NR moderate to very severe† NR

Dransfield, 2013b Adult & elderly (≥18) 44.52 COPD NR moderate to very severe† NR

Dusser, 2006 Adult & elderly (≥18) 12.01 non-asthmatic COPD NR moderate to severe† NR

Engel, 1989 Adult (18-64) 55.56 cough and expectoration

for at least three months

a year during at least the

NR mild to moderate† at least the

preceding 2

years

29

preceding 2 years, and

moderate to severe

bronchial

hyperresponsiveness as

judged by a bronchial

histamine challenge

(provocative

concentration producing

a 20% fall in FEV1

≤2.0mg/ histamine ml)

Feldman, 2010 Adult & elderly (≥18) 47.6 COPD NR moderate to severe† < 12 to >

240

Feldman, 2012 Adult & elderly (≥18) 39.22 COPD NR mild to very severe† NR

Ferguson, 2008 Adult & elderly (≥18) 44.88 non-asthmatic COPD NR moderate to very severe† NR

Freeman, 2007 Adult & elderly (≥18) 45.72 complex of respiratory

symptoms/events of

>3days in duration

requiring a change in

treatment

NR mild to very severe† NR

Fukuchi, 2013 Adult & elderly (≥18) 11.03 COPD NR moderate to very severe† ≥24

Gelb, 2013 Adult & elderly (≥18) 41.69 COPD NR moderate to severe NR

Gupta,2002 Adult (18-64) 0 COPD NR moderate or severe NR

Hagedorn, 2013 Adult & elderly (≥18) 29.2 COPD III, IV severe or very severe NR

Hanania, 2003 Adult & elderly (≥18) 36.79 COPD with moderate

dyspnea

NR moderate to very severe† 12-636

Hanania, 2012[26] Adult & elderly (≥18) 53.46 COPD II, III mild to severe† NR

Hanania, 2012[161] Adult & elderly (≥18) 38.54 COPD NR moderate to severe† NR

Hasani, 2004 Adult & elderly (≥18) 20.59 COPD NR stable NR

Hattotuwa,

2002[157] CR:[260]

Adult & elderly (≥18) 13.33 COPD NR mild to very severe† NR

Hoshino, 2011 Adult & elderly (≥18) 6.67 non-asthmatic COPD I-IV NR NR

Hoshino, 2013 Adult & elderly (≥18) 13.33 COPD NR NR NR

Johansson, 2008 Adult & elderly (≥18) 47.78 COPD I, II, III mild to severe† NR

Jones, 1997 Adult & elderly (≥18) 14.49 COPD NR NR NR

Jones, 2011a Adult & elderly (≥18) 21.35 non-asthmatic COPD NR moderate to very severe† NR

30

Jones, 2011b Adult & elderly (≥18) 36.94 COPD NR moderate to severe† NR

Jones, 2012 Adult & elderly (≥18) 32.6 COPD II-III moderate to very severe† NR

Jung, 2012 Adult & elderly (≥18) 1.98 COPD II, III, IV moderate to very severe† NR

Kardos, 2007 Adult & elderly (≥18) 24.25 COPD GOLD stages III

and IV

severe to very severe† NR

Kaushik, 1999 Adult & elderly (≥18) 13.33 COPD NR NR -stable NR

Kerwin, 2011a Adult & elderly (≥18) 45.5 COPD NR moderate to severe† NR

Kerwin, 2011b Adult & elderly (≥18) 46 COPD NR moderate to severe† NR

Kerwin, 2012[68]

CR:[244]

Adult & elderly (≥18) 47 COPD NR moderate to severe† NR

Kerwin, 2012[78] Adult & elderly (≥18) 35.85 COPD Yes moderate to severe† NR

Kerwin, 2013 Adult & elderly (≥18) 33.5 COPD NR moderate† NR

Kinoshita, 2012[75]

CR: [253]

Adult & elderly (≥18) 3.47 COPD II, III moderate to severe† NR

Korn, 2011 Adult & elderly (≥18) 29.9 COPD Yes moderate to severe† NR

Kornmann, 2011 Adult & elderly (≥18) 25.32 COPD NR moderate to severe† NR

Koser, 2010 Adult & elderly (≥18) 46.56 COPD NR NR NR

Kuna, 2013 Adult & elderly (≥18) 25 COPD NR mild to severe† 0-348

Lapperre, 2009[49]

CR:[252]

Adult & elderly (≥18) 13.86 non-asthmatic COPD II-III moderate to severe NR

Littner, 2000 Adult & elderly (≥18) 43.19 COPD NR moderate to severe† NR

Llewellyn-Jones,

1996

Adult & elderly (≥18) 50 chronic bronchitis and

emphysema

NR moderate to severe† >24

Lomas,2012 Adult & elderly (≥18) 26.4 COPD stage II moderate† NR

Lotvall, 2012 Adult & elderly (≥18) 33.33 COPD Grade II, Grade III moderate to severe† NR

Magnussen, 2008 Adult & elderly (≥18) 38.56 COPD NR moderate to very severe† NR

Mahler, 1999 Adult & elderly (≥18) 26.28 COPD NR mild to severe† NR

Mahler, 2002 Adult & elderly (≥18) 33.98 non-asthmatic COPD NR moderate to very severe† 12-552

Mahler, 2012a Adult & elderly (≥18) 31.49 COPD II moderate to severe† NR

Mahler, 2012b Adult & elderly (≥18) 34.5 COPD II moderate to severe† NR

Maltais, 2005 Adult & elderly (≥18) 27.59 COPD NR moderate to very severe† NR

Maltais, 2011 Adult & elderly (≥18) 41.99 COPD NR moderate to severe† NR

31

Mansori, 2010 Adult & elderly (≥18) 0 COPD NR NR NR

Martinez, 2013 Adult & elderly (≥18) 27.7 COPD NR moderate to very severe† NR

Mathioudakis, 2013 Adult & elderly (≥18) 0 "predominantly

emphysematic" and

"predominantly

bronchitic patients."

II and III NR NR

McNicholas, 2004 Adult & elderly (≥18) 30.53 COPD NR NR NR

Mirici, 2001 Adult & elderly (≥18) 25 COPD NR moderate to severe NR

Moita, 2008 Adult & elderly (≥18) 4.84 NR NA moderate to very severe† NR

Mroz, 2013 Adult & elderly (≥18) 11.76 COPD GOLD criteria cited

in the appendix but

linked only to the

introduction section

that describes

COPD as a

progressive,

inflammatory

condition leading to

airflow limitation,

pulmonary

hyperinflation,

resulting in

dyspnea, decreased

exercise tolerance

and impaired QoL.

NR NR

Nanshan/Zhong,

2012


Nicolini, 2012 Adult & elderly (≥18) 32 COPD stages 2, 3, 4 stable NR

Niewoehner,

2005[126] CR:[211,

212]


O'Donnell, 2004 Adult & elderly (≥18) 26.2 COPD NR moderate to very severe† NR

O'Donnell, 2006 Adult & elderly (≥18) 30.12 COPD NR moderate to very severe† NR

Ozol, 2005 Adult & elderly (≥18) 18.18 COPD NR mild to moderate NR

Paggiaro, 1998 Adult & elderly (≥18) 22.78 COPD: "as a disorder

characterised by

decreased maximum

NR mild to severe† NR

32

expiratory flow and slow

forced emptying of the

lungs, which is slowly

progressive, irreversible,

and does not change

markedly over several

months."

Pasqua, 2010 Adult & elderly (≥18) 13.64 COPD NR advanced NR

Pauwels, 1999[117]

CR:[245, 246]

Adult (18-64) 27.15 COPD NR mild to moderate† NR

Perng, 2009 Adult & elderly (≥18) 4.04 COPD NR moderate to very severe† NR

Powrie, 2007 Adult & elderly (≥18) 37.3 non-asthmatic COPD NR mild to severe† NR

Pukhta, 2010 Adult & elderly (≥18) 19 COPD NR stable NR

Rabe, 2008 Adult & elderly (≥18) 32 COPD NR mild to moderate† 1-504

Reid, 2008 Adult & elderly (≥18) 50 COPD I, II mild to moderate† NR

Renkema, 1996 Adult & elderly (≥18) 0 COPD NR NR NR

Rennard, 2001 Adult & elderly (≥18) 37.08 COPD NR moderate to very severe† NR

Rennard, 2009 Adult & elderly (≥18) 36.1 COPD NR moderate to very severe† > 24

Rossi, 2002 Adult & elderly (≥18) 16.7 COPD NR moderate to very severe† 0-600

Rubin, 2008 Adult & elderly (≥18) NR COPD II-IV NR NR

Rutgers, 1998 Adult & elderly (≥18) 40.91 COPD NR mild to severe NR

Rutten-van, 1999 Adult & elderly (≥18) 12.5 COPD NR moderate or severe NR

Santus, 2012 Adult & elderly (≥18) 4.17 COPD II NR NR

Schermer, 2007 Adult & elderly (≥18) 52.5 COPD NR NR ≥3 months

Scherr, 2012 Adult & elderly (≥18) 45.59 COPD I, II mild to moderate NR

Sechaud, 2012 Adult & elderly (≥18) 41.46 COPD NR mild to moderate NR

Senderovitz, 1999 Adult & elderly (≥18) 46.15 COPD NR stable NR

Shaker, 2009[151]

CR:[256]

Adult & elderly (≥18) 42 COPD is defined as a

"preventable and

treatable disease state

characterised by airflow

limitation that is not

fully reversible. The

airflow limitation is

NR moderate to severe† ≥24

33

usually progressive and

is associated with an

abnormal inflammatory

response of the lungs to

noxious particles or

gases, primarily caused

by cigarette smoking."

Sharafkhaneh, 2012 Adult & elderly (≥18) 38.01 COPD NR moderate to very severe† >24

Sin, 2008 Adult & elderly (≥18) 37.03 stable COPD (absence of

exacerbation for at least

4 weeks)

NR moderate to very severe† NR

Sposato, 2008 Adult & elderly (≥18) 32.43 COPD moderate-to-severe

COPD as per

GOLD

moderate to severe, stable NR

Sridevi, 2012 Adult & elderly (≥18) stable or exacerbated

COPD


Stahl, 2001 Adult & elderly (≥18) 46.99 COPD NR moderate to severe NR

Stockley, 2006 Adult & elderly (≥18) 24.04 COPD NR moderate to very severe† NR

Struijs, 1997 Adult & elderly (≥18) 39.39 COPD NR NR NR

Sugiura, 2002 Adult & elderly (≥18) 11.11 COPD NR NR NR

Suzuki, 2010 Adult & elderly (≥18) 10 COPD I; II-III moderate to severe NR

Szafranski,

2003[73] CR:[259]

Adult & elderly (≥18) 21.26 COPD moderate-to-severe moderate to very severe† ≥24

Tashkin DP, 2012 Adult & elderly (≥18) 22.46 COPD NR moderate to very severe† ≥24

Tashkin, 2008[2]

CR: [217-224, 227-

232]

Adult & elderly (≥18) 25 COPD II (44.5%); III

(44%); IV (8.5%)

moderate to very severe† NR

Tashkin, 2008[72] Adult & elderly (≥18) 31.87 COPD who had previous

exacerbations

NR moderate to verey severe† >24

Tashkin, 2009 Adult & elderly (≥18) 33.73 COPD NR severe to very severe† NR

The Lung Health

Study Research

Group, 2000[51]

CR: [209]

Adult & elderly (≥18) 36.95 COPD NR mild to severe† NR

Tonnel, 2008 Adult & elderly (≥18) 13.9 non-asthmatic COPD NR moderate to very severe† NR

Troosters, 2014 Adult & elderly (≥18) 31.5 non-asthmatic COPD II moderate† NR

34

Tzani, 2011 Adult & elderly (≥18) 16.67 COPD confirmed

diagnosis according

to GOLD

guidelines

NR NR

Ulubay, 2005 Adult & elderly (≥18) 18.92 COPD II and III moderate to severe NR

Um, 2007 Adult & elderly (≥18) 8.64 COPD NR severe to very severe NR

Van de Maele, 2010 Adult & elderly (≥18) 23.53 COPD NR mild to severe† NR

van Den Boom,

2001[149] CR:

[247, 248]

Adult & elderly (≥18) 58.1 Obstructive airway

disease

NA moderate to severe† NR

van den Broek,

2008

Adult & elderly (≥18) 33.77 COPD NR NR ≥6

van der Valk, 2002 Adult & elderly (≥18) 15.5 non-asthmatic COPD NR moderate to very severe† NR

van Noord, 2000 Adult & elderly (≥18) 25.69 Patients with COPD

according to ATS.

COPD is "defined as a

disease state

characterized by the

presence of airflow

obstruction, due to

chronic bronchitis or

emphysema, and is

generally progressive but

may be partially

reversible."

NR mild to moderate† NR

Verhoeven,

2002[59] CR: [254,

255]

Adult & elderly (≥18) 17.39 COPD NR mild to moderate NR

Verkindre, 2006 Adult & elderly (≥18) 6 COPD NR moderate to severe NR

Vestbo, 1999 Adult & elderly (≥18) 39.66 COPD NR mild to moderate† NR

Vogelmeier, 2008 Adult & elderly (≥18) 22.08 stable COPD NR moderate to severe† NR

Vogelmeier, 2010 Adult & elderly (≥18) 32.38 moderate to severe

COPD according to 2006

GOLD guidelines

moderate to severe moderate to severe† NR

Vogelmeier,

2011[169] CR:[213]

Adult & elderly (≥18) 25.35 COPD II, III, IV moderate to very severe† NR

Vogelmeier, 2013 Adult & elderly (≥18) 29 COPD II or III moderate to severe† NR

35

Wadbo, 2002 Adult & elderly (≥18) 46.99 COPD NR moderate to very severe† 12-408

Watkins, 2013 Adult & elderly (≥18) 42.82 COPD NR moderate to very severe† NR

Wedzicha, 2008[22]

CR:[233]

Adult & elderly (≥18) 17.49 COPD III-IV moderate to very severe† NR

Wedzicha,2013 Adult & elderly (≥18) 25.16 COPD III or IV severe to very severe† NR

Weir, 1999 Adult & elderly (≥18) 25.5 COPD NR NR NR

Welte, 2008 Adult & elderly (≥18) 33.64 COPD II, III moderate to severe at least 2

years

Welte, 2009 Adult & elderly (≥18) 24.85 COPD II-IV mild to very severe† NR

Wesseling, 1991 Adult & elderly (≥18) 37.1 chronic bronchitis

without marked airflow

obstruction (FEV ~70%

predicted)

NR NR NR

Wielders, 2013 Adult & elderly (≥18) 34.54 COPD NR moderate to severe† NR

Wise, 2013 Adult & elderly (≥18) 28.47 NR NR moderate to very severe† NR

Woolhouse, 2001 Adult & elderly (≥18) 47.83 chronic bronchitis, as

defined by daily sputum

production for at least 3

months of 2 consecutive

years

NA NR NR

Wouters, 2005 Adult & elderly (≥18) 26.3 COPD NR moderate to severe† NR

Yao, 2014 Adult & elderly (≥18) 5.7 COPD NR moderate to severe† NR

Yildiz, 2004 Adult & elderly (≥18) 0 COPD II moderate NR

Zheng, 2007 Adult & elderly (≥18) 10.79 European Respiratory

Society and GOLD

guidelines


Unpublished Studies (n=20)

Calverley,

2003*[186] NR NR COPD NR moderate to very severe† NR

Cheng, 2012* NR NR COPD NR NR NR

da Fonseca Reis,

2010* NR NR COPD III Severe NR

Dawber, 2005* NR NR COPD NR moderate to severe NR

GlaxoSmithKline,

2005 (SCO100470)* Adult & elderly (≥18) 22.19 COPD II NR† NR

36

GlaxoSmithKline,

2005 (SCO40034)* Adult & elderly (≥18) 25.6 COPD NR moderate to very severe†

NR

GlaxoSmithKline,

2005 (SLMF 4010)* Adult (18-64) 11.76 COPD NR moderate to severe†

NR

GlaxoSmithKline,

2005 (SMS40298)* Adult & elderly (≥18) 41.21 COPD NR moderate to very severe†

NR

GlaxoSmithKline,

2005 (SMS40315)* Adult & elderly (≥18) 39.18 COPD NR moderate to severe†

NR

GlaxoSmithKline,

2005 ,SFCT01

(SCO30002)* Adult & elderly (≥18) 17.57 COPD NR moderate to very severe†

NR

GlaxoSmithKline,


NR

GlaxoSmithKline,

2007 (SCO104925)* Adult & elderly (≥18) 23.6 bronchitis and COPD NR moderate to severe†

NR

GlaxoSmithKline,


NR

Kelleher, 2011* NR NR COPD NR NR† NR

Maltais, 2010* NR 45.5 COPD NR NR NR

Novartis, 2006

(CQAB149B2205)* Adult & elderly (≥18) 33.23 COPD NR moderate to severe†

NR

Ohar, 2013* Adult (18-64) 45.5 COPD NR NR† NR

Sekiya, 2012* Adult & elderly (≥18) 2.45 COPD II, III moderate to severe† NR

Sricharoenchai,

2008* NR NR COPD NR NR

NR

To, 2011* NR NR COPD NR moderate to severe† NR

Note: † As determined by a clinician (SES), *Unpublished data (n=20 studies)

Abbreviations: NR, not reported; CR, Companion report; FEV1, Forced expiratory volume; FVC, Forced vital capacity, ; ATS, American Thoracic Society;

GOLD, Global Initiative for Chronic Obstructive Lung Disease; GOLD I,II, III,IV: Mild, Moderate, Severe, Very Severe

37

Appendix 9: Risk of bias results for the included studies

Author, year 1 2 3 4 5 6 7

Aalbers, 2002 Low Unclear Low Low Low Unclear Unclear

Aaron, 2007 Low Low Low Low Low Low Low

Abrahams, 2013 Unclear Unclear Low Low Low High High

Agusti, 2014 Low Low Low Low Low Low High

Ambrosino, 2008 Unclear Unclear Low Low Low Unclear High

Anzueto, 2009 Low Unclear Low Low Unclear Unclear High

Auffarth, 1991 Unclear Unclear Low Low Low Unclear Unclear

Barnes, 2006 Unclear Unclear Low Low Low Unclear High

Bateman, 2008 Unclear Unclear Low Low Low Unclear Unclear

Bateman, 2010 Low Unclear Low Low Low Low High

Bateman, 2012 Unclear Unclear Low Low Low Low High

Bateman, 2013 Low Unclear Low Low Low Low Unclear

Bedard, 2012 Low Low Low Low Low High Low

Beier, 2007 Unclear Unclear Low Low Low Unclear Unclear

Beier, 2013 Low Low Low Low Low Low High

Bogdan,2011 Unclear Unclear Low Low Low Low Low

Bolukbas,2010 Unclear Unclear Low Low Low Unclear Unclear

Bourbeau,1998 Unclear Unclear Low Low Low Unclear Unclear

Bourbeau, 2007 Low Low Low Low Unclear Unclear Unclear

Boyd,1997 Unclear Unclear Low Low Low Unclear Unclear

Briggs, 2005 Unclear Unclear Low Low Low Unclear High

Buhl, 2011 Unclear Unclear Low Low Low Low High

Burge, 2000 Low Unclear Low Low Low Low High

Caillaud, 2007 Unclear Unclear Low Low Low Unclear High

Calverley, 2003[186] Unclear Unclear Low Low Unclear Unclear Unclear

Calverley, 2003[34] Low Low Low Low Low Low High

Calverly, 2003[53] Unclear Unclear Low Low Unclear Unclear High

Calverly, 2003[119] Unclear Unclear Low Low High Unclear High

Calverley, 2007 Unclear Unclear Low Low High Low High

Calverly, 2008 Low Unclear Low Low Low Unclear High

Calverley, 2010 Low Low Low Low Low Low High

Campbell, 2007 Unclear Unclear Low Low Low Unclear High

Casaburi, 2005 Unclear Unclear Low Low Low Unclear High

Cazzola, 2000 Low Unclear Low Unclear High Unclear Unclear

Cazzola, 2007 Unclear Unclear Low Low Unclear Unclear Unclear

Celli, 2003[146] Unclear Unclear Low Low Low Unclear High

Celli, 2003[104] Low Unclear Low Low Low High High

Chan, 2007 Low Unclear Low Low Low Unclear High

Chanez, 2010 Unclear Unclear Low Low Low Unclear Unclear

Chapman, 2002 Low Unclear Low Low Low Unclear Unclear

38

Chapman, 2011 Unclear Unclear Low Low Low Low High

Cheng, 2012 Unclear Unclear Low Low Unclear Unclear Unclear

Choudhury, 2007 Low Low Low Low Low Low Low

Cooper, 2013 Unclear Unclear Low Low Low High High

Cote, 2009 High Unclear Low Low Low Unclear Unclear

Covelli, 2005 Unclear Unclear Low Low Low Unclear Unclear

Criner, 2008 Unclear Unclear Low Low Unclear Low High

D’Urzo, 2011 Unclear Unclear Low Low Low Low High

da Fonseca Reis, 2010 Unclear Unclear Low Low Unclear Unclear Unclear

Dahl, 2013[82] Unclear Unclear Low Low Low Unclear High

Dahl, 2001 Unclear Unclear Low Low Unclear Unclear Unclear

Dahl, 2010 Low Unclear Low Low High Low High

Dahl, 2013[131] Unclear Unclear Low Low Low Low High

Dal Negro, 2003 Unclear Unclear Low Low Low High Unclear

Dawber, 2005 Unclear Unclear Low Low Unclear Unclear Unclear

Decramer, 2013 Low Low Low Low High Low High

Decramer, 2014a Low Low Low Low Low Low High

Decramer, 2014b Low Low Low Low Low Low High

Doherty, 2012 Unclear Unclear Low Low Low Low High

Donohue, 2002 Unclear Unclear Low Low High Unclear High

Donohue, 2013 Low Low Low Low Low Low High

Dransfield, 2011 Unclear Unclear Low Low Low High High

Dransfield, 2013a Low Low Low Low Low Low High

Dransfield, 2013b Low Low Low Low Low Low High

Dusser, 2006 Unclear Unclear Low Low Low Unclear High

Engel, 1989 Unclear Unclear Low Low High Unclear Unclear

Feldman, 2010 Unclear Unclear Low Low Low Low High

Feldman, 2012 Low Low Low Low Low Low High

Ferguson, 2008 Unclear Unclear Low Low High Low High

Freeman, 2007 Unclear Unclear Low Low Low Low High

Fukuchi, 2013 Unclear Unclear Low Low Low Low Unclear

Gelb, 2013 Unclear Unclear Low Low Low Low High

GlaxoSmithKline, 2005

(SMS40298)

Unclear Unclear Low Low Low Unclear Unclear


(SMS40315)


GlaxoSmithKline,

2005(SCO40034)



(SCO100470)

Unclear Unclear Low Low Low Low High


(SCO30002)

Unclear Unclear Low Low Low Low High


(SLMF4010)

Unclear Unclear Low Low Low Unclear High


(SCO100540)


39

Glaxo 2007 (SCO104925) Unclear Unclear Low Low Unclear Unclear High

Glaxo 2008 (SCO40041) Unclear Unclear Low Low Unclear Unclear High

Gupta, 2002 Low Unclear Low Low Low Unclear Unclear

Hagedorn , 2013 Unclear Unclear Low Low Low Low High

Hanania, 2003 Unclear Unclear Low Low Unclear Unclear Unclear

Hanania, 2012[26] Unclear Unclear Low Low Low Low High

Hanania, 2012[161] Low Unclear Low Low Low Low High

Hasani, 2004 Unclear Unclear Low Low Low Unclear High

Hattotuwa, 2002 Low Unclear Low Low High Unclear Unclear

Hoshino, 2011 Unclear Unclear Low Low Unclear Low Low

Hoshino, 2013 Low Unclear Low Low Unclear Unclear Unclear

Johansson, 2008 Unclear Unclear Low Low Low Unclear Unclear

Jones, 1997 Unclear Unclear Low Low Unclear Unclear High

Jones, 2011a Unclear Unclear Low Low Low Low High

Jones, 2011b Unclear Unclear Low Low Low Low High

Jones, 2012 Unclear Unclear Low Low Low Low High

Jung, 2012 Low Unclear Low Low Low Unclear High

Kardos, 2007 Low Unclear Low Low Low Unclear Unclear

Kaushik, 1999 Unclear Unclear Low Low Unclear Unclear Unclear

Kelleher, 2011 Unclear Unclear Low Low High Unclear Unclear

Kerwin, 2011a Low Low Low Low Low Low High

Kerwin, 2011b Low Low Low Low Low Low High

Kerwin, 2012[78] Unclear Unclear Low Low Low High High

Kerwin, 2012[68] Unclear Unclear Low Low Low Low High

Kerwin, 2013 Low Unclear Low Low Low Low Unclear

Kinoshita, 2012 Low Unclear Low Low Low Low High

Korn, 2011 Low Low Low Low Low Low High

Kornmann, 2011 Low Unclear Low Low Low Low High

Koser, 2010 Unclear Unclear Low Low Low Low High

Kuna, 2013 Unclear Unclear Low Low Low Low High

Lapperre, 2009 Unclear Unclear Low Low Unclear High Unclear

Littner, 2000 Unclear Unclear Low Low Low Unclear Unclear

Llewellyn-Jones, 1996 Unclear Unclear Low Low Low Unclear Unclear

Lomas, 2012 Low Unclear Low Low Low High High

Lötvall, 2012 Low Low Low Low Low Low High

Magnussen, 2008 Unclear Unclear Low Low Low Unclear High

Mahler, 1999 Unclear Unclear Low Low Unclear Unclear Unclear

Mahler, 2002 Unclear Unclear Low Low High Unclear Unclear

Mahler, 2012a Low Low Low Low Low Unclear High

Mahler, 2012b Low Low Low Low Low Low High

Maltais, 2005 Unclear Unclear Low Low High Unclear Unclear

Maltais, 2010 Unclear Unclear Low Low Low Unclear Unclear

40

Maltais, 2011 Unclear Unclear Low Low Low Low High

Mansori, 2010 Unclear Unclear Low Low Unclear Unclear Low

Martinez, 2013 Low Low Low Low Low Low High

Mathioudakis, 2013 Unclear Unclear Low Low Low Unclear Unclear

McNicholas, 2004 Unclear Unclear Low Low Low Unclear High

Mirici, 2001 Low High Low Low Low Unclear Unclear

Moita, 2008 Unclear Unclear Low Low Low Unclear Unclear

Mroz, 2013 Unclear Unclear Unclear Low Unclear Unclear Unclear

Nanshan Z/ or Zhong

N,2012

Low Unclear Low Low Low Low Low

Nicolini, 2012 Low Unclear Low Low Low Unclear Low

Niewoehner, 2005 Low Unclear Low Low Low Low High

Novartis, 2006 Unclear Unclear Low Low Low Unclear Unclear

O'Donnell, 2004 Unclear Unclear Low Low High Unclear Unclear

O'Donnell, 2006 Unclear Unclear Low Low Low Unclear High

Ohar, 2013 Unclear Unclear Low Low Low Low High

Ozol, 2005 Low Unclear Low Low High Unclear Unclear

Paggiaro, 1998 Low Unclear Low Low Low Unclear Unclear

Pasqua, 2010 Unclear Unclear Low Low Unclear Unclear Low

Pauwels, 1999 Unclear Unclear Low Low Low Unclear High

Perng, 2009 Low Unclear Low Low Unclear Unclear Low

Powrie, 2007 Unclear Unclear Low Low High Low High

Pukhta, 2010 Unclear Unclear Low Low Low Unclear Unclear

Rabe, 2008 Unclear Unclear Low Low Low Low High

Reid, 2008 Low Unclear Low Low High Unclear Low

Renkema, 1996 Low Unclear Low Low Low Unclear Low

Rennard, 2009 Unclear Unclear Low Low Low Low High

Rennard, 2001 Unclear Unclear Low Low High Unclear High

Rossi, 2002 Unclear Unclear Low Low Low Unclear High

Rubin, 2008 Unclear Unclear Low Low Low Unclear Unclear

Rutgers, 1998 Unclear Unclear Low Low Low Unclear Unclear

Rutten-van Molken, 1999 Unclear Unclear Low Low Low Unclear High

Santus, 2012 Unclear Unclear Unclear Unclear Unclear Unclear Low

Schermer, 2007 Low Unclear Low Low Low Unclear High

Scherr, 2012 Unclear Unclear Low Low Low High Low

Sechaud, 2012 Unclear Unclear Low Low Low Unclear High

Sekiya, 2012 Unclear Unclear High Low High Unclear Unclear

Senderovitz, 1999 Unclear Unclear Low Low Low Unclear Unclear

Shaker, 2009 Low Unclear Low Low High Low Unclear

Sharafkhaneh, 2012 Low Low Low Low Unclear Low High

Sin, 2008 Low Low Low Low Low Low Low

Sposato, 2008 Unclear Unclear Low Low Unclear Unclear Unclear

Sricharoenchai, 2008 Unclear Unclear Low Low Unclear Unclear Unclear

41

Sridevi, 2012 Unclear Unclear Unclear Unclear High High Unclear

Stahl, 2001 Unclear Unclear Low Low Unclear Unclear Unclear

Stockley, 2006 Low Low Low Low Low Low Unclear

Struijs, 1997 Unclear Unclear Low Low Low Unclear Unclear

Sugiura H, 2002 Unclear Unclear Low Low Low Low Low

Suzuki, 2010 Unclear Unclear Low Low Low Low Unclear

Szafranski, 2003 Unclear Unclear Low Low Low Unclear Unclear

Tashkin, 2008[72] Low Unclear Low Low Low Low High

Tashkin, 2008[2] Low Low Low Low Low Low High

Tashkin, 2009 Low Unclear Low Low Low Unclear High

Tashkin, 2012 Low Low Low Low High Low High

The Lung Health Study

Research Group, 2000


To, 2011 Unclear Unclear Low Unclear Low Unclear Unclear

Tonnel, 2008 Low Unclear Low Low High Unclear High

Troosters, 2014 Low Unclear Low Low Low Low Unclear

Tzani, 2011 Low Unclear Low Low Low Low High

Ulubay, 2005 Unclear Unclear Low Low Unclear Unclear Unclear

Um, 2007 Low Unclear High Low High Unclear Low

Van de Maele, 2010 Low Unclear Low Low Low Unclear Unclear

van Den Boom, 2001 Unclear Unclear Low Low Low Unclear Low

van den Broek , 2008 Low Unclear Low Low Low Unclear Unclear

van der Valk, 2002 Low Unclear Low Low Low Unclear Unclear

van Noord, 2000 Unclear Unclear Low Low Low Unclear High

Verhoeven, 2002 Unclear Unclear Low Low Low Low Unclear

Verkindre, 2006 Unclear Unclear Low Low Low Unclear High

Vestbo, 1999 Low Low Low Low Low Unclear Unclear

Vogelmeier, 2008 Unclear Unclear Low Low Low Low High

Vogelmeier, 2010 Unclear Unclear Low Low Low Low High

Vogelmeier, 2011 Low Low Low Low Low Low High

Vogelmeier, 2013 Low Low Low Low Low Low High

Wadbo, 2002 Unclear Unclear Low Low High Unclear Unclear

Watkins, 2013 Unclear Unclear Low Low Low Low High

Wedzicha, 2008 Low Low Low Low Low Low Unclear

Wedzicha, 2013 Low Low Low Low Low Low High

Weir, 1999 Unclear Unclear Low Low High Unclear Unclear

Welte, 2008 Unclear Unclear Low Low Low Unclear High

Welte, 2009 Low Unclear Low Low Low Low High

Wesseling, 1991 Unclear Unclear Low Low Low Unclear Unclear

Wielders, 2013 Unclear Unclear Low Low Low Low High

Wise, 2013 Unclear Unclear Low Low Low Low Low

Woolhouse, 2001 Unclear Unclear Low Low Low Unclear Unclear

Wouters, 2005 Low Unclear Low Low High Unclear High

42

Yao, 2014 Low Low Low Low Low Low High

Yildiz, 2004 Unclear Unclear Low Low Low Unclear Unclear

Zheng, 2007 Unclear Unclear Low Low Low Unclear Unclear

43

Appendix 10. Network Meta-analysis Results Outcome

Network Meta-analysis Results Pairwise Meta-analysis

Treatment Comparison Odds

Ratio

CI PrI Odds

Ratio

CI Heteroge

neity

Variance

# studies # patients

Exacerbations in past year: 20 studies (1 four-arm, 3 three-arm, 16 two-arm), 17 treatments, 26141 patients

Budesonide vs Placebo 0.75 0.51-1.10 - 0.75 0.51-1.10 -- 1 522

Fluticasone vs Placebo 0.80 0.49-1.31 - 0.80 0.49-1.31 -- 1 281

Formoterol vs Placebo 0.84 0.60-1.18 - 0.94 0.65-1.38 -- 1 520

Indacaterol vs Placebo 0.78 0.61-1.00 - 0.00 0.00-0.00

Salmeterol vs Placebo 0.79 0.64-0.97 - 0.80 0.58-1.09 -- 1 634

Vilanterol vs Placebo 0.75 0.24-2.36 - 0.00 0.00-0.00

Glycopyrronium vs Placebo 0.77 0.57-1.03 - 0.00 0.00-0.00

Tiotropium vs Placebo 0.65 0.53-0.79 - 0.64 0.50-0.83 -- 1 1003

Beclomethasone/Formoterol vs Placebo 0.73 0.45-1.19 - 0.00 0.00-0.00

Budesonide/Formoterol vs Placebo 0.64 0.45-0.91 - 0.55 0.36-0.83 -- 1 519

Fluticasone/Vilanterol vs Placebo 0.57 0.18-1.75 - - - - -

Fluticasone/Salmeterol vs Placebo 0.67 0.53-0.85 - - - - -

Tiotropium/Salmeterol vs Placebo 0.71 0.43-1.18 - - - - -

Indacaterol/Glycopyrronium vs Placebo 0.48 0.36-0.64 - - - - -

Tiotropium/Fluticasone/Salmeterol vs Placebo 0.58 0.35-0.96 - - - - -

Tiotropium/Budesonide/Formoterol vs Placebo 0.23 0.14-0.40 - - - - -

Fluticasone vs Budesonide 1.07 0.57-2.01 - - - - -

Formoterol vs Budesonide 1.12 0.78-1.61 - 1.26 0.85-1.87 -- 1 512

Indacaterol vs Budesonide 1.04 0.66-1.65 - - - - -

Salmeterol vs Budesonide 1.05 0.68-1.64 - - - - -

Vilanterol vs Budesonide 1.00 0.30-3.36 - - - - -

Glycopyrronium vs Budesonide 1.02 0.63-1.67 - - - - -

Tiotropium vs Budesonide 0.87 0.56-1.34 - - - - -

Beclomethasone/Formoterol vs Budesonide 0.98 0.60-1.61 - - - - -

Budesonide/Formoterol vs Budesonide 0.86 0.59-1.24 - 0.73 0.48-1.12 -- 1 511

44

Fluticasone/Vilanterol vs Budesonide 0.76 0.23-2.50 - - - - -

Fluticasone/Salmeterol vs Budesonide 0.90 0.57-1.42 - - - - -

Tiotropium/Salmeterol vs Budesonide 0.95 0.50-1.80 - - - - -

Indacaterol/Glycopyrronium vs Budesonide 0.64 0.39-1.04 - - - - -

Tiotropium/Fluticasone/Salmeterol vs Budesonide 0.77 0.41-1.46 - - - - -

Tiotropium/Budesonide/Formoterol vs Budesonide 0.31 0.16-0.60 - - - - -

Formoterol vs Fluticasone 1.05 0.58-1.92 - - - - -

Indacaterol vs Fluticasone 0.97 0.56-1.69 - - - - -

Salmeterol vs Fluticasone 0.99 0.58-1.69 - - - - -

Vilanterol vs Fluticasone 0.94 0.27-3.26 - - - - -

Glycopyrronium vs Fluticasone 0.96 0.54-1.70 - - - - -

Tiotropium vs Fluticasone 0.81 0.48-1.38 - - - - -

Beclomethasone/Formoterol vs Fluticasone 0.92 0.46-1.83 - - - - -

Budesonide/Formoterol vs Fluticasone 0.80 0.44-1.47 - - - - -

Fluticasone/Vilanterol vs Fluticasone 0.71 0.21-2.42 - - - - -

Fluticasone/Salmeterol vs Fluticasone 0.84 0.49-1.45 - - - - -

Tiotropium/Salmeterol vs Fluticasone 0.89 0.44-1.80 - - - - -

Indacaterol/Glycopyrronium vs Fluticasone 0.60 0.34-1.06 - - - - -

Tiotropium/Fluticasone/Salmeterol vs Fluticasone 0.72 0.35-1.46 - - - - -

Tiotropium/Budesonide/Formoterol vs Fluticasone 0.29 0.14-0.60 - - - - -

Indacaterol vs Formoterol 0.93 0.61-1.42 - - - - -

Salmeterol vs Formoterol 0.94 0.63-1.40 - - - - -

Vilanterol vs Formoterol 0.89 0.27-2.95 - - - - -

Glycopyrronium vs Formoterol 0.91 0.58-1.43 - - - - -

Tiotropium vs Formoterol 0.77 0.52-1.15 - - - - -

Beclomethasone/Formoterol vs Formoterol 0.87 0.61-1.26 - 0.96 0.64-1.45 -- 1 465

Budesonide/Formoterol vs Formoterol 0.76 0.64-0.91 - 0.76 0.62-0.93 0.01 4 3080

Fluticasone/Vilanterol vs Formoterol 0.67 0.21-2.19 - - - - -

Fluticasone/Salmeterol vs Formoterol 0.80 0.53-1.21 - - - - -

Tiotropium/Salmeterol vs Formoterol 0.84 0.46-1.56 - - - - -

Indacaterol/Glycopyrronium vs Formoterol 0.57 0.36-0.90 - - - - -

45

Tiotropium/Fluticasone/Salmeterol vs Formoterol 0.69 0.37-1.26 - - - - -

Tiotropium/Budesonide/Formoterol vs Formoterol 0.28 0.15-0.52 - - - - -

Salmeterol vs Indacaterol 1.01 0.84-1.22 - - - - -

Vilanterol vs Indacaterol 0.96 0.31-3.01 - - - - -

Glycopyrronium vs Indacaterol 0.98 0.76-1.27 - - - - -

Tiotropium vs Indacaterol 0.83 0.72-0.96 - 0.83 0.72-0.96 -- 1 3439

Beclomethasone/Formoterol vs Indacaterol 0.94 0.55-1.62 - - - - -

Budesonide/Formoterol vs Indacaterol 0.82 0.54-1.26 - - - - -

Fluticasone/Vilanterol vs Indacaterol 0.73 0.24-2.23 - - - - -

Fluticasone/Salmeterol vs Indacaterol 0.86 0.70-1.06 - - - - -

Tiotropium/Salmeterol vs Indacaterol 0.91 0.56-1.48 - - - - -

Indacaterol/Glycopyrronium vs Indacaterol 0.62 0.48-0.79 - - - - -

Tiotropium/Fluticasone/Salmeterol vs Indacaterol 0.74 0.45-1.20 - - - - -

Tiotropium/Budesonide/Formoterol vs Indacaterol 0.30 0.18-0.50 - - - - -

Vilanterol vs Salmeterol 0.95 0.31-2.94 - - - - -

Glycopyrronium vs Salmeterol 0.97 0.76-1.24 - - - - -

Tiotropium vs Salmeterol 0.82 0.73-0.93 - 0.84 0.76-0.92 -- 1 7376

Beclomethasone/Formoterol vs Salmeterol 0.93 0.55-1.58 - - - - -

Budesonide/Formoterol vs Salmeterol 0.81 0.54-1.22 - - - - -

Fluticasone/Vilanterol vs Salmeterol 0.72 0.24-2.18 - - - - -

Fluticasone/Salmeterol vs Salmeterol 0.85 0.75-0.97 - 0.82 0.70-0.95 0.00 4 2784

Tiotropium/Salmeterol vs Salmeterol 0.90 0.55-1.46 - - - - -

Indacaterol/Glycopyrronium vs Salmeterol 0.61 0.48-0.78 - - - - -

Tiotropium/Fluticasone/Salmeterol vs Salmeterol 0.73 0.45-1.18 - - - - -

Tiotropium/Budesonide/Formoterol vs Salmeterol 0.30 0.18-0.49 - - - - -

Glycopyrronium vs Vilanterol 1.02 0.32-3.23 - - - - -

Tiotropium vs Vilanterol 0.87 0.28-2.69 - - - - -

Beclomethasone/Formoterol vs Vilanterol 0.98 0.28-3.40 - - - - -

Budesonide/Formoterol vs Vilanterol 0.86 0.26-2.84 - - - - -

Fluticasone/Vilanterol vs Vilanterol 0.75 0.62-0.92 - 0.75 0.61-0.94 0.00 2 1624

Fluticasone/Salmeterol vs Vilanterol 0.90 0.29-2.76 - - - - -

46

Tiotropium/Salmeterol vs Vilanterol 0.95 0.28-3.22 - - - - -

Indacaterol/Glycopyrronium vs Vilanterol 0.64 0.20-2.03 - - - - -

Tiotropium/Fluticasone/Salmeterol vs Vilanterol 0.77 0.23-2.61 - - - - -

Tiotropium/Budesonide/Formoterol vs Vilanterol 0.31 0.09-1.07 - - - - -

Tiotropium vs Glycopyrronium 0.85 0.68-1.05 - 0.85 0.68-1.05 -- 1 1477

Beclomethasone/Formoterol vs Glycopyrronium 0.96 0.54-1.69 - - - - -

Budesonide/Formoterol vs Glycopyrronium 0.84 0.53-1.32 - - - - -

Fluticasone/Vilanterol vs Glycopyrronium 0.74 0.24-2.30 - - - - -

Fluticasone/Salmeterol vs Glycopyrronium 0.88 0.68-1.14 - - - - -

Tiotropium/Salmeterol vs Glycopyrronium 0.93 0.55-1.55 - - - - -

Indacaterol/Glycopyrronium vs Glycopyrronium 0.63 0.51-0.78 - 0.63 0.51-0.77 -- 1 1469

Tiotropium/Fluticasone/Salmeterol vs Glycopyrronium 0.75 0.45-1.26 - - - - -

Tiotropium/Budesonide/Formoterol vs Glycopyrronium 0.30 0.18-0.52 - - - - -

Beclomethasone/Formoterol vs Tiotropium 1.13 0.67-1.91 - - - - -

Budesonide/Formoterol vs Tiotropium 0.99 0.66-1.48 - - - - -

Fluticasone/Vilanterol vs Tiotropium 0.87 0.29-2.66 - - - - -

Fluticasone/Salmeterol vs Tiotropium 1.04 0.89-1.21 - 1.14 0.91-1.42 -- 1 1323

Tiotropium/Salmeterol vs Tiotropium 1.09 0.68-1.75 - 1.09 0.68-1.75 -- 1 304

Indacaterol/Glycopyrronium vs Tiotropium 0.74 0.60-0.91 - 0.74 0.60-0.91 -- 1 1466

Tiotropium/Fluticasone/Salmeterol vs Tiotropium 0.89 0.56-1.41 - 0.89 0.56-1.41 -- 1 301

Tiotropium/Budesonide/Formoterol vs Tiotropium 0.36 0.22-0.59 - 0.36 0.22-0.59 -- 1 660

Budesonide/Formoterol vs Beclomethasone/Formoterol 0.87 0.61-1.26 - 0.97 0.64-1.45 -- 1 470

Fluticasone/Vilanterol vs Beclomethasone/Formoterol 0.77 0.23-2.64 - - - - -

Fluticasone/Salmeterol vs Beclomethasone/Formoterol 0.92 0.53-1.57 - - - - -

Tiotropium/Salmeterol vs Beclomethasone/Formoterol 0.97 0.48-1.95 - - - - -

Indacaterol/Glycopyrronium vs

Beclomethasone/Formoterol

0.65 0.37-1.15 - - - - -

Tiotropium/Fluticasone/Salmeterol vs


0.78 0.39-1.58 - - - - -

Tiotropium/Budesonide/Formoterol vs


0.32 0.15-0.65 - - - - -

Fluticasone/Vilanterol vs Budesonide/Formoterol 0.88 0.27-2.88 - - - - -

47

Fluticasone/Salmeterol vs Budesonide/Formoterol 1.05 0.69-1.60 - - - - -

Tiotropium/Salmeterol vs Budesonide/Formoterol 1.11 0.60-2.05 - - - - -

Indacaterol/Glycopyrronium vs Budesonide/Formoterol 0.75 0.48-1.18 - - - - -


Budesonide/Formoterol

0.90 0.49-1.66 - - - - -



0.36 0.19-0.69 - - - - -

Fluticasone/Salmeterol vs Fluticasone/Vilanterol 1.19 0.39-3.59 - 1.19 0.39-3.59 -- 1 528

Tiotropium/Salmeterol vs Fluticasone/Vilanterol 1.25 0.37-4.20 - - - - -

Indacaterol/Glycopyrronium vs Fluticasone/Vilanterol 0.85 0.27-2.64 - - - - -


Fluticasone/Vilanterol

1.02 0.30-3.41 - - - - -



0.41 0.12-1.39 - - - - -

Tiotropium/Salmeterol vs Fluticasone/Salmeterol 1.05 0.64-1.72 - - - - -

Indacaterol/Glycopyrronium vs Fluticasone/Salmeterol 0.71 0.55-0.92 - - - - -


Fluticasone/Salmeterol

0.86 0.52-1.40 - - - - -



0.35 0.21-0.58 - - - - -

Indacaterol/Glycopyrronium vs Tiotropium/Salmeterol 0.68 0.41-1.13 - - - - -


Tiotropium/Salmeterol

0.81 0.51-1.31 - 0.81 0.51-1.30 -- 1 293


Tiotropium/Salmeterol

0.33 0.17-0.65 - - - - -


Indacaterol/Glycopyrronium

1.20 0.72-2.00 - - - - -



0.48 0.28-0.83 - - - - -


Tiotropium/Fluticasone/Salmeterol

0.40 0.21-0.80 - - - - -

Common within-network heterogeneity variance 0.00

Design-by-treatment interaction model for

inconsistency χ² (d.f., P-value, heterogeneity variance)

3.37 (4,0.498,0.00)

Overall Mortality: 88 studies (1 five-arm, 12 four-arm, 14 three-arm, 61 two-arm), 28 treatments, 97526 patients

AZD3199 (Ultra LABA) vs Placebo 0.46 0.02-10.32 0.02-11.85 0.32 0.01-7.95 -- 1 128

Aclidinium vs Placebo 0.74 0.31-1.72 0.30-1.81 0.74 0.32-1.72 0.00 4 2565

48

Beclomethasone/Formoterol vs Placebo 0.76 0.15-3.80 0.14-4.10 - - - -

Budesonide vs Placebo 0.80 0.50-1.29 0.48-1.35 0.87 0.53-1.43 0.00 6 3312

Formoterol/Budesonide vs Placebo 1.06 0.64-1.75 0.62-1.82 0.96 0.53-1.75 <0.0001 4 2479

Formoterol/Budesonide/Tiotropium vs Placebo 2.91 0.12-72.26 0.10-83.32 - - - -

Fluticasone vs Placebo 1.04 0.84-1.28 0.81-1.34 1.04 0.87-1.24 0.00 9 5860

Salmeterol/Fluticasone vs Placebo 0.78 0.63-0.96 0.60-1.01 0.81 0.66-1.00 0.00 6 4852

Salmeterol/Fluticasone/Tiotropium vs Placebo 1.58 0.43-5.81 0.40-6.19 - - - -

Fluticasone/Tiotropium vs Placebo 0.91 0.08-10.48 0.07-11.69 - - - -

Vilanterol/Fluticasone vs Placebo 1.22 0.42-3.54 0.40-3.73 1.05 0.15-7.23 0.00 2 822

Formoterol vs Placebo 1.28 0.82-1.99 0.79-2.07 1.19 0.67-2.09 0.1306 10 5223

Formoterol/Tiotropium vs Placebo 0.66 0.08-5.18 0.08-5.68 0.33 0.01-8.27 -- 1 416

Glycopyrronium vs Placebo 0.75 0.45-1.25 0.43-1.30 0.66 0.22-2.03 0.00 3 2315

Indacaterol vs Placebo 0.82 0.52-1.29 0.50-1.34 0.37 0.12-1.11 0.00 6 3461

Indacaterol/Glycopyrronium vs Placebo 0.85 0.49-1.47 0.47-1.53 1.83 0.30-

11.24

0.00 2 1044

Indacaterol/Tiotropium vs Placebo 1.07 0.23-5.09 0.21-5.48 - - - -

Mometasone vs Placebo 1.39 0.59-3.28 0.56-3.44 1.75 0.64-4.79 0.00 3 1514

Formoterol/Mometasone vs Placebo 0.69 0.19-2.55 0.17-2.72 1.00 0.20-4.98 0.00 2 894

Salmeterol vs Placebo 0.89 0.74-1.08 0.70-1.13 0.85 0.70-1.03 0.00 9 7464

Salmeterol/Tiotropium vs Placebo 1.55 0.42-5.68 0.39-6.05 - - - -

Tiotropium vs Placebo 0.96 0.82-1.13 0.78-1.19 0.94 0.82-1.08 0.00 13 13408

Tiotropium Respimat vs Placebo 0.97 0.74-1.28 0.71-1.33 0.97 0.32-2.93 0.4011 2 4773

Triamcinoloneacetonide vs Placebo 0.78 0.39-1.57 0.37-1.64 0.78 0.39-1.55 -- 1 1116

Umeclidinium vs Placebo 1.13 0.27-4.68 0.26-5.01 4.73 0.24-

91.84

-- 1 698

Vilanterol vs Placebo 1.49 0.57-3.91 0.54-4.11 2.05 0.44-9.69 0.00 3 1521

Vilanterol/Umeclidinium vs Placebo 1.29 0.39-4.25 0.37-4.51 4.78 0.25-

92.96

-- 1 693

Aclidinium vs AZD3199 (Ultra LABA) 1.61 0.06-40.90 0.06-47.20 - - - -

Beclomethasone/Formoterol vs AZD3199 (Ultra LABA) 1.67 0.05-55.31 0.04-64.56 - - - -

Budesonide vs AZD3199 (Ultra LABA) 1.76 0.08-41.12 0.07-47.29 - - - -

Formoterol/Budesonide vs AZD3199 (Ultra LABA) 2.32 0.10-54.07 0.09-62.18 - - - -

49

Formoterol/Budesonide/Tiotropium vs AZD3199 (Ultra

LABA)

6.39 0.07-561.41 0.06-683.41 - - - -

Fluticasone vs AZD3199 (Ultra LABA) 2.28 0.10-51.84 0.09-59.55 - - - -

Salmeterol/Fluticasone vs AZD3199 (Ultra LABA) 1.71 0.08-38.98 0.07-44.78 - - - -

Salmeterol/Fluticasone/Tiotropium vs AZD3199 (Ultra

LABA)

3.46 0.12-101.64 0.10-118.04 - - - -

Fluticasone/Tiotropium vs AZD3199 (Ultra LABA) 1.99 0.04-104.80 0.03-124.79 - - - -

Vilanterol/Fluticasone vs AZD3199 (Ultra LABA) 2.68 0.10-72.36 0.09-83.73 - - - -

Formoterol vs AZD3199 (Ultra LABA) 2.81 0.12-64.47 0.11-74.10 - - - -

Formoterol/Tiotropium vs AZD3199 (Ultra LABA) 1.45 0.03-60.78 0.03-71.67 - - - -

Glycopyrronium vs AZD3199 (Ultra LABA) 1.64 0.07-38.75 0.06-44.59 - - - -

Indacaterol vs AZD3199 (Ultra LABA) 1.79 0.08-41.93 0.07-48.23 - - - -

Indacaterol/Glycopyrronium vs AZD3199 (Ultra LABA) 1.87 0.08-44.30 0.07-50.98 - - - -

Indacaterol/Tiotropium vs AZD3199 (Ultra LABA) 2.35 0.07-76.80 0.06-89.60 - - - -

Mometasone vs AZD3199 (Ultra LABA) 3.04 0.12-76.67 0.10-88.47 - - - -

Formoterol/Mometasone vs AZD3199 (Ultra LABA) 1.51 0.05-44.00 0.04-51.09 - - - -

Salmeterol vs AZD3199 (Ultra LABA) 1.96 0.09-44.52 0.07-51.14 - - - -

Salmeterol/Tiotropium vs AZD3199 (Ultra LABA) 3.39 0.12-99.48 0.10-115.53 - - - -

Tiotropium vs AZD3199 (Ultra LABA) 2.11 0.09-47.93 0.08-55.05 - - - -

Tiotropium Respimat vs AZD3199 (Ultra LABA) 2.13 0.09-48.78 0.08-56.05 - - - -

Triamcinoloneacetonide vs AZD3199 (Ultra LABA) 1.71 0.07-41.83 0.06-48.20 - - - -

Umeclidinium vs AZD3199 (Ultra LABA) 2.48 0.08-76.28 0.07-88.76 - - - -

Vilanterol vs AZD3199 (Ultra LABA) 3.26 0.12-85.33 0.11-98.61 - - - -

Vilanterol/Umeclidinium vs AZD3199 (Ultra LABA) 2.83 0.10-79.65 0.09-92.34 - - - -

Beclomethasone/Formoterol vs Aclidinium 1.04 0.17-6.38 0.15-6.94 - - - -

Budesonide vs Aclidinium 1.09 0.41-2.90 0.39-3.05 - - - -

Formoterol/Budesonide vs Aclidinium 1.44 0.53-3.86 0.51-4.07 - - - -

Formoterol/Budesonide/Tiotropium vs Aclidinium 3.96 0.14-109.67 0.12-127.05 - - - -

Fluticasone vs Aclidinium 1.41 0.59-3.39 0.56-3.55 - - - -

Salmeterol/Fluticasone vs Aclidinium 1.06 0.44-2.55 0.42-2.67 - - - -

Salmeterol/Fluticasone/Tiotropium vs Aclidinium 2.15 0.45-10.16 0.42-10.93 - - - -

50

Fluticasone/Tiotropium vs Aclidinium 1.23 0.09-16.44 0.08-18.46 - - - -

Vilanterol/Fluticasone vs Aclidinium 1.66 0.43-6.48 0.40-6.92 - - - -

Formoterol vs Aclidinium 1.74 0.67-4.54 0.63-4.77 - - - -

Formoterol/Tiotropium vs Aclidinium 0.90 0.10-8.33 0.09-9.21 - - - -

Glycopyrronium vs Aclidinium 1.02 0.38-2.75 0.36-2.89 - - - -

Indacaterol vs Aclidinium 1.11 0.42-2.92 0.40-3.07 - - - -

Indacaterol/Glycopyrronium vs Aclidinium 1.16 0.42-3.18 0.40-3.35 - - - -

Indacaterol/Tiotropium vs Aclidinium 1.46 0.25-8.59 0.23-9.33 - - - -

Mometasone vs Aclidinium 1.88 0.56-6.32 0.53-6.71 - - - -

Formoterol/Mometasone vs Aclidinium 0.93 0.20-4.45 0.18-4.79 - - - -

Salmeterol vs Aclidinium 1.21 0.51-2.90 0.48-3.04 - - - -

Salmeterol/Tiotropium vs Aclidinium 2.10 0.44-9.95 0.41-10.70 - - - -

Tiotropium vs Aclidinium 1.31 0.55-3.11 0.53-3.26 - - - -

Tiotropium Respimat vs Aclidinium 1.32 0.54-3.22 0.52-3.38 - - - -

Triamcinoloneacetonide vs Aclidinium 1.06 0.35-3.19 0.33-3.37 - - - -

Umeclidinium vs Aclidinium 1.54 0.29-8.04 0.27-8.69 - - - -

Vilanterol vs Aclidinium 2.02 0.56-7.32 0.52-7.80 - - - -

Vilanterol/Umeclidinium vs Aclidinium 1.75 0.40-7.58 0.38-8.12 - - - -

Budesonide vs Beclomethasone/Formoterol 1.05 0.21-5.39 0.19-5.82 - - - -

Formoterol/Budesonide vs Beclomethasone/Formoterol 1.39 0.30-6.43 0.28-6.91 1.97 0.36-

10.84

-- 1 470

Formoterol/Budesonide/Tiotropium vs


3.82 0.11-138.30 0.09-162.06 - - - -

Fluticasone vs Beclomethasone/Formoterol 1.36 0.27-6.88 0.25-7.42 - - - -

Salmeterol/Fluticasone vs Beclomethasone/Formoterol 1.02 0.20-5.17 0.19-5.58 - - - -

Salmeterol/Fluticasone/Tiotropium vs


2.07 0.26-16.35 0.24-17.96 - - - -

Fluticasone/Tiotropium vs Beclomethasone/Formoterol 1.19 0.06-22.19 0.06-25.28 - - - -

Vilanterol/Fluticasone vs Beclomethasone/Formoterol 1.60 0.23-11.00 0.21-12.01 - - - -

Formoterol vs Beclomethasone/Formoterol 1.68 0.34-8.20 0.32-8.83 0.20 0.01-4.13 -- 1 465

Formoterol/Tiotropium vs Beclomethasone/Formoterol 0.87 0.06-11.74 0.06-13.19 - - - -

Glycopyrronium vs Beclomethasone/Formoterol 0.98 0.18-5.30 0.17-5.73 - - - -

51

Indacaterol vs Beclomethasone/Formoterol 1.07 0.20-5.69 0.19-6.15 - - - -



1.12 0.20-6.08 0.19-6.58 - - - -

Indacaterol/Tiotropium vs Beclomethasone/Formoterol 1.41 0.15-13.15 0.14-14.55 - - - -

Mometasone vs Beclomethasone/Formoterol 1.82 0.30-10.87 0.28-11.80 - - - -

Formoterol/Mometasone vs Beclomethasone/Formoterol 0.90 0.12-6.89 0.11-7.56 - - - -

Salmeterol vs Beclomethasone/Formoterol 1.17 0.23-5.89 0.22-6.36 - - - -

Salmeterol/Tiotropium vs Beclomethasone/Formoterol 2.03 0.26-16.00 0.23-17.58 - - - -

Tiotropium vs Beclomethasone/Formoterol 1.26 0.25-6.33 0.23-6.83 - - - -

Tiotropium Respimat vs Beclomethasone/Formoterol 1.27 0.25-6.48 0.23-6.99 - - - -

Triamcinoloneacetonide vs Beclomethasone/Formoterol 1.02 0.18-5.90 0.16-6.39 - - - -

Umeclidinium vs Beclomethasone/Formoterol 1.48 0.17-12.64 0.16-13.93 - - - -

Vilanterol vs Beclomethasone/Formoterol 1.95 0.30-12.69 0.27-13.84 - - - -

Vilanterol/Umeclidinium vs Beclomethasone/Formoterol 1.69 0.23-12.48 0.21-13.67 - - - -

Formoterol/Budesonide vs Budesonide 1.32 0.74-2.35 0.71-2.45 1.19 0.57-2.49 0.00 4 1781

Formoterol/Budesonide/Tiotropium vs Budesonide 3.62 0.14-93.06 0.12-107.46 - - - -

Fluticasone vs Budesonide 1.29 0.77-2.17 0.74-2.26 - - - -

Salmeterol/Fluticasone vs Budesonide 0.97 0.58-1.63 0.56-1.70 - - - -

Salmeterol/Fluticasone/Tiotropium vs Budesonide 1.96 0.49-7.85 0.46-8.39 - - - -

Fluticasone/Tiotropium vs Budesonide 1.13 0.09-13.64 0.08-15.25 - - - -

Vilanterol/Fluticasone vs Budesonide 1.52 0.48-4.87 0.45-5.16 - - - -

Formoterol vs Budesonide 1.59 0.92-2.75 0.89-2.86 1.62 0.79-3.34 0.00 3 1470

Formoterol/Tiotropium vs Budesonide 0.82 0.10-6.78 0.09-7.46 - - - -

Glycopyrronium vs Budesonide 0.93 0.46-1.87 0.44-1.95 - - - -

Indacaterol vs Budesonide 1.02 0.53-1.97 0.51-2.05 - - - -

Indacaterol/Glycopyrronium vs Budesonide 1.06 0.51-2.19 0.49-2.28 - - - -

Indacaterol/Tiotropium vs Budesonide 1.34 0.26-6.79 0.24-7.33 - - - -

Mometasone vs Budesonide 1.72 0.66-4.48 0.63-4.71 - - - -

Formoterol/Mometasone vs Budesonide 0.86 0.22-3.35 0.20-3.58 - - - -

Salmeterol vs Budesonide 1.11 0.67-1.85 0.64-1.93 - - - -

Salmeterol/Tiotropium vs Budesonide 1.92 0.48-7.69 0.45-8.21 - - - -

52

Tiotropium vs Budesonide 1.20 0.73-1.98 0.70-2.05 - - - -

Tiotropium Respimat vs Budesonide 1.21 0.70-2.08 0.67-2.17 - - - -

Triamcinoloneacetonide vs Budesonide 0.97 0.42-2.26 0.40-2.37 - - - -

Umeclidinium vs Budesonide 1.41 0.31-6.29 0.29-6.75 - - - -

Vilanterol vs Budesonide 1.85 0.63-5.43 0.60-5.74 - - - -

Vilanterol/Umeclidinium vs Budesonide 1.60 0.44-5.79 0.42-6.16 - - - -

Formoterol/Budesonide/Tiotropium vs

Formoterol/Budesonide

2.75 0.11-71.01 0.09-82.01 - - - -

Fluticasone vs Formoterol/Budesonide 0.98 0.57-1.69 0.55-1.76 - - - -

Salmeterol/Fluticasone vs Formoterol/Budesonide 0.74 0.43-1.27 0.41-1.32 - - - -


Formoterol/Budesonide

1.49 0.37-6.02 0.35-6.44 - - - -

Fluticasone/Tiotropium vs Formoterol/Budesonide 0.86 0.07-10.42 0.06-11.66 - - - -

Vilanterol/Fluticasone vs Formoterol/Budesonide 1.16 0.36-3.74 0.34-3.97 - - - -

Formoterol vs Formoterol/Budesonide 1.21 0.77-1.90 0.74-1.98 1.14 0.69-1.91 0.0587 7 5046

Formoterol/Tiotropium vs Formoterol/Budesonide 0.63 0.08-5.17 0.07-5.69 - - - -

Glycopyrronium vs Formoterol/Budesonide 0.71 0.35-1.45 0.33-1.51 - - - -

Indacaterol vs Formoterol/Budesonide 0.77 0.39-1.52 0.38-1.59 - - - -

Indacaterol/Glycopyrronium vs Formoterol/Budesonide 0.81 0.38-1.69 0.37-1.77 - - - -

Indacaterol/Tiotropium vs Formoterol/Budesonide 1.01 0.20-5.20 0.18-5.62 - - - -

Mometasone vs Formoterol/Budesonide 1.31 0.51-3.35 0.49-3.52 - - - -

Formoterol/Mometasone vs Formoterol/Budesonide 0.65 0.17-2.51 0.16-2.67 - - - -

Salmeterol vs Formoterol/Budesonide 0.84 0.49-1.44 0.47-1.50 - - - -

Salmeterol/Tiotropium vs Formoterol/Budesonide 1.46 0.36-5.90 0.34-6.30 - - - -

Tiotropium vs Formoterol/Budesonide 0.91 0.54-1.54 0.52-1.60 - - - -

Tiotropium Respimat vs Formoterol/Budesonide 0.92 0.52-1.62 0.50-1.69 - - - -

Triamcinoloneacetonide vs Formoterol/Budesonide 0.74 0.31-1.75 0.30-1.83 - - - -

Umeclidinium vs Formoterol/Budesonide 1.07 0.24-4.82 0.22-5.18 - - - -

Vilanterol vs Formoterol/Budesonide 1.41 0.47-4.18 0.45-4.42 - - - -

Vilanterol/Umeclidinium vs Formoterol/Budesonide 1.22 0.33-4.44 0.31-4.73 - - - -

Fluticasone vs Formoterol/Budesonide/Tiotropium 0.36 0.01-8.89 0.01-10.26 - - - -

53

Salmeterol/Fluticasone vs

Formoterol/Budesonide/Tiotropium

0.27 0.01-6.68 0.01-7.71 - - - -



0.54 0.02-17.20 0.01-20.04 - - - -

Fluticasone/Tiotropium vs


0.31 0.01-17.58 0.00-21.00 - - - -

Vilanterol/Fluticasone vs


0.42 0.01-12.34 0.01-14.33 - - - -

Formoterol vs Formoterol/Budesonide/Tiotropium 0.44 0.02-11.23 0.01-12.97 - - - -

Formoterol/Tiotropium vs


0.23 0.01-10.28 0.00-12.16 - - - -

Glycopyrronium vs Formoterol/Budesonide/Tiotropium 0.26 0.01-6.60 0.01-7.63 - - - -

Indacaterol vs Formoterol/Budesonide/Tiotropium 0.28 0.01-7.15 0.01-8.26 - - - -



0.29 0.01-7.54 0.01-8.71 - - - -

Indacaterol/Tiotropium vs


0.37 0.01-12.96 0.01-15.17 - - - -

Mometasone vs Formoterol/Budesonide/Tiotropium 0.48 0.02-13.21 0.01-15.31 - - - -

Formoterol/Mometasone vs


0.24 0.01-7.57 0.01-8.82 - - - -

Salmeterol vs Formoterol/Budesonide/Tiotropium 0.31 0.01-7.62 0.01-8.79 - - - -

Salmeterol/Tiotropium vs


0.53 0.02-16.83 0.01-19.61 - - - -

Tiotropium vs Formoterol/Budesonide/Tiotropium 0.33 0.01-8.16 0.01-9.41 0.33 0.01-8.14 -- 1 660

Tiotropiumropium Respimat vs


0.33 0.01-8.30 0.01-9.57 - - - -

Triamcinoloneacetonide vs


0.27 0.01-7.16 0.01-8.29 - - - -

Umeclidinium vs Formoterol/Budesonide/Tiotropium 0.39 0.01-12.95 0.01-15.12 - - - -

Vilanterol vs Formoterol/Budesonide/Tiotropium 0.51 0.02-14.56 0.02-16.88 - - - -

Vilanterol/Umeclidinium vs


0.44 0.01-13.54 0.01-15.75 - - - -

Salmeterol/Fluticasone vs Fluticasone 0.75 0.60-0.94 0.58-0.98 0.76 0.62-0.93 0.00 3 3752

Salmeterol/Fluticasone/Tiotropium vs Fluticasone 1.52 0.41-5.68 0.38-6.06 - - - -

Fluticasone/Tiotropium vs Fluticasone 0.88 0.08-10.14 0.07-11.32 - - - -

Vilanterol/Fluticasone vs Fluticasone 1.18 0.40-3.44 0.38-3.63 1.36 0.09-

19.56

1.163 2 820

Formoterol vs Fluticasone 1.23 0.76-2.01 0.73-2.09 - - - -

54

Formoterol/Tiotropium vs Fluticasone 0.64 0.08-5.01 0.07-5.51 - - - -

Glycopyrronium vs Fluticasone 0.72 0.42-1.25 0.40-1.30 - - - -

Indacaterol vs Fluticasone 0.79 0.48-1.29 0.46-1.34 - - - -

Indacaterol/Glycopyrronium vs Fluticasone 0.82 0.46-1.47 0.44-1.53 - - - -

Indacaterol/Tiotropium vs Fluticasone 1.03 0.22-4.97 0.20-5.35 - - - -

Mometasone vs Fluticasone 1.33 0.55-3.24 0.52-3.40 - - - -

Formoterol/Mometasone vs Fluticasone 0.66 0.18-2.49 0.17-2.66 - - - -

Salmeterol vs Fluticasone 0.86 0.69-1.07 0.66-1.12 0.81 0.67-0.99 0.00 2 3472

Salmeterol/Tiotropium vs Fluticasone 1.49 0.40-5.56 0.37-5.93 - - - -

Tiotropium vs Fluticasone 0.93 0.71-1.20 0.69-1.25 - - - -

Tiotropium Respimat vs Fluticasone 0.94 0.65-1.34 0.63-1.39 - - - -

Triamcinoloneacetonide vs Fluticasone 0.75 0.36-1.56 0.35-1.63 - - - -

Umeclidinium vs Fluticasone 1.09 0.26-4.55 0.24-4.87 - - - -

Vilanterol vs Fluticasone 1.43 0.54-3.81 0.51-4.01 2.10 0.27-

16.33

0.00 2 818

Vilanterol/Umeclidinium vs Fluticasone 1.24 0.37-4.14 0.35-4.40 - - - -


Salmeterol/Fluticasone

2.02 0.54-7.54 0.51-8.04 - - - -

Fluticasone/Tiotropium vs Salmeterol/Fluticasone 1.16 0.10-13.41 0.09-14.97 1.03 0.06-

17.24

-- 1 65

Vilanterol/Fluticasone vs Salmeterol/Fluticasone 1.57 0.54-4.58 0.51-4.84 2.97 0.12-

73.14

-- 1 528

Formoterol vs Salmeterol/Fluticasone 1.64 1.01-2.67 0.97-2.78 - - - -

Formoterol/Tiotropium vs Salmeterol/Fluticasone 0.85 0.11-6.62 0.10-7.27 0.99 0.06-

15.90

-- 1 605

Glycopyrronium vs Salmeterol/Fluticasone 0.96 0.56-1.66 0.54-1.72 - - - -

Indacaterol vs Salmeterol/Fluticasone 1.05 0.64-1.71 0.62-1.78 - - - -

Indacaterol/Glycopyrronium vs Salmeterol/Fluticasone 1.09 0.61-1.95 0.59-2.03 - - - -

Indacaterol/Tiotropium vs Salmeterol/Fluticasone 1.38 0.29-6.60 0.27-7.10 - - - -

Mometasone vs Salmeterol/Fluticasone 1.77 0.73-4.31 0.70-4.52 - - - -

Formoterol/Mometasone vs Salmeterol/Fluticasone 0.88 0.23-3.32 0.22-3.54 - - - -

Salmeterol vs Salmeterol/Fluticasone 1.14 0.93-1.41 0.88-1.48 1.08 0.89-1.31 0.00 8 8202

Salmeterol/Tiotropium vs Salmeterol/Fluticasone 1.98 0.53-7.38 0.50-7.87 - - - -

55

Tiotropium vs Salmeterol/Fluticasone 1.23 0.96-1.58 0.92-1.65 1.80 1.05-3.07 0.00 2 1515

Tiotropium Respimat vs Salmeterol/Fluticasone 1.25 0.88-1.76 0.85-1.83 - - - -

Triamcinoloneacetonide vs Salmeterol/Fluticasone 1.00 0.48-2.07 0.46-2.17 - - - -

Umeclidinium vs Salmeterol/Fluticasone 1.45 0.35-6.06 0.32-6.48 - - - -

Vilanterol vs Salmeterol/Fluticasone 1.90 0.71-5.08 0.68-5.35 - - - -

Vilanterol/Umeclidinium vs Salmeterol/Fluticasone 1.65 0.49-5.51 0.47-5.85 - - - -

Fluticasone/Tiotropium vs

Salmeterol/Fluticasone/Tiotropium

0.58 0.04-9.14 0.03-10.34 - - - -

Vilanterol/Fluticasone vs


0.78 0.15-4.14 0.13-4.48 - - - -

Formoterol vs Salmeterol/Fluticasone/Tiotropium 0.81 0.21-3.21 0.19-3.43 - - - -

Formoterol/Tiotropium vs


0.42 0.04-4.77 0.03-5.32 - - - -

Glycopyrronium vs Salmeterol/Fluticasone/Tiotropium 0.47 0.12-1.90 0.11-2.03 - - - -

Indacaterol vs Salmeterol/Fluticasone/Tiotropium 0.52 0.13-2.03 0.12-2.17 - - - -



0.54 0.13-2.18 0.12-2.33 - - - -



0.68 0.09-5.11 0.08-5.60 - - - -

Mometasone vs Salmeterol/Fluticasone/Tiotropium 0.88 0.18-4.18 0.17-4.50 - - - -

Formoterol/Mometasone vs


0.44 0.07-2.76 0.06-3.01 - - - -

Salmeterol vs Salmeterol/Fluticasone/Tiotropium 0.57 0.15-2.10 0.14-2.23 - - - -

Salmeterol/Tiotropium vs


0.98 0.31-3.13 0.29-3.32 0.98 0.31-3.11 -- 1 293

Tiotropium vs Salmeterol/Fluticasone/Tiotropium 0.61 0.17-2.22 0.16-2.36 0.61 0.17-2.21 -- 1 301

Tiotropiumropium Respimat vs


0.62 0.17-2.28 0.16-2.43 - - - -

Triamcinoloneacetonide vs


0.49 0.11-2.17 0.11-2.33 - - - -

Umeclidinium vs Salmeterol/Fluticasone/Tiotropium 0.72 0.10-4.89 0.10-5.34 - - - -

Vilanterol vs Salmeterol/Fluticasone/Tiotropium 0.94 0.19-4.74 0.17-5.12 - - - -

Vilanterol/Umeclidinium vs


0.82 0.14-4.74 0.13-5.14 - - - -

Vilanterol/Fluticasone vs Fluticasone/Tiotropium 1.35 0.09-19.30 0.08-21.74 - - - -

Formoterol vs Fluticasone/Tiotropium 1.41 0.12-16.90 0.11-18.89 - - - -

56

Formoterol/Tiotropium vs Fluticasone/Tiotropium 0.73 0.03-17.70 0.03-20.39 - - - -

Glycopyrronium vs Fluticasone/Tiotropium 0.83 0.07-9.98 0.06-11.16 - - - -

Indacaterol vs Fluticasone/Tiotropium 0.90 0.08-10.78 0.07-12.05 - - - -

Indacaterol/Glycopyrronium vs Fluticasone/Tiotropium 0.94 0.08-11.42 0.07-12.78 - - - -

Indacaterol/Tiotropium vs Fluticasone/Tiotropium 1.18 0.07-21.32 0.06-24.25 - - - -

Mometasone vs Fluticasone/Tiotropium 1.52 0.11-20.37 0.10-22.87 - - - -

Formoterol/Mometasone vs Fluticasone/Tiotropium 0.76 0.05-12.12 0.04-13.71 - - - -

Salmeterol vs Fluticasone/Tiotropium 0.98 0.09-11.35 0.08-12.67 - - - -

Salmeterol/Tiotropium vs Fluticasone/Tiotropium 1.70 0.11-27.00 0.09-30.54 - - - -

Tiotropium vs Fluticasone/Tiotropium 1.06 0.09-12.20 0.08-13.62 0.94 0.06-

15.68

-- 1 66

Tiotropiumropium Respimat vs Fluticasone/Tiotropium 1.07 0.09-12.45 0.08-13.91 - - - -

Triamcinoloneacetonide vs Fluticasone/Tiotropium 0.86 0.07-10.92 0.06-12.24 - - - -

Umeclidinium vs Fluticasone/Tiotropium 1.24 0.07-20.96 0.07-23.77 - - - -

Vilanterol vs Fluticasone/Tiotropium 1.64 0.12-22.60 0.11-25.42 - - - -

Vilanterol/Umeclidinium vs Fluticasone/Tiotropium 1.42 0.09-21.46 0.08-24.23 - - - -

Formoterol vs Vilanterol/Fluticasone 1.05 0.33-3.30 0.31-3.49 - - - -

Formoterol/Tiotropium vs Vilanterol/Fluticasone 0.54 0.05-5.45 0.05-6.05 - - - -

Glycopyrronium vs Vilanterol/Fluticasone 0.61 0.19-1.98 0.18-2.10 - - - -

Indacaterol vs Vilanterol/Fluticasone 0.67 0.21-2.11 0.20-2.24 - - - -

Indacaterol/Glycopyrronium vs Vilanterol/Fluticasone 0.70 0.21-2.28 0.20-2.42 - - - -

Indacaterol/Tiotropium vs Vilanterol/Fluticasone 0.88 0.13-5.75 0.12-6.26 - - - -

Mometasone vs Vilanterol/Fluticasone 1.13 0.29-4.44 0.27-4.74 - - - -

Formoterol/Mometasone vs Vilanterol/Fluticasone 0.56 0.10-3.03 0.10-3.28 - - - -

Salmeterol vs Vilanterol/Fluticasone 0.73 0.25-2.13 0.24-2.25 - - - -

Salmeterol/Tiotropium vs Vilanterol/Fluticasone 1.26 0.24-6.74 0.22-7.29 - - - -

Tiotropium vs Vilanterol/Fluticasone 0.79 0.27-2.29 0.26-2.41 - - - -

Tiotropium Respimat vs Vilanterol/Fluticasone 0.79 0.27-2.36 0.25-2.50 - - - -

Triamcinoloneacetonide vs Vilanterol/Fluticasone 0.64 0.18-2.27 0.17-2.42 - - - -

Umeclidinium vs Vilanterol/Fluticasone 0.92 0.22-3.94 0.20-4.22 - - - -

Vilanterol vs Vilanterol/Fluticasone 1.21 0.59-2.49 0.57-2.60 1.30 0.62-2.74 0.00 4 2442

57

Vilanterolnterol/Umeclidinium vs Vilanterol/Fluticasone 1.05 0.30-3.72 0.28-3.96 - - - -

Formoterol/Tiotropium vs Formoterol 0.52 0.06-4.20 0.06-4.62 - - - -

Glycopyrronium vs Formoterol 0.59 0.30-1.15 0.29-1.20 - - - -

Indacaterol vs Formoterol 0.64 0.34-1.20 0.33-1.25 0.33 0.03-3.18 -- 1 871

Indacaterol/Glycopyrronium vs Formoterol 0.67 0.33-1.34 0.32-1.40 - - - -

Indacaterol/Tiotropium vs Formoterol 0.84 0.17-4.23 0.15-4.56 - - - -

Mometasone vs Formoterol 1.08 0.45-2.58 0.43-2.71 0.84 0.28-2.51 0.00 2 915

Formoterol/Mometasone vs Formoterol 0.54 0.15-1.96 0.14-2.08 0.43 0.11-1.70 0.00 2 898

Salmeterol vs Formoterol 0.70 0.43-1.13 0.42-1.17 - - - -

Salmeterol/Tiotropium vs Formoterol 1.21 0.31-4.77 0.29-5.10 - - - -

Tiotropium vs Formoterol 0.75 0.47-1.20 0.45-1.25 - - - -

Tiotropium Respimat vs Formoterol 0.76 0.45-1.28 0.43-1.33 - - - -

Triamcinoloneacetonide vs Formoterol 0.61 0.27-1.39 0.25-1.46 - - - -

Umeclidinium vs Formoterol 0.88 0.20-3.91 0.19-4.19 - - - -

Vilanterol vs Formoterol 1.16 0.40-3.36 0.38-3.55 - - - -

Vilanterol/Umeclidinium vs Formoterol 1.01 0.28-3.59 0.27-3.82 - - - -

Glycopyrronium vs Formoterol/Tiotropium 1.13 0.14-9.40 0.12-10.34 - - - -

Indacaterol vs Formoterol/Tiotropium 1.24 0.15-10.12 0.14-11.14 - - - -

Indacaterol/Glycopyrronium vs Formoterol/Tiotropium 1.29 0.15-10.77 0.14-11.86 - - - -

Indacaterol/Tiotropium vs Formoterol/Tiotropium 1.62 0.12-21.32 0.11-23.92 - - - -

Mometasone vs Formoterol/Tiotropium 2.09 0.23-19.36 0.20-21.41 - - - -

Formoterol/Mometasone vs Formoterol/Tiotropium 1.04 0.09-11.83 0.08-13.19 - - - -

Salmeterol vs Formoterol/Tiotropium 1.35 0.17-10.57 0.16-11.61 - - - -

Salmeterol/Tiotropium vs Formoterol/Tiotropium 2.33 0.21-26.55 0.18-29.61 - - - -

Tiotropium vs Formoterol/Tiotropium 1.45 0.19-11.40 0.17-12.52 - - - -

Tiotropiumropium Respimat vs Formoterol/Tiotropium 1.47 0.18-11.66 0.17-12.82 - - - -

Triamcinoloneacetonide vs Formoterol/Tiotropium 1.18 0.13-10.34 0.12-11.41 - - - -

Umeclidinium vs Formoterol/Tiotropium 1.71 0.14-20.72 0.13-23.18 - - - -

Vilanterol vs Formoterol/Tiotropium 2.24 0.23-21.71 0.21-24.05 - - - -

Vilanterol/Umeclidinium vs Formoterol/Tiotropium 1.95 0.18-20.91 0.16-23.27 - - - -

58

Indacaterol vs Glycopyrronium 1.09 0.57-2.10 0.54-2.19 1.99 0.18-

22.04

-- 1 431

Indacaterol/Glycopyrronium vs Glycopyrronium 1.14 0.65-1.99 0.62-2.08 1.06 0.59-1.89 0.00 2 428

Indacaterol/Tiotropium vs Glycopyrronium 1.43 0.28-7.28 0.26-7.85 - - - -

Mometasone vs Glycopyrronium 1.85 0.68-5.03 0.64-5.30 - - - -

Formoterol/Mometasone vs Glycopyrronium 0.92 0.23-3.74 0.21-4.00 - - - -

Salmeterol vs Glycopyrronium 1.19 0.70-2.03 0.67-2.11 - - - -

Salmeterol/Tiotropium vs Glycopyrronium 2.06 0.52-8.23 0.48-8.80 - - - -

Tiotropium vs Glycopyrronium 1.28 0.78-2.11 0.75-2.19 1.22 0.71-2.10 0.00 3 3385

Tiotropium Respimat vs Glycopyrronium 1.30 0.75-2.23 0.72-2.32 - - - -

Triamcinoloneacetonide vs Glycopyrronium 1.04 0.44-2.47 0.42-2.60 - - - -

Umeclidinium vs Glycopyrronium 1.51 0.34-6.78 0.31-7.28 - - - -

Vilanterol vs Glycopyrronium 1.98 0.67-5.88 0.63-6.22 - - - -

Vilanterol/Umeclidinium vs Glycopyrronium 1.72 0.47-6.24 0.44-6.65 - - - -

Indacaterol/Glycopyrronium vs Indacaterol 1.04 0.53-2.06 0.51-2.14 0.50 0.05-5.54 -- 1 950

Indacaterol/Tiotropium vs Indacaterol 1.31 0.26-6.57 0.24-7.09 - - - -

Mometasone vs Indacaterol 1.69 0.64-4.49 0.61-4.72 - - - -

Formoterol/Mometasone vs Indacaterol 0.84 0.21-3.36 0.20-3.59 - - - -

Salmeterol vs Indacaterol 1.09 0.68-1.76 0.65-1.83 0.48 0.09-2.51 0.00 3 1970

Salmeterol/Tiotropium vs Indacaterol 1.89 0.48-7.42 0.45-7.92 - - - -

Tiotropium vs Indacaterol 1.18 0.75-1.84 0.72-1.91 1.08 0.65-1.78 0.00 3 5988

Tiotropium Respimat vs Indacaterol 1.19 0.72-1.97 0.69-2.04 - - - -

Triamcinoloneacetonide vs Indacaterol 0.95 0.41-2.20 0.39-2.31 - - - -

Umeclidinium vs Indacaterol 1.38 0.31-6.11 0.29-6.56 - - - -

Vilanterol vs Indacaterol 1.82 0.63-5.27 0.59-5.56 - - - -

Vilanterol/Umeclidinium vs Indacaterol 1.58 0.44-5.61 0.42-5.97 - - - -

Indacaterol/Tiotropium vs Indacaterol/Glycopyrronium 1.26 0.25-6.47 0.23-6.98 - - - -

Mometasone vs Indacaterol/Glycopyrronium 1.63 0.59-4.51 0.56-4.76 - - - -

Formoterol/Mometasone vs Indacaterol/Glycopyrronium 0.81 0.20-3.34 0.18-3.57 - - - -

Salmeterol vs Indacaterol/Glycopyrronium 1.05 0.59-1.85 0.57-1.92 - - - -

Salmeterol/Tiotropium vs Indacaterol/Glycopyrronium 1.81 0.45-7.33 0.42-7.84 - - - -

59

Tiotropium vs Indacaterol/Glycopyrronium 1.13 0.66-1.92 0.64-2.00 1.15 0.66-2.00 0.00 2 2420

Tiotropium Respimat vs Indacaterol/Glycopyrronium 1.14 0.64-2.02 0.62-2.10 - - - -

Triamcinoloneacetonide vs Indacaterol/Glycopyrronium 0.92 0.38-2.23 0.36-2.34 - - - -

Umeclidinium vs Indacaterol/Glycopyrronium 1.33 0.29-6.04 0.27-6.49 - - - -

Vilanterol vs Indacaterol/Glycopyrronium 1.74 0.58-5.27 0.55-5.57 - - - -

Vilanterol/Umeclidinium vs Indacaterol/Glycopyrronium 1.51 0.41-5.57 0.39-5.93 - - - -

Mometasone vs Indacaterol/Tiotropium 1.29 0.22-7.64 0.20-8.30 - - - -

Formoterol/Mometasone vs Indacaterol/Tiotropium 0.64 0.08-4.90 0.08-5.37 - - - -

Salmeterol vs Indacaterol/Tiotropium 0.83 0.17-3.97 0.16-4.27 - - - -

Salmeterol/Tiotropium vs Indacaterol/Tiotropium 1.44 0.19-10.81 0.17-11.85 - - - -

Tiotropium vs Indacaterol/Tiotropium 0.90 0.19-4.21 0.18-4.53 0.82 0.13-5.00 0.3954 2 2273

Tiotropiumropium Respimat vs Indacaterol/Tiotropium 0.91 0.19-4.31 0.18-4.64 - - - -

Triamcinoloneacetonide vs Indacaterol/Tiotropium 0.73 0.13-4.00 0.12-4.33 - - - -

Umeclidinium vs Indacaterol/Tiotropium 1.05 0.13-8.61 0.12-9.48 - - - -

Vilanterol vs Indacaterol/Tiotropium 1.38 0.22-8.62 0.20-9.37 - - - -

Vilanterol/Umeclidinium vs Indacaterol/Tiotropium 1.20 0.17-8.47 0.16-9.26 - - - -

Formoterol/Mometasone vs Mometasone 0.50 0.13-1.92 0.12-2.05 0.53 0.13-2.16 0.00 2 909

Salmeterol vs Mometasone 0.64 0.27-1.56 0.25-1.63 - - - -

Salmeterol/Tiotropium vs Mometasone 1.12 0.23-5.32 0.22-5.72 - - - -

Tiotropium vs Mometasone 0.69 0.29-1.67 0.28-1.75 - - - -

Tiotropium Respimat vs Mometasone 0.70 0.28-1.73 0.27-1.82 - - - -

Triamcinoloneacetonide vs Mometasone 0.56 0.19-1.71 0.18-1.81 - - - -

Umeclidinium vs Mometasone 0.82 0.15-4.30 0.14-4.64 - - - -

Vilanterol vs Mometasone 1.07 0.29-3.92 0.28-4.17 - - - -

Vilanterol/Umeclidinium vs Mometasone 0.93 0.21-4.05 0.20-4.34 - - - -

Salmeterol vs Formoterol/Mometasone 1.30 0.35-4.87 0.32-5.19 - - - -

Salmeterol/Tiotropium vs Formoterol/Mometasone 2.25 0.35-14.24 0.33-15.51 - - - -

Tiotropium vs Formoterol/Mometasone 1.40 0.37-5.23 0.35-5.58 - - - -

Tiotropium Respimat vs Formoterol/Mometasone 1.41 0.37-5.38 0.35-5.74 - - - -

Triamcinoloneacetonide vs Formoterol/Mometasone 1.14 0.26-5.01 0.24-5.37 - - - -

60

Umeclidinium vs Formoterol/Mometasone 1.64 0.24-11.34 0.22-12.39 - - - -

Vilanterol vs Formoterol/Mometasone 2.16 0.42-11.00 0.39-11.87 - - - -

Vilanterol/Umeclidinium vs Formoterol/Mometasone 1.87 0.32-11.01 0.29-11.95 - - - -

Salmeterol/Tiotropium vs Salmeterol 1.73 0.47-6.42 0.44-6.84 - - - -

Tiotropium vs Salmeterol 1.08 0.87-1.34 0.83-1.40 0.80 0.58-1.12 <0.0001 3 8451

Tiotropium Respimat vs Salmeterol 1.09 0.79-1.49 0.76-1.56 0.62 0.17-2.25 -- 1 304

Triamcinoloneacetonide vs Salmeterol 0.87 0.42-1.80 0.41-1.88 - - - -

Umeclidinium vs Salmeterol 1.27 0.30-5.28 0.28-5.66 - - - -

Vilanterol vs Salmeterol 1.67 0.63-4.43 0.59-4.66 - - - -

Vilanterol/Umeclidinium vs Salmeterol 1.44 0.43-4.80 0.41-5.10 - - - -

Tiotropium vs Salmeterol/Tiotropium 0.62 0.17-2.27 0.16-2.41 - - - -

Tiotropiumropium Respimat vs Salmeterol/Tiotropium 0.63 0.17-2.33 0.16-2.48 - - - -

Triamcinoloneacetonide vs Salmeterol/Tiotropium 0.51 0.12-2.21 0.11-2.37 - - - -

Umeclidinium vs Salmeterol/Tiotropium 0.73 0.11-4.99 0.10-5.45 - - - -

Vilanterol vs Salmeterol/Tiotropium 0.96 0.19-4.85 0.18-5.23 - - - -

Vilanterol/Umeclidinium vs Salmeterol/Tiotropium 0.83 0.14-4.84 0.13-5.25 - - - -

Tiotropiumropium Respimat vs Tiotropium 1.01 0.82-1.24 0.78-1.30 0.96 0.83-1.10 -- 1 11405

Triamcinoloneacetonide vs Tiotropium 0.81 0.40-1.66 0.38-1.73 - - - -

Umeclidinium vs Tiotropium 1.17 0.28-4.87 0.26-5.21 0.19 0.01-4.02 -- 1 437

Vilanterol vs Tiotropium 1.54 0.58-4.08 0.55-4.30 3.00 0.12-

74.07

-- 1 417

Vilanterol/Umeclidinium vs Tiotropium 1.34 0.41-4.41 0.38-4.68 0.94 0.14-6.45 0.00 2 852

Triamcinoloneacetonide vs Tiotropium Respimat 0.80 0.38-1.70 0.36-1.78 - - - -

Umeclidinium vs Tiotropium Respimat 1.16 0.28-4.90 0.26-5.25 - -

Vilanterol vs Tiotropium Respimat 1.53 0.56-4.15 0.54-4.37 - -

Vilanterol/Umeclidinium vs Tiotropium Respimat 1.33 0.39-4.45 0.37-4.73 - -

Umeclidinium vs Triamcinoloneacetonide 1.45 0.30-7.05 0.28-7.60 - -

Vilanterol vs Triamcinoloneacetonide 1.90 0.58-6.28 0.54-6.66 - -

Vilanterol/Umeclidinium vs Triamcinoloneacetonide 1.65 0.41-6.58 0.39-7.03 - -

Vilanterol vs Umeclidinium 1.32 0.36-4.83 0.34-5.15 0.99 0.20-4.95 -- 1 1270

Vilanterol/Umeclidiniumlidinium vs Umeclidinium 1.14 0.31-4.20 0.29-4.47 1.27 0.30-5.32 0.00 2 839

61

Vilanterolnterol/Umeclidinium vs Vilanterol 0.87 0.29-2.59 0.27-2.74 1.01 0.25-4.06 0.00 2 1255




31.44 (50,0.982,0.00)

Cardiovascular Related Mortality: 37 studies (6 four-arm, 6 three-arm, 25 two-arm), 20 treatments, 55156 patients

AZD3199 (Ultra LABA) vs Placebo 0.41 0.02-9.44 0.00-67.10 0.32 0.01-7.95 -- 1 128

Aclidinium vs Placebo 3.06 0.12-75.35 0.02-556.25 3.06 0.12-

75.35

-- 1 542

Budesonide vs Placebo 1.07 0.27-4.23 0.12-9.95 1.35 0.30-6.08 -- 1 1852

Formoterol/Budesonide vs Placebo 2.38 0.30-18.87 0.08-68.73 5.38 0.26-

112.46

-- 1 581


Salmeterol/Fluticasone vs Placebo 0.78 0.57-1.07 0.47-1.30 0.85 0.60-1.20 0.00 2 3839

Vilanterol/Fluticasone vs Placebo 0.91 0.15-5.73 0.05-18.00 0.33 0.01-8.23 -- 1 822


Glycopyrronium vs Placebo 0.23 0.02-2.83 0.00-13.38 0.16 0.01-3.97 -- 1 817


Indacaterol/Glycopyrronium vs Placebo 0.26 0.01-6.63 0.00-49.40 - - - -

Indacaterol/Tiotropium vs Placebo 2.00 0.23-16.97 0.06-64.48 - - - -



Tiotropium Respimat vs Placebo 1.46 0.93-2.29 0.70-3.03 1.86 0.92-3.76 -- 1 3917

Triamcinolone Acetonide vs Placebo 3.01 0.61-14.98 0.22-40.76 3.01 0.61-

14.98

-- 1 1116

Umeclidinium vs Placebo 1.12 0.09-13.59 0.02-64.54 - - - -

Vilanterol/Umeclidinium vs Placebo 2.19 0.39-12.12 0.14-35.26 2.04 0.08-

50.25

-- 1 693


Aclidinium vs AZD3199 (Ultra LABA) 7.50 0.08-668.55 0.01-

10996.94

- - - -

Budesonide vs AZD3199 (Ultra LABA) 2.63 0.09-78.91 0.01-657.90 - - - -

Formoterol/Budesonide vs AZD3199 (Ultra LABA) 5.84 0.15-222.91 0.02-

2161.81

- - - -

Fluticasone vs AZD3199 (Ultra LABA) 2.04 0.09-48.09 0.01-345.00 - - - -

62

Salmeterol/Fluticasone vs AZD3199 (Ultra LABA) 1.91 0.08-45.05 0.01-323.30 - - - -

Vilanterol/Fluticasone vs AZD3199 (Ultra LABA) 2.24 0.06-85.46 0.01-827.83 - - - -

Formoterol vs AZD3199 (Ultra LABA) 2.01 0.07-57.97 0.01-471.72 - - - -

Glycopyrronium vs AZD3199 (Ultra LABA) 0.58 0.01-31.78 0.00-387.79 - - - -

Indacaterol vs AZD3199 (Ultra LABA) 1.86 0.07-49.85 0.01-387.15 - - - -

Indacaterol/Glycopyrronium vs AZD3199 (Ultra LABA) 0.65 0.01-58.53 0.00-969.44 - - - -

Indacaterol/Tiotropium vs AZD3199 (Ultra LABA) 4.90 0.11-219.81 0.01-

2356.05

- - - -

Salmeterol vs AZD3199 (Ultra LABA) 1.54 0.07-36.44 0.01-261.85 - - - -

Tiotropium vs AZD3199 (Ultra LABA) 3.09 0.13-73.67 0.02-532.92 - - - -

Tiotropium Respimat vs AZD3199 (Ultra LABA) 3.58 0.15-85.61 0.02-620.54 - - - -

Triamcinolone Acetonide vs AZD3199 (Ultra LABA) 7.39 0.22-252.24 0.02-

2280.00

- - - -

Umeclidinium vs AZD3199 (Ultra LABA) 2.74 0.05-152.16 0.00-

1862.07

- - - -

Vilanterol/Umeclidinium vs AZD3199 (Ultra LABA) 5.37 0.15-192.61 0.02-

1796.31

- - - -

Vilanterol vs AZD3199 (Ultra LABA) 3.94 0.12-126.20 0.01-

1097.02

- - - -

Budesonide vs Aclidinium 0.35 0.01-11.46 0.00-100.86 - - - -

Formoterol/Budesonide vs Aclidinium 0.78 0.02-35.35 0.00-382.09 - - - -

Fluticasone vs Aclidinium 0.27 0.01-6.81 0.00-50.76 - - - -

Salmeterol/Fluticasone vs Aclidinium 0.25 0.01-6.38 0.00-47.57 - - - -

Vilanterol/Fluticasone vs Aclidinium 0.30 0.01-12.01 0.00-120.23 - - - -

Formoterol vs Aclidinium 0.27 0.01-10.05 0.00-96.34 - - - -


Indacaterol vs Aclidinium 0.25 0.01-7.13 0.00-57.84 - - - -


Indacaterol/Tiotropium vs Aclidinium 0.65 0.01-30.82 0.00-341.04 - - - -

Salmeterol vs Aclidinium 0.21 0.01-5.16 0.00-38.53 - - - -


Tiotropium Respimat vs Aclidinium 0.48 0.02-12.12 0.00-91.28 - - - -

Triamcinolone Acetonide vs Aclidinium 0.99 0.03-35.50 0.00-331.99 - - - -


63

Vilanterol/Umeclidinium vs Aclidinium 0.72 0.02-27.09 0.00-261.29 - - - -

Vilanterol vs Aclidinium 0.52 0.02-17.78 0.00-160.02 - - - -

Formoterol/Budesonide vs Budesonide 2.22 0.24-20.44 0.06-81.70 4.93 0.24-

103.12

-- 1 556


Salmeterol/Fluticasone vs Budesonide 0.73 0.18-2.97 0.07-7.15 - - - -

Vilanterol/Fluticasone vs Budesonide 0.85 0.09-8.43 0.02-35.21 - - - -

Formoterol vs Budesonide 0.76 0.11-5.55 0.03-19.11 2.92 0.12-

71.87

-- 1 559




Indacaterol/Tiotropium vs Budesonide 1.86 0.15-23.66 0.03-115.54 - - - -



Tiotropium Respimat vs Budesonide 1.36 0.32-5.76 0.13-14.17 - - - -

Triamcinolone Acetonide vs Budesonide 2.81 0.34-23.20 0.09-86.58 - - - -


Vilanterol/Umeclidinium vs Budesonide 2.04 0.23-18.30 0.06-71.94 - - - -


Fluticasone vs Formoterol/Budesonide 0.35 0.04-2.84 0.01-10.50 - - - -

Salmeterol/Fluticasone vs Formoterol/Budesonide 0.33 0.04-2.66 0.01-9.84 - - - -

Vilanterol/Fluticasone vs Formoterol/Budesonide 0.38 0.02-6.12 0.00-34.40 - - - -

Formoterol vs Formoterol/Budesonide 0.34 0.05-2.28 0.02-7.39 0.49 0.04-5.47 -- 1 565

Glycopyrronium vs Formoterol/Budesonide 0.10 0.00-2.52 0.00-18.99 - - - -

Indacaterol vs Formoterol/Budesonide 0.32 0.03-3.05 0.01-12.46 - - - -

Indacaterol/Glycopyrronium vs Formoterol/Budesonide 0.11 0.00-5.12 0.00-55.85 - - - -

Indacaterol/Tiotropium vs Formoterol/Budesonide 0.84 0.04-16.51 0.01-105.77 - - - -

Salmeterol vs Formoterol/Budesonide 0.26 0.03-2.16 0.01-7.98 - - - -

Tiotropium vs Formoterol/Budesonidesonide 0.53 0.06-4.38 0.02-16.39 - - - -

Tiotropium Respimat vs Formoterol/Budesonidesonide 0.61 0.07-5.10 0.02-19.14 - - - -

Triamcinolone Acetonide vs Formoterol/Budesonide 1.27 0.09-17.41 0.02-89.29 - - - -

64

Umeclidinium vs Formoterol/Budesonide 0.47 0.02-12.07 0.00-91.35 - - - -

Vilanterol/Umeclidinium vs Formoterol/Budesonide 0.92 0.06-13.52 0.01-72.29 - - - -

Vilanterol vs Formoterol/Budesonide 0.67 0.05-8.52 0.01-41.42 - - - -

Salmeterol/Fluticasone vs Fluticasone 0.94 0.67-1.32 0.54-1.63 0.98 0.69-1.41 0.00 3 3410

Vilanterol/Fluticasone vs Fluticasone 1.10 0.17-6.94 0.05-21.94 - - - -





Indacaterol/Tiotropium vs Fluticasone 2.40 0.28-20.71 0.07-79.38 - - - -



Tiotropium Respimat vs Fluticasone 1.75 1.04-2.94 0.75-4.07 - - - -

Triamcinolone Acetonide vs Fluticasone 3.62 0.71-18.57 0.25-51.47 - - - -


Vilanterol/Umeclidinium vs Fluticasone 2.63 0.47-14.82 0.16-43.57 - - - -

Vilanterol vs Fluticasone 1.93 0.44-8.44 0.18-21.20 3.03 0.12-

74.80

-- 1 818

Vilanterol/Fluticasone vs Salmeterol/Fluticasone 1.17 0.19-7.38 0.06-23.26 2.97 0.12-

73.14

-- 1 528

Formoterol vs Salmeterol/Fluticasone 1.05 0.19-5.87 0.06-17.17 - - - -

Glycopyrronium vs Salmeterol/Fluticasone 0.30 0.02-3.69 0.01-17.59 - - - -

Indacaterol vs Salmeterol/Fluticasone 0.97 0.35-2.75 0.18-5.25 - - - -

Indacaterol/Glycopyrronium vs Salmeterol/Fluticasone 0.34 0.01-8.38 0.00-61.86 0.34 0.01-8.38 -- 1 522

Indacaterol/Tiotropium vs Salmeterol/Fluticasone 2.56 0.30-21.95 0.08-83.79 - - - -

Salmeterol vs Salmeterol/Fluticasone 0.81 0.56-1.16 0.45-1.45 0.84 0.47-1.48 0.0552 3 4367

Tiotropium vs Salmeterol/Fluticasone 1.61 1.02-2.56 0.76-3.42 2.12 0.95-4.72 -- 1 1448

Tiotropium Respimat vs Salmeterol/Fluticasone 1.87 1.14-3.06 0.84-4.16 - - - -

Triamcinolone Acetonide vs Salmeterol/Fluticasone 3.87 0.75-19.84 0.27-55.04 - - - -

Umeclidinium vs Salmeterol/Fluticasone 1.44 0.12-17.64 0.02-84.37 - - - -

Vilanterol/Umeclidinium vs Salmeterol/Fluticasone 2.81 0.50-15.81 0.17-46.48 - - - -

Vilanterol vs Salmeterol/Fluticasone 2.06 0.47-9.05 0.19-22.77 - - - -

65

Formoterol vs Vilanterol/Fluticasone 0.90 0.07-10.89 0.02-51.67 - - - -

Glycopyrronium vs Vilanterol/Fluticasone 0.26 0.01-5.65 0.00-38.83 - - - -

Indacaterol vs Vilanterol/Fluticasone 0.83 0.10-6.70 0.03-24.63 - - - -

Indacaterol/Glycopyrronium vs Vilanterol/Fluticasone 0.29 0.01-11.67 0.00-117.04 - - - -

Indacaterol/Tiotropium vs Vilanterol/Fluticasone 2.19 0.13-36.32 0.02-209.56 - - - -

Salmeterol vs Vilanterol/Fluticasone 0.69 0.11-4.40 0.03-13.98 - - - -

Tiotropium vs Vilanterol/Fluticasone 1.38 0.21-8.94 0.07-28.69 - - - -

Tiotropium Respimat vs Vilanterol/Fluticasone 1.59 0.24-10.43 0.08-33.63 - - - -

Triamcinolone Acetonide vs Vilanterol/Fluticasone 3.30 0.29-37.79 0.06-172.95 - - - -

Umeclidinium vs Vilanterol/Fluticasone 1.22 0.06-24.97 0.01-163.73 - - - -

Vilanterol/Umeclidinium vs Vilanterol/Fluticasone 2.40 0.22-25.69 0.05-112.87 - - - -

Vilanterol vs Vilanterol/Fluticasone 1.76 0.22-14.00 0.06-51.11 3.03 0.12-

74.80

-- 1 818


Indacaterol vs Formoterol 0.93 0.14-6.09 0.04-19.69 2.99 0.12-

73.51

-- 1 871


Indacaterol/Tiotropium vs Formoterol 2.44 0.16-37.25 0.03-204.03 - - - -



Tiotropium Respimat vs Formoterol 1.78 0.31-10.22 0.10-30.41 - - - -

Triamcinolone Acetonide vs Formoterol 3.68 0.36-37.84 0.08-162.01 - - - -


Vilanterol/Umeclidinium vs Formoterol 2.67 0.24-29.61 0.05-132.83 - - - -


Indacaterol vs Glycopyrronium 3.24 0.22-47.20 0.04-251.10 - - - -

Indacaterol/Glycopyrronium vs Glycopyrronium 1.13 0.02-65.94 0.00-833.90 - - - -

Indacaterol/Tiotropium vs Glycopyrronium 8.51 0.33-222.12 0.04-

1698.51

- - - -

Salmeterol vs Glycopyrronium 2.68 0.22-32.94 0.05-157.50 - - - -

Tiotropium vs Glycopyrronium 5.36 0.44-65.17 0.09-309.53 - - - -

Tiotropium Respimat vs Glycopyrronium 6.21 0.51-76.08 0.11-363.10 - - - -

Triamcinolone Acetonide vs Glycopyrronium 12.84 0.66-248.48 0.10-

1577.10

- - - -

66

Umeclidinium vs Glycopyrronium 4.77 0.14-160.55 0.02-

1439.95

- - - -

Vilanterol/Umeclidinium vs Glycopyrronium 9.33 0.46-189.52 0.07-

1240.19

- - - -

Vilanterol vs Glycopyrronium 6.84 0.38-121.89 0.06-734.82 - - - -

Indacaterol/Glycopyrronium vs Indacaterol 0.35 0.01-10.13 0.00-82.82 - - - -

Indacaterol/Tiotropium vs Indacaterolacaterol 2.63 0.25-27.65 0.06-119.88 - - - -

Salmeterol vs Indacaterol 0.83 0.29-2.33 0.15-4.44 0.25 0.03-2.29 0.00 2 1784

Tiotropium vs Indacaterol 1.66 0.57-4.81 0.29-9.34 2.99 0.12-

73.38

-- 1 1593

Tiotropium Respimat vs Indacaterol 1.92 0.65-5.64 0.33-11.04 - - - -

Triamcinolone Acetonide vs Indacaterol 3.97 0.60-26.27 0.18-85.38 - - - -


Vilanterol/Umeclidinium vs Indacaterol 2.88 0.40-20.80 0.12-71.39 - - - -



Indacaterolacaterol/Glycopyrronium

7.55 0.16-357.46 0.01-

3965.59

- - - -

Salmeterol vs Indacaterol/Glycopyrronium 2.37 0.09-59.75 0.01-446.73 - - - -

Tiotropium vs Indacaterol/Glycopyrronium 4.75 0.19-121.10 0.02-912.78 - - - -

Tiotropium Respimat vs Indacaterol/Glycopyrronium 5.50 0.21-140.91 0.03-

1065.04

- - - -

Triamcinolone Acetonide vs Indacaterol/Glycopyrronium 11.38 0.31-415.80 0.03-

3922.96

- - - -

Umeclidinium vs Indacaterol/Glycopyrronium 4.22 0.07-247.43 0.01-

3133.71

- - - -

Vilanterol/Umeclidinium vs Indacaterol/Glycopyrronium 8.26 0.22-315.30 0.02-

3055.92

- - - -

Vilanterol vs Indacaterol/Glycopyrronium 6.06 0.18-206.94 0.02-

1871.33

- - - -

Salmeterol vs Indacaterol/Tiotropium 0.31 0.04-2.71 0.01-10.38 - - - -

Tiotropium vs Indacaterol/Tiotropium 0.63 0.08-5.12 0.02-18.95 0.63 0.08-5.12 0.00 2 2273

Tiotropium Respimat vs Indacaterol/Tiotropium 0.73 0.09-6.03 0.02-22.53 - - - -

Triamcinolone Acetonide vs Indacaterol/Tiotropium 1.51 0.10-21.89 0.02-116.08 - - - -

Umeclidinium vs Indacaterol/Tiotropium 0.56 0.02-14.60 0.00-111.66 - - - -

Vilanterol/Umeclidinium vs Indacaterol/Tiotropium 1.10 0.07-16.48 0.01-89.41 - - - -

Vilanterol vs Indacaterol/Tiotropium 0.80 0.06-10.50 0.01-52.18 - - - -

67

Tiotropium vs Salmeterol 2.00 1.23-3.26 0.90-4.42 1.32 0.46-3.81 -- 1 7798

Tiotropium Respimat vs Salmeterol 2.32 1.38-3.88 1.00-5.35 - - - -

Triamcinolone Acetonide vs Salmeterol 4.79 0.93-24.71 0.33-68.73 - - - -


Vilanterol/Umeclidinium vs Salmeterol 3.48 0.61-19.73 0.21-58.22 - - - -


Tiotropium Respimat vs Tiotropium 1.16 0.89-1.50 0.76-1.76 1.12 0.85-1.47 -- 1 11405

Triamcinolone Acetonide vs Tiotropium 2.40 0.46-12.61 0.16-35.53 - - - -

Umeclidinium vs Tiotropium 0.89 0.07-10.81 0.02-51.35 - - - -

Vilanterol/Umeclidinium vs Tiotropium 1.74 0.31-9.70 0.11-28.34 2.96 0.12-

73.01

-- 1 852

Vilanterol vs Tiotropium 1.28 0.29-5.64 0.11-14.26 3.00 0.12-

74.07

-- 1 417

Triamcinolone Acetonide vs Tiotropium Respimat 2.07 0.39-10.95 0.14-30.97 - - - -

Umeclidinium vs Tiotropium Respimat 0.77 0.06-9.41 0.01-44.96 - - - -

Vilanterol/Umeclidinium vs Tiotropium Respimat 1.50 0.27-8.48 0.09-24.94 - - - -

Vilanterol vs Tiotropium Respimat 1.10 0.25-4.93 0.10-12.54 - - - -

Umeclidinium vs Triamcinolone Acetonide 0.37 0.02-7.23 0.00-46.05 - - - -

Vilanterol/Umeclidinium vs Triamcinolone Acetonide 0.73 0.07-7.59 0.02-32.81 - - - -

Vilanterol vs Triamcinolone Acetonide 0.53 0.06-4.67 0.02-18.08 - - - -

Vilanterol/Umeclidinium vs Umeclidinium 1.96 0.18-20.93 0.04-91.76 3.04 0.12-

74.93

-- 1 1270

Vilanterol vs Umeclidinium 1.44 0.11-18.58 0.02-91.79 - - - -

Vilanterol vs Vilanterol/Umeclidinium 0.73 0.14-3.79 0.05-10.54 0.62 0.08-5.08 0.00 2 1255




11.79 (27,0.995,0.00)

Pneumonia: 54 studies (1 five-arm, 1 four-arm, 2 three-arm, 23 two-arm), 21 treatments, 61551 patients

Budesonide vs Placebo 0.75 0.44-1.27 0.39-1.45 1.01 0.44-2.28 0.20 3 1378


Mometasone vs Placebo 1.23 0.51-2.96 0.42-3.60 1.75 0.64-4.81 0.00 3 1514



68




Glycopyrronium vs Placebo 0.82 0.55-1.23 0.49-1.38 0.61 0.32-1.17 0.00 3 2315


Umeclidinium vs Placebo 0.74 0.11-4.99 0.07-7.44 - - - -

Beclomethasone/Formoterol vs Placebo 1.13 0.33-3.84 0.26-4.99 - - - -

Budesonide/Formoterol vs Placebo 1.26 0.80-2.00 0.70-2.26 1.45 0.50-4.18 0.55 3 2066

Fluticasone/Vilanterol vs Placebo 2.13 0.98-4.64 0.82-5.54 1.87 0.50-6.97 0.00 2 822

Fluticasone/Salmeterol vs Placebo 1.90 1.53-2.34 1.39-2.59 1.75 1.44-2.13 <0.0001 4 3872

Mometasone/Formoterol vs Placebo 0.88 0.31-2.51 0.24-3.16 1.66 0.39-7.11 0.00 2 894


26.65

2.81 2 1044

Umeclidinium/Vilanterol vs Placebo 0.61 0.12-3.21 0.08-4.55 - - - -

Tiotropium/Fluticasone/Salmeterol vs Placebo 1.56 0.29-8.27 0.21-11.75 - - - -

Tiotropium/Budesonide/Formoterol vs Placebo 0.94 0.19-4.78 0.13-6.73 - - - -


Mometasone vs Budesonide 1.63 0.60-4.43 0.48-5.52 - - - -

Formoterol vs Budesonide 1.21 0.67-2.17 0.58-2.51 1.19 0.51-2.79 0.00 2 1071




Aclidinium vs Budesonide 0.90 0.36-2.23 0.30-2.73 - - - -




Beclomethasone/Formoterol vs Budesonide 1.50 0.42-5.39 0.32-7.09 - - - -

Budesonide/Formoterol vs Budesonide 1.68 0.93-3.03 0.80-3.49 1.51 0.67-3.39 0.00 2 1067

Fluticasone/Vilanterol vs Budesonide 2.83 1.10-7.25 0.90-8.93 - - - -

Fluticasone/Salmeterol vs Budesonide 2.52 1.44-4.43 1.25-5.09 - - - -

Mometasone/Formoterol vs Budesonide 1.17 0.37-3.66 0.29-4.68 - - - -

69


Umeclidinium/Vilanterol vs Budesonide 0.82 0.14-4.64 0.10-6.69 - - - -

Tiotropium/Fluticasone/Salmeterol vs Budesonide 2.07 0.36-11.95 0.25-17.28 - - - -

Tiotropium/Budesonide/Formoterol vs Budesonide 1.25 0.23-6.92 0.16-9.93 - - - -

Mometasone vs Fluticasone 0.74 0.30-1.83 0.24-2.24 - - - -




Vilanterol vs Fluticasone 0.69 0.32-1.47 0.27-1.75 1.18 0.39-3.54 0.00 2 818

Aclidinium vs Fluticasone 0.41 0.19-0.88 0.16-1.06 - - - -




Beclomethasone/Formoterol vs Fluticasone 0.68 0.20-2.36 0.15-3.08 - - - -

Budesonide/Formoterol vs Fluticasone 0.76 0.45-1.27 0.40-1.44 - - - -

Fluticasone/Vilanterol vs Fluticasone 1.28 0.59-2.78 0.49-3.32 1.01 0.32-3.24 0.00 2 820

Fluticasone/Salmeterol vs Fluticasone 1.14 0.91-1.43 0.83-1.57 1.08 0.90-1.29 0.00 3 3441

Mometasone/Formoterol vs Fluticasone 0.53 0.18-1.55 0.14-1.96 - - - -


Umeclidinium/Vilanterol vs Fluticasone 0.37 0.07-1.95 0.05-2.77 - - - -

Tiotropium/Fluticasone/Salmeterol vs Fluticasone 0.94 0.18-5.04 0.12-7.18 - - - -

Tiotropium/Budesonide/Formoterol vs Fluticasone 0.57 0.11-2.91 0.08-4.11 - - - -

Formoterol vs Mometasone 0.74 0.30-1.82 0.25-2.22 1.91 0.20-

18.09

1.55 2 915

Indacaterol vs Mometasone 0.79 0.30-2.12 0.24-2.64 - - - -

Salmeterol vs Mometasone 0.91 0.37-2.25 0.30-2.75 - - - -

Vilanterol vs Mometasone 0.93 0.29-2.99 0.23-3.85 - - - -

Aclidinium vs Mometasone 0.55 0.17-1.75 0.14-2.24 - - - -

Glycopyrronium vs Mometasone 0.67 0.25-1.77 0.20-2.19 - - - -

Tiotropium vs Mometasone 0.77 0.31-1.91 0.26-2.33 - - - -

Umeclidinium vs Mometasone 0.61 0.07-4.94 0.05-7.68 - - - -

70

Beclomethasone/Formoterol vs Mometasone 0.92 0.21-4.00 0.16-5.46 - - - -

Budesonide/Formoterol vs Mometasone 1.03 0.40-2.62 0.33-3.23 - - - -

Fluticasone/Vilanterol vs Mometasone 1.74 0.53-5.63 0.41-7.26 - - - -

Fluticasone/Salmeterol vs Mometasone 1.55 0.63-3.82 0.51-4.68 - - - -

Mometasone/Formoterol vs Mometasone 0.72 0.23-2.21 0.18-2.83 1.02 0.30-3.47 0.00 2 909

Indacaterol/Glycopyrronium vs Mometasone 0.69 0.25-1.89 0.20-2.35 - - - -

Umeclidinium/Vilanterol vs Mometasone 0.50 0.08-3.27 0.05-4.84 - - - -

Tiotropium/Fluticasone/Salmeterol vs Mometasone 1.27 0.19-8.40 0.13-12.48 - - - -

Tiotropium/Budesonide/Formoterol vs Mometasone 0.77 0.12-4.88 0.08-7.20 - - - -

Indacaterol vs Formoterol 1.07 0.57-2.01 0.49-2.34 - - - -



Aclidinium vs Formoterol 0.74 0.31-1.76 0.26-2.14 - - - -




Beclomethasone/Formoterol vs Formoterol 1.24 0.38-4.07 0.29-5.26 5.13 0.59-

44.24

-- 1 474

Budesonide/Formoterol vs Formoterol 1.39 0.95-2.03 0.85-2.26 1.49 0.98-2.26 0.04 6 4646

Fluticasone/Vilanterol vs Formoterol 2.34 0.95-5.73 0.78-7.00 - - - -

Fluticasone/Salmeterol vs Formoterol 2.09 1.29-3.37 1.14-3.83 - - - -

Mometasone/Formoterol vs Formoterol 0.96 0.34-2.71 0.27-3.39 0.66 0.18-2.36 0.11 2 898


Umeclidinium/Vilanterol vs Formoterol 0.68 0.12-3.75 0.08-5.38 - - - -

Tiotropium/Fluticasone/Salmeterol vs Formoterol 1.72 0.30-9.65 0.21-13.90 - - - -

Tiotropium/Budesonide/Formoterol vs Formoterol 1.03 0.19-5.59 0.13-7.98 - - - -

Salmeterol vs Indacaterol 1.15 0.73-1.81 0.64-2.05 - - - -


Aclidinium vs Indacaterol 0.70 0.29-1.65 0.24-2.00 - - - -

Glycopyrronium vs Indacaterol 0.84 0.50-1.44 0.43-1.65 1.01 0.20-5.01 -- 1 949


71


Beclomethasone/Formoterol vs Indacaterol 1.17 0.32-4.29 0.24-5.68 - - - -

Budesonide/Formoterol vs Indacaterol 1.30 0.68-2.48 0.58-2.89 - - - -

Fluticasone/Vilanterol vs Indacaterol 2.19 0.91-5.30 0.74-6.46 - - - -

Fluticasone/Salmeterol vs Indacaterol 1.95 1.20-3.17 1.06-3.60 - - - -

Mometasone/Formoterol vs Indacaterol 0.90 0.29-2.83 0.23-3.62 - - - -


Umeclidinium/Vilanterol vs Indacaterol 0.63 0.12-3.43 0.08-4.90 - - - -

Tiotropium/Fluticasone/Salmeterol vs Indacaterol 1.61 0.29-8.83 0.20-12.65 - - - -

Tiotropium/Budesonide/Formoterol vs Indacaterol 0.97 0.18-5.11 0.13-7.25 - - - -


Aclidinium vs Salmeterol 0.61 0.28-1.31 0.24-1.56 - - - -

Glycopyrronium vs Salmeterol 0.74 0.48-1.13 0.43-1.27 - - - -

Tiotropium vs Salmeterol 0.85 0.68-1.06 0.61-1.17 0.78 0.57-1.08 -- 1 7376


Beclomethasone/Formoterol vs Salmeterol 1.01 0.29-3.51 0.22-4.58 - - - -

Budesonide/Formoterol vs Salmeterol 1.13 0.68-1.88 0.60-2.14 - - - -

Fluticasone/Vilanterol vs Salmeterol 1.91 0.87-4.19 0.73-5.01 - - - -

Fluticasone/Salmeterol vs Salmeterol 1.70 1.38-2.09 1.25-2.31 1.69 1.40-2.04 0.00 8 7613

Mometasone/Formoterol vs Salmeterol 0.79 0.27-2.30 0.21-2.90 - - - -

Indacaterol/Glycopyrronium vs Salmeterol 0.76 0.47-1.25 0.41-1.42 - - - -

Umeclidinium/Vilanterol vs Salmeterol 0.55 0.11-2.89 0.07-4.10 - - - -

Tiotropium/Fluticasone/Salmeterol vs Salmeterol 1.40 0.26-7.45 0.18-10.60 - - - -

Tiotropium/Budesonide/Formoterol vs Salmeterol 0.84 0.17-4.30 0.12-6.08 - - - -

Aclidinium vs Vilanterol 0.59 0.20-1.72 0.16-2.17 - - - -

Glycopyrronium vs Vilanterol 0.72 0.31-1.70 0.25-2.06 - - - -

Tiotropium vs Vilanterol 0.83 0.38-1.81 0.32-2.16 2.03 0.18-

22.56

-- 1 408

Umeclidinium vs Vilanterol 0.65 0.09-4.97 0.06-7.61 - - - -

Beclomethasone/Formoterol vs Vilanterol 0.99 0.23-4.19 0.17-5.70 - - - -

Budesonide/Formoterol vs Vilanterol 1.11 0.45-2.70 0.37-3.29 - - - -

72

Fluticasone/Vilanterol vs Vilanterol 1.87 1.18-2.96 1.04-3.34 1.90 1.20-3.01 0.00 4 2442

Fluticasone/Salmeterol vs Vilanterol 1.66 0.77-3.60 0.64-4.30 - - - -

Mometasone/Formoterol vs Vilanterol 0.77 0.21-2.82 0.16-3.73 - - - -

Indacaterol/Glycopyrronium vs Vilanterol 0.75 0.31-1.82 0.25-2.22 - - - -

Umeclidinium/Vilanterol vs Vilanterol 0.54 0.09-3.19 0.06-4.65 0.33 0.01-8.11 -- 1 412

Tiotropium/Fluticasone/Salmeterol vs Vilanterol 1.37 0.22-8.53 0.15-12.54 - - - -

Tiotropium/Budesonide/Formoterol vs Vilanterol 0.82 0.14-4.95 0.09-7.22 - - - -




Beclomethasone/Formoterol vs Aclidinium 1.67 0.40-6.99 0.30-9.47 - - - -

Budesonide/Formoterol vs Aclidinium 1.87 0.78-4.47 0.64-5.43 - - - -

Fluticasone/Vilanterol vs Aclidinium 3.15 1.07-9.24 0.85-11.68 - - - -

Fluticasone/Salmeterol vs Aclidinium 2.81 1.30-6.07 1.09-7.24 - - - -

Mometasone/Formoterol vs Aclidinium 1.30 0.36-4.70 0.27-6.19 - - - -


Umeclidinium/Vilanterol vs Aclidinium 0.91 0.15-5.57 0.10-8.15 - - - -

Tiotropium/Fluticasone/Salmeterol vs Aclidinium 2.31 0.37-14.33 0.25-21.03 - - - -

Tiotropium/Budesonide/Formoterol vs Aclidinium 1.39 0.23-8.31 0.16-12.11 - - - -

Tiotropium vs Glycopyrronium 1.15 0.80-1.67 0.71-1.87 1.06 0.71-1.58 <0.0001 4 3385

Umeclidinium vs Glycopyrronium 0.90 0.13-6.25 0.09-9.38 - - - -

Beclomethasone/Formoterol vs Glycopyrronium 1.38 0.38-5.02 0.29-6.63 - - - -

Budesonide/Formoterol vs Glycopyrronium 1.54 0.82-2.86 0.71-3.32 - - - -

Fluticasone/Vilanterol vs Glycopyrronium 2.59 1.09-6.18 0.90-7.51 - - - -

Fluticasone/Salmeterol vs Glycopyrronium 2.31 1.47-3.64 1.30-4.11 - - - -

Mometasone/Formoterol vs Glycopyrronium 1.07 0.35-3.31 0.27-4.22 - - - -


Umeclidinium/Vilanterol vs Glycopyrronium 0.75 0.14-4.04 0.10-5.76 - - - -

Tiotropium/Fluticasone/Salmeterol vs Glycopyrronium 1.90 0.35-10.39 0.24-14.87 - - - -

Tiotropium/Budesonide/Formoterol vs Glycopyrronium 1.15 0.22-6.01 0.15-8.52 - - - -

Umeclidinium vs Tiotropium 0.78 0.12-5.23 0.08-7.79 0.97 0.14-6.94 -- 1 437

73

Beclomethasone/Formoterol vs Tiotropium 1.20 0.35-4.14 0.26-5.41 - - - -

Budesonide/Formoterol vs Tiotropium 1.33 0.80-2.22 0.70-2.53 - - - -

Fluticasone/Vilanterol vs Tiotropium 2.25 1.02-4.96 0.85-5.93 - - - -

Fluticasone/Salmeterol vs Tiotropium 2.00 1.52-2.64 1.38-2.92 2.20 1.33-3.62 -- 1 1323

Mometasone/Formoterol vs Tiotropium 0.93 0.32-2.71 0.25-3.42 - - - -

Indacaterol/Glycopyrronium vs Tiotropium 0.90 0.58-1.40 0.51-1.58 0.98 0.62-1.57 0.00 2 2420

Umeclidinium/Vilanterol vs Tiotropium 0.65 0.13-3.36 0.09-4.75 0.61 0.12-3.20 0.00 2 842

Tiotropium/Fluticasone/Salmeterol vs Tiotropium 1.65 0.31-8.65 0.22-12.27 1.65 0.32-8.61 0.00 2 797

Tiotropium/Budesonide/Formoterol vs Tiotropium 0.99 0.20-4.99 0.14-7.02 0.99 0.20-4.96 -- 1 660

Beclomethasone/Formoterol vs Umeclidinium 1.52 0.16-14.71 0.10-23.63 - - - -

Budesonide/Formoterol vs Umeclidinium 1.70 0.24-12.11 0.16-18.28 - - - -

Fluticasone/Vilanterol vs Umeclidinium 2.87 0.37-22.07 0.24-33.84 - - - -

Fluticasone/Salmeterol vs Umeclidinium 2.56 0.38-17.36 0.25-25.96 - - - -

Mometasone/Formoterol vs Umeclidinium 1.18 0.13-10.44 0.08-16.46 - - - -

Indacaterol/Glycopyrronium vs Umeclidinium 1.15 0.16-8.04 0.11-12.10 - - - -

Umeclidinium/Vilanterol vs Umeclidinium 0.83 0.12-5.52 0.08-8.23 1.02 0.14-7.33 -- 1 439

Tiotropium/Fluticasone/Salmeterol vs Umeclidinium 2.10 0.17-26.10 0.10-44.13 - - - -

Tiotropium/Budesonide/Formoterol vs Umeclidinium 1.27 0.10-15.30 0.06-25.72 - - - -

Budesonide/Formoterol vs Beclomethasone/Formoterol 1.11 0.36-3.48 0.28-4.46 1.38 0.43-4.40 -- 1 478

Fluticasone/Vilanterol vs Beclomethasone/Formoterol 1.88 0.44-8.02 0.32-10.91 - - - -

Fluticasone/Salmeterol vs Beclomethasone/Formoterol 1.68 0.49-5.77 0.37-7.53 - - - -

Mometasone/Formoterol vs Beclomethasone/Formoterol 0.78 0.16-3.68 0.12-5.12 - - - -



0.75 0.20-2.80 0.15-3.71 - - - -

Umeclidinium/Vilanterol vs Beclomethasone/Formoterol 0.54 0.07-4.26 0.05-6.55 - - - -



1.38 0.17-10.93 0.11-16.87 - - - -



0.83 0.11-6.37 0.07-9.77 - - - -

Fluticasone/Vilanterol vs Budesonide/Formoterol 1.69 0.68-4.18 0.56-5.11 - - - -

Fluticasone/Salmeterol vs Budesonide/Formoterol 1.50 0.91-2.48 0.80-2.82 - - - -

Mometasone/Formoterol vs Budesonide/Formoterol 0.70 0.24-2.04 0.19-2.58 - - - -

74

Indacaterol/Glycopyrronium vs Budesonide/Formoterol 0.67 0.35-1.31 0.30-1.54 - - - -

Umeclidinium/Vilanterol vs Budesonide/Formoterol 0.49 0.09-2.72 0.06-3.91 - - - -



1.24 0.22-7.00 0.15-10.09 - - - -



0.75 0.14-4.05 0.10-5.79 - - - -

Fluticasone/Salmeterol vs Fluticasone/Vilanterol 0.89 0.41-1.96 0.34-2.34 2.04 0.18-

22.62

-- 1 528

Mometasone/Formoterol vs Fluticasone/Vilanterol 0.41 0.11-1.53 0.08-2.02 - - - -

Indacaterol/Glycopyrronium vs Fluticasone/Vilanterol 0.40 0.16-0.98 0.13-1.20 - - - -

Umeclidinium/Vilanterol vs Fluticasone/Vilanterol 0.29 0.05-1.73 0.03-2.52 - - - -



0.73 0.12-4.60 0.08-6.76 - - - -



0.44 0.07-2.67 0.05-3.89 - - - -

Mometasone/Formoterol vs Fluticasone/Salmeterol 0.46 0.16-1.35 0.13-1.70 - - - -

Indacaterol/Glycopyrronium vs Fluticasone/Salmeterol 0.45 0.27-0.75 0.24-0.85 0.11 0.01-2.09 -- 1 522

Umeclidinium/Vilanterol vs Fluticasone/Salmeterol 0.32 0.06-1.71 0.04-2.43 - - - -



0.82 0.15-4.41 0.11-6.29 - - - -



0.50 0.10-2.55 0.07-3.60 - - - -

Indacaterol/Glycopyrronium vs Mometasone/Formoterol 0.97 0.31-3.08 0.24-3.95 - - - -

Umeclidinium/Vilanterol vs Mometasone/Formoterol 0.70 0.10-4.98 0.07-7.51 - - - -


Mometasone/Formoterol

1.78 0.25-12.79 0.16-19.35 - - - -


Mometasone/Formoterol

1.07 0.15-7.44 0.10-11.18 - - - -

Umeclidinium/Vilanterol vs Indacaterol/Glycopyrronium 0.72 0.13-3.97 0.09-5.68 - - - -



1.84 0.33-10.21 0.23-14.66 - - - -



1.11 0.21-5.90 0.15-8.41 - - - -


Umeclidinium/Vilanterol

2.54 0.25-26.17 0.15-42.60 - - - -


Umeclidinium/Vilanterol

1.53 0.15-15.30 0.09-24.76 - - - -


Tiotropium/Fluticasone/Salmeterol

0.60 0.06-6.09 0.04-9.87 - - - -

75




34.33 (31,0.311,0.00)

Arrhythmia: 26 studies (1 five-arm, 1 four-arm, 2 three-arm, 22 two-arm), 12 treatments, 27407 patients

Budesonide vs Placebo 1.97 0.35-11.19 0.17-23.08 1.09 0.15-7.80 -- 1 575





Glycopyrronium vs Placebo 1.52 0.63-3.62 0.44-5.21 2.92 0.35-

24.37

0.00 2 1522


Budesonide/Formoterol vs Placebo 2.75 0.87-8.64 0.54-13.93 2.93 0.27-

32.10

1.50 2 1556

Fluticasone/Vilanterol vs Placebo 8.88 0.33-240.14 0.08-948.41 - - - -

Fluticasone/Salmeterolvs Placebo 0.80 0.17-3.86 0.09-7.43 - - - -


51.45

-- 1 706

Formoterol vs Budesonide 0.77 0.13-4.37 0.06-9.03 0.48 0.04-5.35 -- 1 559



Aclidinium vs Budesonide 0.57 0.08-4.12 0.03-9.37 - - - -



Budesonide/Formoterol vs Budesonide 1.40 0.24-8.11 0.12-16.87 0.98 0.14-7.00 -- 1 556

Fluticasone/Vilanterol vs Budesonide 4.52 0.11-187.86 0.02-887.62 - - - -

Fluticasone/Salmeterolvs Budesonide 0.41 0.04-4.26 0.01-11.29 - - - -


Indacaterol vs Formoterol 0.96 0.29-3.15 0.18-5.16 - - - -


Aclidinium vs Formoterol 0.75 0.22-2.60 0.13-4.36 - - - -



76

Budesonide/Formoterol vs Formoterol 1.83 0.67-4.98 0.44-7.57 2.12 0.69-6.54 0.00 3 2364

Fluticasone/Vilanterol vs Formoterol 5.91 0.20-176.66 0.05-727.72 - - - -

Fluticasone/Salmeterolvs Formoterol 0.53 0.09-3.15 0.04-6.58 - - - -


Salmeterol vs Indacaterol 0.69 0.20-2.42 0.12-4.09 - - - -

Aclidinium vs Indacaterol 0.78 0.22-2.77 0.13-4.69 - - - -

Glycopyrronium vs Indacaterol 1.05 0.38-2.89 0.25-4.40 0.67 0.11-4.02 -- 1 949


Budesonide/Formoterol vs Indacaterol 1.91 0.46-7.97 0.25-14.46 - - - -

Fluticasone/Vilanterol vs Indacaterol 6.16 0.21-182.74 0.05-750.24 - - - -

Fluticasone/Salmeterolvs Indacaterol 0.56 0.10-3.23 0.05-6.71 - - - -


Aclidinium vs Salmeterol 1.13 0.30-4.25 0.17-7.37 - - - -

Glycopyrronium vs Salmeterol 1.52 0.43-5.34 0.26-9.01 - - - -

Tiotropium vs Salmeterol 1.18 0.41-3.36 0.27-5.21 - - - -

Budesonide/Formoterol vs Salmeterol 2.77 0.63-12.16 0.34-22.52 - - - -

Fluticasone/Vilanterol vs Salmeterol 8.94 0.36-220.89 0.10-840.28 - - - -

Fluticasone/Salmeterolvs Salmeterol 0.81 0.21-3.19 0.12-5.64 1.01 0.15-6.83 1.07 3 1875

Indacaterol/Glycopyrronium vs Salmeterol 1.64 0.48-5.66 0.28-9.47 - - - -



Budesonide/Formoterol vs Aclidinium 2.44 0.56-10.70 0.30-19.80 - - - -

Fluticasone/Vilanterol vs Aclidinium 7.89 0.26-242.89 0.06-

1012.35

- - - -

Fluticasone/Salmeterolvs Aclidinium 0.71 0.12-4.44 0.05-9.49 - - - -


Tiotropium vs Glycopyrronium 0.77 0.36-1.68 0.26-2.33 0.75 0.31-1.80 0.00 2 2430

Budesonide/Formoterol vs Glycopyrronium 1.81 0.43-7.65 0.24-13.94 - - - -

Fluticasone/Vilanterol vs Glycopyrronium 5.86 0.20-171.85 0.05-701.95 - - - -

Fluticasone/Salmeterolvs Glycopyrronium 0.53 0.09-3.00 0.05-6.18 - - - -


77

Budesonide/Formoterol vs Tiotropium 2.35 0.67-8.19 0.40-13.79 - - - -

Fluticasone/Vilanterol vs Tiotropium 7.58 0.27-209.82 0.07-836.67 - - - -

Fluticasone/Salmeterolvs Tiotropium 0.69 0.14-3.46 0.07-6.79 - - - -

Indacaterol/Glycopyrronium vs Tiotropium 1.39 0.64-3.01 0.47-4.16 1.46 0.62-3.45 0.00 2 2420

Fluticasone/Vilanterol vs Budesonide/Formoterol 3.23 0.10-105.98 0.02-453.67 - - - -

Fluticasone/Salmeterolvs Budesonide/Formoterol 0.29 0.04-2.04 0.02-4.59 - - - -

Indacaterol/Glycopyrronium vs Budesonide/Formoterol 0.59 0.14-2.50 0.08-4.55 - - - -

Fluticasone/Salmeterolvs Fluticasone/Vilanterol 0.09 0.00-1.65 0.00-5.51 0.09 0.00-1.65 -- 1 528

Indacaterol/Glycopyrronium vs Fluticasone/Vilanterol 0.18 0.01-5.27 0.00-21.36 - - - -

Indacaterol/Glycopyrronium vs Fluticasone/Salmeterol 2.03 0.37-11.01 0.18-22.28 3.08 0.12-

75.99

-- 1 522




3.06 (11,0.9899,0.36)

Abbreviations and symbols: OR, Odds Ratio, NMA, Network Meta-analysis, MA, Meta-analysis, CI, Confidence Interval; PrI, Predictive Interval; LABA, long acting

beta agonists, χ², Chi Square Test, d.f., degrees of freedom

78

Appendix 11. Sensitivity Network Meta-analysis results (only statistically significant results

are presented)

Network Meta-analysis Results Pairwise Meta-anlaysis Results

Treatment Comparison Odds

Ratio CI

Odds

Ratio CI # studies # patients

Exacerbations: 25 studies (2 four-arm, 6 three-arm, 17 two-arm), 20 treatments, 33211 patients

Fluticasone vs Placebo 0.28 0.13-0.62 0.21 0.09-0.48 2.00 541.00

Vilanterol vs Fluticasone 3.88 1.68-8.93 4.86 1.62-14.64 1.00 407.00

Fluticasone/Vilanterol vs Fluticasone 2.86 1.23-6.64 3.40 1.09-10.62 1.00 408.00

Fluticasone/Vilanterol vs Vilanterol 0.74 0.59-0.92 0.75 0.62-0.91 3.00 2031.00


Glycopyrronium 0.62 0.47-0.82 0.63 0.51-0.77 1.00 1469.00

Indacaterol/Glycopyrronium vs Tiotropium 0.73 0.57-0.94 0.74 0.60-0.91 1.00 1466.00

Indacterol/Tiotropium vs Placebo 0.67 0.46-0.98

Indacaterol/Glycopyrronium vs Placebo 0.60 0.43-0.84

Indacaterol vs Fluticasone 3.30 1.44-7.55

Salmeterol vs Fluticasone 3.40 1.49-7.72

Glycopyrronium vs Fluticasone 3.44 1.47-8.07

Tiotropium vs Fluticasone 2.93 1.30-6.57

Umeclidinium vs Fluticasone 4.71 1.71-12.96

Fluticasone/Salmeterol vs Fluticasone 3.14 1.37-7.20 1.19 0.31-4.59 1.00 179.00

Tiotropium/Salmeterol vs Fluticasone 3.20 1.23-8.29

Indacterol/Tiotropium vs Fluticasone 2.41 1.02-5.73

Umeclidinium/Vilanterol vs Fluticasone 4.37 1.73-11.05


Fluticasone 2.60 1.00-6.73

Indacaterol/Glycopyrronium vs Indacaterol 0.65 0.47-0.90

Indacaterol/Glycopyrronium vs Salmeterol 0.63 0.46-0.86

Indacaterol/Glycopyrronium vs Vilanterol 0.55 0.33-0.92


Umeclidinium 0.46 0.23-0.90


Fluticasone/Salmeterol 0.68 0.50-0.93 0.67 0.44-1.03 1.00 522.00

Umeclidinium/Vilanterol vs

Indacterol/Tiotropium 1.81 1.00-3.27

Common within-network heterogeneity

variance

0.01

Design-by-treatment interaction model

for inconsistency χ² (d.f., P-value,

heterogeneity variance)

13.51(12,0.333,0.00)

Mortality Overall: 23 studies (3 four-arm, 5 three-arm, 15 two-arm), 21 treatments, 33624 patients

Salmeterol/Fluticasone vs Placebo 0.50 0.29-0.88

Salmeterol vs Salmeterol/Fluticasone 2.25 1.20-4.20

Tiotropium vs Salmeterol/Fluticasone 1.84 1.07-3.15 1.84 1.07 1 1323

Vilanterol vs Salmeterol/Fluticasone 3.56 1.03-12.38

Common within-network heterogeneity 0.00

79

variance




9.51 (12, 0.659,0.00)

Pneumonia: 19 studies (2 four-arm, 4 three-arm, 13 two-arm), 18 treatments, 28763 patients

Budesonide/Formoterol vs Placebo 8.39 1.16-60.69

Fluticasone/Salmeterol vs Placebo 2.45 1.48-4.07

Salmeterol vs Budesonide 2.15 1.00-4.61

Beclomethasone/Formoterol vs Budesonide 11.02

1.05-

116.02

Budesonide/Formoterol vs Budesonide 13.42

1.66-

108.72

Fluticasone/Salmeterol vs Budesonide 3.92 1.68-9.15

Budesonide/Formoterol vs Mometasone 25.06

1.24-

506.42

Budesonide/Formoterol vs Formoterol 2.72 1.38-5.37 2.72 1.38-5.37 2.00 1290.00

Fluticasone/Salmeterol vs Indacaterol 2.08 1.10-3.93

Fluticasone/Salmeterol vs Salmeterol 1.82 1.02-3.26

Fluticasone/Vilanterol vs Vilanterol 2.06 1.27-3.34 2.10 1.28-3.44 3.00 2031.00

Fluticasone/Salmeterol vs Glycopyrronium 2.24 1.14-4.41

Budesonide/Formoterol vs Tiotropium 7.97 1.10-57.95

Fluticasone/Salmeterol vs Tiotropium 2.33 1.43-3.78 2.20 1.33-3.62 1.00 1323.00

Mometasone/Formoterol vs

Budesonide/Formoterol 0.12 0.02-0.88


Budesonide/Formoterol 0.12 0.02-0.91


Fluticasone/Salmeterol 0.41 0.21-0.80 0.11 0.01-2.09 1.00 522.00

Common within-network heterogeneity

variance

0.00




4.88 (7, 0.675, 0.00)

Abbreviations: CI, Confidence Interval; d.f., degrees of freedom

80

Appendix 12. SUCRA Values

The SUCRA allows identifying which treatment is the most effective overall and can be interpreted as 1 =

treatment is certain to be the best and 0 = treatment is certain to be the worst.

Panel A: SUCRA curves for the 17 treatments included in the exacerbations network meta-analysis;

Panel B: SUCRA curves for the 28 treatments included in the mortality overall network meta-analysis;

Panel C: SUCRA curves for the 20 treatments included in the cardiovascular-related mortality network

meta-analysis; Panel D: SUCRA curves for the 21 treatments included in the pneumonia network meta-

analysis; Panel E: SUCRA curves for the 12 treatments included in the arrythmia network meta-analysis.

A

B

81

C

D

82

E

Abbreviations: BECL, beclomethasone; BUDE, budesonide; FLUT, fluticasone; MOME, mometasone; TRIAM, triamcinolone

acetonide; AZD3199, AZD3199 (ultra LABA); FORM, formoterol; INDAC, indacaterol ; SALM, salmeterol; VILA, vilanterol;

ACLI, aclidinium bromide; GLYC, glycopyrronium bromide; DAROT, darotropium bromide; TIOT, tiotropium; UMEC,

umeclidinium; FORM/BECLO, formoterol/beclomethasone; FORM/BUDE, formoterol/budesonide; VILA/FLUT,

vilanterol/fluticasone; SALM/FLUT, salmeterol/fluticasone/; FORM/MOME, formoterol/mometasone; TIOT/BUDE,

tiotropium/budesonide; TIOT/FLUT, tiotropium/fluticasone; TIOT/FORM, tiotropium/formoterol; TIOT/SALM,

tiotropium/salmeterol; IND/TIOT, indacaterol/tiotropium; INDA/GLYC, indacaterol/glycopyrronium; VILA/UMEC,

vilanterol/umeclidinium; GSK961081, GSK961081; FORM/IPRATR, formoterol + ipratropium bromide; TIOT/FLUT/SALM,

tiotropium/ fluticasone /salmeterol; TIOT/BUDE/FORM, tiotropium/budesonide/formoterol; BUDE/FORM/IPRATR,

budesonide/formoterol/ipratropium bromide; TIOT+Resp, Tiotropium Respimat (Soft Mist Inhaler).

83

Appendix 13. Forest Plots Forest Plots show all treatments are compared to placebo. The black horizontal lines represent the 95% confidence

intervals (CI) of the summary treatment effects and red horizontal lines the 95% predictive intervals (PrI). The

results are presented on the odds ratio scale.

Panel A: Cardiovascular-related mortality network meta-analysis forest plot versus placebo; Panel B: Pneumonia

network meta-analysis forest plot versus placebo; Panel C: Arrhythmia network meta-analysis forest plot versus

placebo.

A

B

84

C

Abbreviations: CI, confidence interval; PrI, predictive interval; NMA, network meta-analysis; REML, restrictive

maximum likelihood.

Treatment Abbreviations: BECL, beclomethasone; BUDE, budesonide; FLUT, fluticasone; MOME, mometasone;

TRIAM, triamcinolone acetonide; AZD3199, AZD3199 (ultra LABA); FORM, formoterol; INDAC, indacaterol ;

SALM, salmeterol; VILA, vilanterol; ACLI, aclidinium bromide; GLYC, glycopyrronium bromide; DAROT,

darotropium bromide; TIOT, tiotropium; UMEC, umeclidinium; FORM/BECLO, formoterol/beclomethasone;

FORM/BUDE, formoterol/budesonide; VILA/FLUT, vilanterol/fluticasone; SALM/FLUT, salmeterol/fluticasone/;

FORM/MOME, formoterol/mometasone; TIOT/BUDE, tiotropium/budesonide; TIOT/FLUT,

tiotropium/fluticasone; TIOT/FORM, tiotropium/formoterol; TIOT/SALM, tiotropium/salmeterol; IND/TIOT,

indacaterol/tiotropium; INDA/GLYC, indacaterol/glycopyrronium; VILA/UMEC, vilanterol/umeclidinium;

GSK961081, GSK961081; FORM/IPRATR, formoterol + ipratropium bromide; TIOT/FLUT/SALM, tiotropium/

fluticasone /salmeterol; TIOT/BUDE/FORM, tiotropium/budesonide/formoterol; BUDE/FORM/IPRATR,

budesonide/formoterol/ipratropium bromide; TIOT+Resp, Tiotropium Respimat (Soft Mist Inhaler).

85

Appendix 14. Included studies in our review versus previous Cochrane reviews

Study

Kew KM, Seniukovich A, 2014

[43 studies]

Kew KM, Dias S, Cates CJ, 2014

[71 studies]

Included Published Studies (n = 208)

Aalbers, 2002 NO NO

Aaron, 2007 NO NO

Abrahams, 2013 NO YES

Agusti, 2014 YES NO

Ambrosino, 2008 NO NO

Anzueto , 2009 YES YES

Auffarth, 1991 NO NO

Barnes, 2006 NO NO

Bateman, 2010 NO YES

Bateman, 2013 NO YES

Bateman, 2012 NO NO

Bateman , 2008 NO NO

Bedard, 2012 NO NO

Beier, 2013 NO NO

Beier, 2007 NO NO

Bogdan, 2011 NO NO

Bolukbas, 2011 NO NO

Bourbeau, 2007 YES NO

Bourbeau, 1998 YES YES

Boyd, 1997 NO NO

Briggs, 2005 NO NO

Buhl, 2011 NO NO

Burge, 2000 YES YES

Caillaud, 2007 NO NO

Calverley, 2010 YES YES

Calverley, 2003[34] YES YES

Calverley, 2007 YES YES

Calverley, 2003[53] NO NO

Calverley, 2003[119] YES YES

Calverley, 2008 NO YES

Campbell, 2007 NO NO

Casaburi, 2005 NO NO

Cazzola, 2007 NO NO

Cazzola, 2000 NO NO

Celli, 2003[146] NO NO

Celli, 2003[104] NO NO

Chan, 2007 NO YES

Chanez, 2010 NO NO

Chapman, 2011 NO NO

86

Chapman, 2002 NO NO

Choudhury , 2007 YES NO

Cooper , 2013 NO YES

Cote, 2009 NO NO

Covelli, 2005 NO NO

Criner , 2008 NO NO

D’Urzo, 2011 NO YES

Dahl, 2013 NO NO

Dahl, 2010 NO YES

Dahl, 2001 NO NO

Dahl, 2013[131] NO NO

Dal Negro, 2003 YES YES

Decramer, 2013 NO NO

Decramer, 2014a/b NO NO

Decramer, 2014b - -

Doherty, 2012 NO YES

Donohue, 2002 NO NO

Donohue, 2013 NO NO

Dransfield, 2011 NO NO

Dransfield, 2013a/b YES NO

Dransfield, 2013b - -

Dusser , 2006 NO YES

Engel, 1989 NO NO

Feldman, 2012 NO NO

Feldman, 2010 NO NO

Ferguson , 2008 YES YES

Freeman, 2007 NO NO

Fukuchi, 2013 YES NO

Gelb, 2013 NO YES

Gupta, 2002 NO NO

Hagedorn , 2012 NO NO

Hanania, 2013 NO NO

Hanania, 2012 NO NO

Hanania , 2003 YES YES

Hasani, 2004 NO NO

Hattotuwa, 2002 YES NO

Hoshino, 2013 NO NO

Hoshino , 2011 NO NO

Johansson , 2008 NO NO

Jones, 2011a/b NO YES

Jones, 2011b - -

Jones, 1997 NO NO

Jones, 2012 NO YES

87

Jung, 2012 NO NO

Kardos, 2007 YES YES

Kaushik, 1999 NO NO

Kerwin, 2013 YES NO

Kerwin, 2012[68] NO NO

Kerwin, 2012[78] NO YES

Kerwin, 2011a/b NO NO

Kerwin, 2011b - -

Kinoshita, 2011 NO NO

Korn, 2011 NO NO

Kornmann, 2011 NO YES

Koser, 2010 NO NO

Kuna, 2013 NO NO

Lapperre , 2009 YES YES

Littner, 2000 NO NO

Llewellyn-Jones, 1996 NO NO

Lomas, 2012 NO NO

Lotvall, 2012 NO NO

Magnussen, 2008 NO NO

Mahler, 1999 NO NO

Mahler, 2012a/b NO NO

Mahler, 2012b - -

Mahler , 2002 YES YES

Maltais , 2011 NO NO

Maltais , 2005 NO NO

Mansori, 2010 NO NO

Martinez, 2013 YES NO

Mathioudakis, 2013 NO NO

McNicholas, 2004 NO NO

Mirici, 2001 YES NO

Moita , 2008 NO NO

Mroz, 2013 NO NO

Nicolini , 2012 NO NO

Niewoehner, 2005 NO YES

O'Donnell, 2006 NO NO

O'Donnell, 2004 NO NO

Ozol, 2005 YES YES

Paggiaro, 1998 YES YES

Pasqua, 2010 NO NO

Pauwels, 1999 YES YES

Perng, 2009 NO NO

Powrie , 2007 NO YES

Pukhta, 2010 NO NO

88

Rabe , 2008 NO NO

Reid, 2008 NO NO

Renkema, 1996 YES YES

Rennard, 2001 NO NO

Rennard , 2009 YES YES

Rossi, 2002 NO YES

Rubin, 2008 NO NO

Rutgers, 1998 NO NO

Rutten-van Molken, 1999 NO NO

Santus, 2012 NO NO

Schermer, 2007 NO NO

Scherr, 2012 NO NO

Sechaud, 2012 NO NO

Senderovitz, 1999 YES YES

Shaker , 2009 YES YES

Sharafkhaneh, 2012 YES YES

Sin , 2008 NO NO

Sposato , 2008 NO NO

Sridevi, 2012 NO NO

Stahl, 2001 NO NO

Stockley , 2005 NO NO

Struijs , 1997 NO NO

Sugiura, 2002 NO NO

Suzuki , 2010 NO NO

Szafranski , 2003 YES YES

Tashkin, 2008[2] NO YES

Tashkin , 2012 NO YES

Tashkin , 2008[72] YES YES

Tashkin , 2009 NO NO

Lung Health Study Group, 2000 NO NO

Tonnel, 2008 NO YES

Troosters, 2014 NO NO

Tzani , 2011 NO NO

Ulubay , 2005 NO NO

Um , 2007 NO NO

Van de Maele , 2010 NO NO

van Den Boom, 2001 NO NO

van den Broek , 2008 NO NO

van der Valk, 2002 NO NO

van Noord , 2000 NO NO

Verhoeven , 2002 YES YES

Verkindre, 2006 NO NO

Vestbo, 1999 YES YES

89

Vogelmeier, 2013 NO NO

Vogelmeier, 2011 NO YES

Vogelmeier , 2008 NO YES

Vogelmeier , 2010 NO NO

Wadbo, 2002 NO NO

Watkins, 2013 NO NO

Wedzicha, 2013 NO YES

Wedzicha, 2008 NO YES

Weir, 1999 NO NO

Welte, 2008 NO NO

Welte , 2009 NO NO

Wesseling, 1991 NO NO

Wielders, 2013 NO NO

Wise, 2013 NO NO

Woolhouse , 2001 NO NO

Wouters, 2005 NO NO

Yao, 2014 NO NO

Yildiz, 2004 YES NO

Zheng , 2007 NO YES

Zhong, 2012 NO YES

Included unpublished studies (n= 20)

GlaxoSmithKline, 2005(SMS40298) NO NO

GlaxoSmithKline, 2005(SMS40315) NO NO

GlaxoSmithKline, 2005(SCO40034) NO NO

GlaxoSmithKline, 2006(SCO100540) NO YES

GlaxoSmithKline, 2005(SCO100470) YES YES

GlaxoSmithKline, 2005 (SCO30002) YES YES

da Fonseca Reis, 2010 NO NO

Cheng, 2012 NO NO

Sricharoenchai, 2008 NO NO

Ohar, 2013 NO YES

Dawber, 2005 NO NO

Maltais, 2010 NO NO

To, 2011 NO YES

GlaxoSmithKline, 2005 (SLMF4010) NO YES

Kelleher, 2011 NO NO

Calverley, 2003[186] NO YES

GlaxoSmithKline, 2008 YES NO

GlaxoSmithKline, 2008 (SCO40041) YES YES

Novartis, 2006 NO NO

Sekiya, 2012 NO NO

90

Appendix 15. Characteristics of new studies published since our search date

Year Citation Trial Name/NCT Interventions Outcomes*

2014

Celli B, Crater G, Kilbride S, Mehta R, Tabberer M, Kalberg C et

al. Once-daily umeclidinium/vilanterol 125/25 mcg in COPD: a

randomized, controlled study. Chest. 2014; 145(5):981-991.

NCT01313637

umeclidinium/vilanterol vs.

umeclidinium vs. vilanterol vs.

placebo

Mortality, Pneumonia, CVM

2014

Chapman KR, Beeh K-M, Beier J, Bateman ED, D’Urzo A,

Nutbrown R et al. A blinded evaluation of the efficacy and safety

of glycopyrronium, a once-daily long-acting muscarinic

antagonist, versus tiotropium, in patients with COPD: the GLOW5

study. BMC pulmonary medicine. 2014; 14(1):4.

GLOW5 glycopyrronium+placebo vs.

tiotropium (HandiHaler)+placebo

Mod/severe exacerbation,

Serious arrhythmia

2014

Donohue JF, Niewoehner D, Brooks J, O’Dell D, Church A.

Safety and tolerability of once-daily umeclidinium/vilanterol

125/25 mcg and umeclidinium 125 mcg in patients with chronic

obstructive pulmonary disease: results from a 52-week,

randomized, double-blind, placebo-controlled study. Respiratory

research. 2014; 15(1):78.

NCT01316887 umeclidinium/vilanterol vs.

umeclidinium vs. placebo

Mod/severe exacerbation, Mortality,

Pneumonia, Serious arrhythmia, CVM

2014

Dransfield MT, Feldman G, Korenblat P, LaForce CF, Locantore

N, Pistolesi M et al. Efficacy and safety of once-daily fluticasone

furoate/vilanterol (100/25 mcg) versus twice-daily fluticasone

propionate/salmeterol (250/50 mcg) in COPD patients. Respiratory

medicine. 2014; 108(8):1171-1179.

(NCT01323634,

NCT01323621,

NCT01706328)

fluticasone/vilanterol vs.

fluticasone/salmeterol Pneumonia, Serious arrhythmia

2014

D’Urzo AD, Rennard SI, Kerwin EM, Mergel V, Leselbaum A,

Caracta C. Efficacy and safety of fixed-dose combinations of

aclidinium bromide/formoterol fumarate: the 24-week,

randomized, placebo-controlled AUGMENT COPD study. Respir

Res. 2014; 15(1):123.

AUGMENT COPD

(NCT01437397)

aclidinium/formoterol (400/12

μg) vs. aclidinium vs. formoterol

vs. placebo

Mortality, Pneumonia,

Serious arrhythmia, CVM

2014

Ferguson GT, Feldman GJ, Hofbauer P, Hamilton A, Allen L,

Korducki L et al. Efficacy and safety of olodaterol once daily

delivered via Respimat® in patients with GOLD 2–4 COPD:

results from two replicate 48-week studies. International journal of

chronic obstructive pulmonary disease. 2014; 9:629.

Olodaterol Phase III

clinical program in COPD; NCT00782210,

NCT00782509

olodaterol (5 μg Respimat) vs.

placebo


CVM (for NCT00782210 only)

2014

Koch A, Pizzichini E, Hamilton A, Hart L, Korducki L, De Salvo

MC et al. Lung function efficacy and symptomatic benefit of

olodaterol once daily delivered via Respimat® versus placebo and

formoterol twice daily in patients with GOLD 2–4 COPD: results

from two replicate 48-week studies. International journal of

chronic obstructive pulmonary disease. 2014; 9:697..

Olodaterol Phase III

clinical program in COPD; NCT00793624,

NCT00796653

olodaterol (5 μg Respimat) vs.

formoterol vs. placebo Mortality, Pneumonia

2014

Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A.

Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and

tiotropium 18 mcg in chronic obstructive pulmonary disease:

NCT01777334 umeclidinium/vilanterol vs.

tiotropium



91

results of a 24-week, randomized, controlled trial. Respiratory

medicine. 2014; 108(12):1752-1760.

2014

Pepin J-L, Cockcroft JR, Midwinter D, Sharma S, Rubin DB,

Andreas S. Long-acting bronchodilators and arterial stiffness in

patients with COPD: a comparison of fluticasone furoate/vilanterol

with tiotropium. CHEST Journal. 2014; 146(6):1521-1530.

NCT01395888 fluticasone/vilanterol vs.

tiotropium (HandiHaler) Mortality, Pneumonia

2014

Rossi A, van der Molen T, del Olmo R, Papi A, Wehbe L, Quinn

M et al. INSTEAD: a randomised switch trial of indacaterol versus

salmeterol/fluticasone in moderate COPD. European Respiratory

Journal. 2014; 44(6):1548-1556.

INSTEAD; NCT01555138 indacaterol vs.

salmeterol/fluticasone


Pneumonia, Serious arrhythmia

2014

Singh D, Jones PW, Bateman ED, Korn S, Serra C, Molins E et al.

Efficacy and safety of aclidinium bromide/formoterol fumarate

fixed-dose combinations compared with individual components

and placebo in patients with COPD (ACLIFORM-COPD): a

multicentre, randomised study. BMC pulmonary medicine. 2014;

14(1):178.

ACLIFORM-COPD; NCT01462942

aclidinium/formoterol (400/12

μg) vs. aclidinium vs. formoterol

vs. placebo


Pneumonia, Serious arrhythmia, CVM

2014

Singh D, Nicolini G, Bindi E, Corradi M, Guastalla D,

Kampschulte J et al. Extrafine Beclomethasone/formoterol

compared to Fluticasone/salmeterol Combination Therapy in

COPD. BMC pulmonary medicine. 2014; 14(1):43.

FUTURE;

NCT01245569

extrafine

beclomethasone/formoterol vs.

fluticasone/salmeterol



2014

Trivedi R, Richard N, Mehta R, Church A. Umeclidinium in

patients with COPD: a randomised, placebo-controlled study.

European Respiratory Journal. 2014; 43(1):72-81.

NCT01387230 umeclidinium (125 μg) vs.

placebo Serious arrhythmia

2014

Wedzicha J, Singh D, Vestbo J, Paggiaro P, Jones P, Bonnet-

Gonod F et al. Extrafine beclomethasone/formoterol in severe

COPD patients with history of exacerbations. Respiratory

medicine. 2014; 108(8):1153-1162.

FORWARD

extrafine

beclomethasone/formoterol vs.

formoterol


Serious arrhythmia

2014

ZuWallack R, Allen L, Hernandez G, Ting N, Abrahams R.

Efficacy and safety of combining olodaterol Respimat® and

tiotropium HandiHaler® in patients with COPD: results of two

randomized, double-blind, active-controlled studies. International

journal of chronic obstructive pulmonary disease. 2014; 9:1133.

ANHELTO 1 and

ANHELTO 2 ; NCT01694771,

NCT01696058

tiotropium (HandiHaler)+

olodaterol (Respimat) vs.

tiotropium (HandiHaler)+

placebo (Respimat)

Mortality

2013

Rennard SI, Scanlon PD, Ferguson GT, Rekeda L, Maurer BT, Gil

EG et al. ACCORD COPD II: a randomized clinical trial to

evaluate the 12-week efficacy and safety of twice-daily aclidinium

bromide in chronic obstructive pulmonary disease patients.

Clinical drug investigation. 2013; 33(12):893-904.

ACCORD COPD II; NCT01045161

placebo vs. aclidinium (400 μg) Mortality, Serious arrhythmia

Notes: *Outcomes from our NMA that were assessed as outcomes in the trial

Abbreviations: CVM, Cardiovascular related mortality; Mod/severe, Moderate/severe

92

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appendices...6 appendix 4. patient ratings of relevant outcomes top 3 - most important efficacy...

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