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.
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.
22 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
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.
23 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
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.
25 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (B2-agonist* or B2-adrenergic* or adrenergic B2-receptor* or B2-receptor
agonist* or B2-adrenoceptor agonist*)).tw.
26 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
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.
28 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and bronchodilator*).tw.
29 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
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.
75 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
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.
120 ((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.
121 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
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.
122 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
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.
124 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (B2-agonist* or B2-adrenergic* or adrenergic B2-receptor* or B2-receptor
agonist* or B2-adrenoceptor agonist*)).tw.
125 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
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.
127 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and bronchodilator*).tw.
12
128 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
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.
182 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
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]
31 countries multi-center 52 48 2 3917
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
multi-center 5 4 3 163
Beier, 2013[70] Czech Republic, Germany,
Hungary, Poland
multi-center 6 6 3 414
Bogdan, 2011[77] Japan, Romania, Russia,
Ukraine
multi-center 12 12 3 613
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
multi-center 12 12 2 653
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
multi-center 12 12 2 1598
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]
25 countries multi-center 54 52 4 1465
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
multi-center 26 24 2 408
Chapman,
2011[115] CR: [249-
251]
USA, Argentina, Canada,
Germany, India, Italy,
Spain, Sweden, Turkey
multi-center 52 52 3 414
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
multi-center 52 52 4 1732
Dahl, 2013[82] Denmark multi-center 4 4 2 193
Dahl, 2013[131] Europe (not specified),
Canada, India, Korea, South
Africa
multi-center 52 52 2 338
Dal Negro,
2003[137]
Italy single center 52 52 3 18
Decramer,
2013[122]
Argentina, Australia,
Austria, Belgium, Brazil,
Canada, China, Columbia,
multi-center 52 52 2 3439
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
Argentina, Australia,
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)
multi-center 52 26 5 1196
Donohue, 2002[3]
CR:[257, 258]
12 countries multi-center 24 24 3 623
Donohue, 2013[81] USA, Bulgaria, Canada,
Chile, Czech Republic,
Greece, Japan, Mexico,
Poland, Russia, South
Africa, Spain, Thailand
multi-center 24 24 4 1532
Dransfield, 2011[47] USA multi-center 16 16 2 249
Dransfield,
2013[180]a
15 countries multi-center 52 52 4 1622
Dransfield,
2013[180]b
15 countries multi-center 52 52 4 1633
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
multi-center 12 12 2 416
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
multi-center 12 12 2 1293
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
multi-center 16 16 3 283
Jones, 2011[176]a
NR - 16 European countries multi-center 52 52 2 843
Jones, 2011[176]b NR - 7 mostly North
American countries
multi-center 52 52 2 804
Jones, 2012[85] 9 European countries (not
specified), South Africa
multi-center 24 24 3 819
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
USA multi-center 12 12 2 323
Kerwin, 2011[177]b
USA multi-center 12 12 2 318
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
multi-center 52 52 3 1066
Kerwin, 2013[10] Chile, Estonia, Germany,
Japan, Korea, Philippines,
Poland, Russian Federation,
USA
multi-center 24 24 5 1030
Kinoshita, 2012[75]
CR: [253]
Hong Kong, India, Japan,
Korea, Singapore, Taiwan
multi-center 12 12 3 347
Korn, 2011[108] USA, Czech, Germany,
Hungary, India, Slovakia,
Spain, Turkey
multi-center 12 12 2 1123
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
multi-center 4 4 5 329
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,
multi-center 12 12 2 197
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
multi-center 12 12 2 472
Mahler, 1999[91] USA multi-center 12 12 2 278
Mahler, 2002[56] Lebanon multi-center 24 24 4 645
Mahler, 2012[175]a
Argentina, Australia,
Colombia, Denmark,
Germany, Greece,
Guatemala, Mexico, Peru,
Philippines, South Africa,
Spain, Turkey, USA
multi-center 12 12 2 1131
Mahler, 2012[175]b Argentina, Canada,
Colombia, Czech Republic,
Hungary, India,
Netherlands, Philippines,
Slovakia, Spain, USA
multi-center 12 12 2 1142
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
multi-center 24 24 6 1224
Mathioudakis,
2013[100]
Greece single center 208 208 5 564
McNicholas,
2004[113]
UK, Ireland, The
Netherlands
multi-center 4 4 3 95
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]
USA multi-center 26 24 2 1829
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
multi-center 24 24 2 281
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
multi-center 156 144 2 1277
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
multi-center 6 6 2 605
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)
multi-center 56 52 4 1964
Rossi, 2002[38] Austria, Belgium, Czech
Republic, France, Germany,
Greece, Hungary, Italy,
Slovakia, South Africa,
Spain, USA
multi-center 52 52 3 854
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]
The Netherlands multi-center 12 12 2 40
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
multi-center 54 52 3 1219
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
multi-center 52 52 2 634
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
multi-center 52 52 4 812
Tashkin, 2008 [2]
CR: [217-224, 227-
37 countries multi-center 208 208 2 5992
23
232]
Tashkin, 2008[72] USA, Czech Republic, The
Netherlands, Poland, South
Africa
multi-center 28 26 6 1704
Tashkin, 2009[95] USA multi-center 12 12 2 255
Tashkin, 2012[69] South America, Asia,
Africa, Europe, North
America (not specified)
multi-center 52 26 5 1055
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
multi-center 24 24 2 457
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]
The Netherlands single center 24 24 2 244
van Noord,
2000[116]
The Netherlands multi-center 14 12 2 97
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]
8 countries multi-center 24 24 4 847
Vogelmeier,
2010[135]
Germany, France, the
Netherland, Spain, Turkey,
USA
multi-center 4 4 3 281
Vogelmeier,
2011[169] CR: [213]
25 countries multi-center 52 52 2 7376
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,
multi-center 104 104 2 1323
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]
The Netherlands single center 6 6 2 35
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]
Adult & elderly (≥18) 24.23 COPD NR moderate to very severe† NR
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]
Adult & elderly (≥18) 43.5 COPD NR moderate to very severe† NR
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
Adult & elderly (≥18) 4.87 COPD NR moderate to very severe† NR
Nicolini, 2012 Adult & elderly (≥18) 32 COPD stages 2, 3, 4 stable NR
Niewoehner,
2005[126] CR:[211,
212]
Adult & elderly (≥18) 1.48 COPD NR moderate to very severe† NR
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
NR moderate to very severe† NR
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
NR moderate to very severe† NR
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,
2006 (SCO100540)* Adult & elderly (≥18) 10.79 COPD NR moderate to very severe†
NR
GlaxoSmithKline,
2007 (SCO104925)* Adult & elderly (≥18) 23.6 bronchitis and COPD NR moderate to severe†
NR
GlaxoSmithKline,
2008 (SCO40041)* Adult & elderly (≥18) 38.71 COPD NR moderate to very severe†
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
GlaxoSmithKline, 2005
(SMS40315)
Unclear Unclear Low Low Low Unclear Unclear
GlaxoSmithKline,
2005(SCO40034)
Unclear Unclear Low Low Low Unclear Unclear
GlaxoSmithKline, 2005
(SCO100470)
Unclear Unclear Low Low Low Low High
GlaxoSmithKline, 2005
(SCO30002)
Unclear Unclear Low Low Low Low High
GlaxoSmithKline, 2005
(SLMF4010)
Unclear Unclear Low Low Low Unclear High
GlaxoSmithKline, 2006
(SCO100540)
Unclear Unclear Low Low Low Unclear Unclear
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
Unclear Unclear Low Low Low Unclear Unclear
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
Beclomethasone/Formoterol
0.78 0.39-1.58 - - - - -
Tiotropium/Budesonide/Formoterol vs
Beclomethasone/Formoterol
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 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Budesonide/Formoterol
0.90 0.49-1.66 - - - - -
Tiotropium/Budesonide/Formoterol vs
Budesonide/Formoterol
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 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Fluticasone/Vilanterol
1.02 0.30-3.41 - - - - -
Tiotropium/Budesonide/Formoterol vs
Fluticasone/Vilanterol
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 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Fluticasone/Salmeterol
0.86 0.52-1.40 - - - - -
Tiotropium/Budesonide/Formoterol vs
Fluticasone/Salmeterol
0.35 0.21-0.58 - - - - -
Indacaterol/Glycopyrronium vs Tiotropium/Salmeterol 0.68 0.41-1.13 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Tiotropium/Salmeterol
0.81 0.51-1.31 - 0.81 0.51-1.30 -- 1 293
Tiotropium/Budesonide/Formoterol vs
Tiotropium/Salmeterol
0.33 0.17-0.65 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Indacaterol/Glycopyrronium
1.20 0.72-2.00 - - - - -
Tiotropium/Budesonide/Formoterol vs
Indacaterol/Glycopyrronium
0.48 0.28-0.83 - - - - -
Tiotropium/Budesonide/Formoterol vs
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
Beclomethasone/Formoterol
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
Beclomethasone/Formoterol
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 - - - -
Indacaterol/Glycopyrronium vs
Beclomethasone/Formoterol
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 - - - -
Salmeterol/Fluticasone/Tiotropium vs
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 - - - -
Salmeterol/Fluticasone/Tiotropium vs
Formoterol/Budesonide/Tiotropium
0.54 0.02-17.20 0.01-20.04 - - - -
Fluticasone/Tiotropium vs
Formoterol/Budesonide/Tiotropium
0.31 0.01-17.58 0.00-21.00 - - - -
Vilanterol/Fluticasone vs
Formoterol/Budesonide/Tiotropium
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
Formoterol/Budesonide/Tiotropium
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 - - - -
Indacaterol/Glycopyrronium vs
Formoterol/Budesonide/Tiotropium
0.29 0.01-7.54 0.01-8.71 - - - -
Indacaterol/Tiotropium vs
Formoterol/Budesonide/Tiotropium
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
Formoterol/Budesonide/Tiotropium
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
Formoterol/Budesonide/Tiotropium
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
Formoterol/Budesonide/Tiotropium
0.33 0.01-8.30 0.01-9.57 - - - -
Triamcinoloneacetonide vs
Formoterol/Budesonide/Tiotropium
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
Formoterol/Budesonide/Tiotropium
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/Tiotropium vs
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
Salmeterol/Fluticasone/Tiotropium
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
Salmeterol/Fluticasone/Tiotropium
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 - - - -
Indacaterol/Glycopyrronium vs
Salmeterol/Fluticasone/Tiotropium
0.54 0.13-2.18 0.12-2.33 - - - -
Indacaterol/Tiotropium vs
Salmeterol/Fluticasone/Tiotropium
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
Salmeterol/Fluticasone/Tiotropium
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
Salmeterol/Fluticasone/Tiotropium
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
Salmeterol/Fluticasone/Tiotropium
0.62 0.17-2.28 0.16-2.43 - - - -
Triamcinoloneacetonide vs
Salmeterol/Fluticasone/Tiotropium
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
Salmeterol/Fluticasone/Tiotropium
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
Common within-network heterogeneity variance 0.00
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity variance)
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
Fluticasone vs Placebo 0.83 0.61-1.14 0.50-1.38 0.85 0.61-1.17 0.00 4 4962
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
Formoterol vs Placebo 0.82 0.15-4.45 0.05-12.77 0.69 0.11-4.39 0.00 3 1580
Glycopyrronium vs Placebo 0.23 0.02-2.83 0.00-13.38 0.16 0.01-3.97 -- 1 817
Indacaterol vs Placebo 0.76 0.28-2.06 0.15-3.84 0.48 0.13-1.83 0.00 5 2753
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 - - - -
Salmeterol vs Placebo 0.63 0.45-0.88 0.36-1.09 0.60 0.42-0.87 0.00 4 5171
Tiotropium vs Placebo 1.26 0.82-1.93 0.63-2.52 0.88 0.37-2.10 0.00 5 4241
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
Vilanterol vs Placebo 1.60 0.37-6.92 0.15-17.22 1.01 0.10-9.75 0.00 2 1521
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 - - - -
Glycopyrronium vs Aclidinium 0.08 0.00-4.44 0.00-55.88 - - - -
Indacaterol vs Aclidinium 0.25 0.01-7.13 0.00-57.84 - - - -
Indacaterol/Glycopyrronium vs Aclidinium 0.09 0.00-8.14 0.00-138.53 - - - -
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 vs Aclidinium 0.41 0.02-10.43 0.00-78.40 - - - -
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 - - - -
Umeclidinium vs Aclidinium 0.37 0.01-21.28 0.00-268.33 - - - -
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
Fluticasone vs Budesonide 0.78 0.19-3.17 0.08-7.62 - - - -
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
Glycopyrronium vs Budesonide 0.22 0.01-3.76 0.00-22.14 - - - -
Indacaterol vs Budesonide 0.71 0.13-3.81 0.05-10.90 - - - -
Indacaterol/Glycopyrronium vs Budesonide 0.25 0.01-8.18 0.00-72.62 - - - -
Indacaterol/Tiotropium vs Budesonide 1.86 0.15-23.66 0.03-115.54 - - - -
Salmeterol vs Budesonide 0.59 0.14-2.41 0.06-5.82 - - - -
Tiotropium vs Budesonide 1.17 0.28-4.93 0.11-12.09 - - - -
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 - - - -
Umeclidinium vs Budesonide 1.04 0.06-18.02 0.01-106.63 - - - -
Vilanterol/Umeclidinium vs Budesonide 2.04 0.23-18.30 0.06-71.94 - - - -
Vilanterol vs Budesonide 1.50 0.20-11.11 0.06-38.80 - - - -
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 - - - -
Formoterol vs Fluticasone 0.99 0.18-5.50 0.06-16.06 - - - -
Glycopyrronium vs Fluticasone 0.28 0.02-3.46 0.00-16.53 - - - -
Indacaterol vs Fluticasone 0.91 0.32-2.58 0.17-4.92 - - - -
Indacaterol/Glycopyrronium vs Fluticasone 0.32 0.01-7.99 0.00-59.66 - - - -
Indacaterol/Tiotropium vs Fluticasone 2.40 0.28-20.71 0.07-79.38 - - - -
Salmeterol vs Fluticasone 0.76 0.52-1.09 0.42-1.37 0.73 0.49-1.08 0.00 2 3135
Tiotropium vs Fluticasone 1.51 0.92-2.48 0.68-3.38 - - - -
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 - - - -
Umeclidinium vs Fluticasone 1.34 0.11-16.54 0.02-79.17 - - - -
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
Glycopyrronium vs Formoterol 0.29 0.01-5.81 0.00-37.98 - - - -
Indacaterol vs Formoterol 0.93 0.14-6.09 0.04-19.69 2.99 0.12-
73.51
-- 1 871
Indacaterol/Glycopyrronium vs Formoterol 0.32 0.01-12.27 0.00-118.66 - - - -
Indacaterol/Tiotropium vs Formoterol 2.44 0.16-37.25 0.03-204.03 - - - -
Salmeterol vs Formoterol 0.77 0.14-4.30 0.05-12.59 - - - -
Tiotropium vs Formoterol 1.53 0.27-8.77 0.09-26.00 - - - -
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 - - - -
Umeclidinium vs Formoterol 1.36 0.07-27.85 0.01-182.79 - - - -
Vilanterol/Umeclidinium vs Formoterol 2.67 0.24-29.61 0.05-132.83 - - - -
Vilanterol vs Formoterol 1.96 0.21-18.30 0.05-73.79 - - - -
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 - - - -
Umeclidinium vs Indacaterol 1.47 0.10-21.61 0.02-115.37 - - - -
Vilanterol/Umeclidinium vs Indacaterol 2.88 0.40-20.80 0.12-71.39 - - - -
Vilanterol vs Indacaterol 2.11 0.36-12.36 0.12-37.16 - - - -
Indacaterol/Tiotropium vs
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 - - - -
Umeclidinium vs Salmeterol 1.78 0.14-21.96 0.03-105.32 - - - -
Vilanterol/Umeclidinium vs Salmeterol 3.48 0.61-19.73 0.21-58.22 - - - -
Vilanterol vs Salmeterol 2.55 0.58-11.31 0.23-28.60 - - - -
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
Common within-network heterogeneity variance 0.00
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity variance)
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
Fluticasone vs Placebo 1.66 1.32-2.08 1.20-2.30 1.60 1.32-1.95 0.00 5 4258
Mometasone vs Placebo 1.23 0.51-2.96 0.42-3.60 1.75 0.64-4.81 0.00 3 1514
Formoterol vs Placebo 0.91 0.59-1.41 0.52-1.59 1.46 0.70-3.03 0.30 7 3499
Indacaterol vs Placebo 0.97 0.63-1.50 0.56-1.69 0.59 0.23-1.52 0.00 6 2787
68
Salmeterol vs Placebo 1.11 0.91-1.37 0.82-1.51 1.09 0.88-1.35 0.00 3 3829
Vilanterol vs Placebo 1.14 0.53-2.45 0.45-2.92 2.08 0.56-7.67 0.00 2 820
Aclidinium vs Placebo 0.68 0.32-1.42 0.27-1.69 0.68 0.32-1.41 0.00 2 1647
Glycopyrronium vs Placebo 0.82 0.55-1.23 0.49-1.38 0.61 0.32-1.17 0.00 3 2315
Tiotropium vs Placebo 0.95 0.78-1.14 0.71-1.26 0.99 0.84-1.17 0.00 6 11522
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
Indacaterol/Glycopyrronium vs Placebo 0.85 0.53-1.36 0.47-1.54 1.62 0.10-
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 - - - -
Fluticasone vs Budesonide 2.21 1.25-3.92 1.08-4.51 - - - -
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
Indacaterol vs Budesonide 1.29 0.65-2.58 0.55-3.03 - - - -
Salmeterol vs Budesonide 1.48 0.84-2.62 0.73-3.01 - - - -
Vilanterol vs Budesonide 1.52 0.60-3.84 0.49-4.72 - - - -
Aclidinium vs Budesonide 0.90 0.36-2.23 0.30-2.73 - - - -
Glycopyrronium vs Budesonide 1.09 0.56-2.13 0.48-2.49 - - - -
Tiotropium vs Budesonide 1.26 0.71-2.22 0.62-2.55 - - - -
Umeclidinium vs Budesonide 0.99 0.14-7.14 0.09-10.81 - - - -
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
Indacaterol/Glycopyrronium vs Budesonide 1.13 0.55-2.30 0.47-2.72 - - - -
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 - - - -
Formoterol vs Fluticasone 0.55 0.33-0.90 0.29-1.02 - - - -
Indacaterol vs Fluticasone 0.58 0.36-0.95 0.32-1.07 - - - -
Salmeterol vs Fluticasone 0.67 0.54-0.84 0.49-0.93 0.68 0.56-0.83 0.00 2 3174
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 - - - -
Glycopyrronium vs Fluticasone 0.49 0.31-0.78 0.28-0.88 - - - -
Tiotropium vs Fluticasone 0.57 0.43-0.75 0.39-0.83 - - - -
Umeclidinium vs Fluticasone 0.45 0.07-3.03 0.04-4.53 - - - -
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 - - - -
Indacaterol/Glycopyrronium vs Fluticasone 0.51 0.31-0.85 0.27-0.97 - - - -
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 - - - -
Salmeterol vs Formoterol 1.23 0.75-2.00 0.66-2.27 - - - -
Vilanterol vs Formoterol 1.25 0.52-3.03 0.43-3.69 - - - -
Aclidinium vs Formoterol 0.74 0.31-1.76 0.26-2.14 - - - -
Glycopyrronium vs Formoterol 0.90 0.49-1.66 0.42-1.92 - - - -
Tiotropium vs Formoterol 1.04 0.64-1.70 0.56-1.93 - - - -
Umeclidinium vs Formoterol 0.82 0.12-5.78 0.08-8.72 - - - -
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
Indacaterol/Glycopyrronium vs Formoterol 0.93 0.49-1.80 0.42-2.10 - - - -
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 - - - -
Vilanterol vs Indacaterol 1.17 0.49-2.81 0.40-3.42 - - - -
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
Tiotropium vs Indacaterol 0.97 0.65-1.45 0.58-1.62 0.90 0.60-1.35 0.00 2 4395
71
Umeclidinium vs Indacaterol 0.76 0.11-5.31 0.07-7.97 - - - -
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 - - - -
Indacaterol/Glycopyrronium vs Indacaterol 0.88 0.49-1.57 0.42-1.81 1.00 0.20-5.00 -- 1 950
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 - - - -
Vilanterol vs Salmeterol 1.02 0.47-2.22 0.40-2.65 - - - -
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
Umeclidinium vs Salmeterol 0.67 0.10-4.49 0.07-6.71 - - - -
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 - - - -
Glycopyrronium vs Aclidinium 1.21 0.52-2.83 0.43-3.42 - - - -
Tiotropium vs Aclidinium 1.40 0.65-3.01 0.55-3.59 - - - -
Umeclidinium vs Aclidinium 1.10 0.14-8.49 0.09-13.03 - - - -
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 - - - -
Indacaterol/Glycopyrronium vs Aclidinium 1.26 0.52-3.03 0.43-3.69 - - - -
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 - - - -
Indacaterol/Glycopyrronium vs Glycopyrronium 1.04 0.66-1.63 0.58-1.84 0.93 0.59-1.48 0.00 2 2416
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 - - - -
Indacaterol/Glycopyrronium vs
Beclomethasone/Formoterol
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 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Beclomethasone/Formoterol
1.38 0.17-10.93 0.11-16.87 - - - -
Tiotropium/Budesonide/Formoterol vs
Beclomethasone/Formoterol
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 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Budesonide/Formoterol
1.24 0.22-7.00 0.15-10.09 - - - -
Tiotropium/Budesonide/Formoterol vs
Budesonide/Formoterol
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 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Fluticasone/Vilanterol
0.73 0.12-4.60 0.08-6.76 - - - -
Tiotropium/Budesonide/Formoterol vs
Fluticasone/Vilanterol
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 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Fluticasone/Salmeterol
0.82 0.15-4.41 0.11-6.29 - - - -
Tiotropium/Budesonide/Formoterol vs
Fluticasone/Salmeterol
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 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Mometasone/Formoterol
1.78 0.25-12.79 0.16-19.35 - - - -
Tiotropium/Budesonide/Formoterol vs
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 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Indacaterol/Glycopyrronium
1.84 0.33-10.21 0.23-14.66 - - - -
Tiotropium/Budesonide/Formoterol vs
Indacaterol/Glycopyrronium
1.11 0.21-5.90 0.15-8.41 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Umeclidinium/Vilanterol
2.54 0.25-26.17 0.15-42.60 - - - -
Tiotropium/Budesonide/Formoterol vs
Umeclidinium/Vilanterol
1.53 0.15-15.30 0.09-24.76 - - - -
Tiotropium/Budesonide/Formoterol vs
Tiotropium/Fluticasone/Salmeterol
0.60 0.06-6.09 0.04-9.87 - - - -
75
Common within-network heterogeneity variance 0.01
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity variance)
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
Formoterol vs Placebo 1.50 0.66-3.43 0.47-4.83 1.63 0.70-3.84 0.02 6 3053
Indacaterol vs Placebo 1.44 0.61-3.40 0.43-4.85 1.48 0.44-4.99 0.00 2 1081
Salmeterol vs Placebo 0.99 0.39-2.54 0.26-3.75 0.90 0.27-2.99 0.37 4 1213
Aclidinium vs Placebo 1.13 0.44-2.86 0.30-4.22 1.13 0.44-2.87 0.00 2 1647
Glycopyrronium vs Placebo 1.52 0.63-3.62 0.44-5.21 2.92 0.35-
24.37
0.00 2 1522
Tiotropium vs Placebo 1.17 0.71-1.93 0.58-2.38 1.37 0.50-3.72 0.37 4 8729
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 - - - -
Indacaterol/Glycopyrronium vs Placebo 1.63 0.68-3.89 0.48-5.60 2.46 0.12-
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
Indacaterol vs Budesonide 0.73 0.11-5.10 0.05-11.43 - - - -
Salmeterol vs Budesonide 0.51 0.07-3.64 0.03-8.30 - - - -
Aclidinium vs Budesonide 0.57 0.08-4.12 0.03-9.37 - - - -
Glycopyrronium vs Budesonide 0.77 0.11-5.39 0.05-12.12 - - - -
Tiotropium vs Budesonide 0.60 0.10-3.64 0.05-7.73 - - - -
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/Glycopyrronium vs Budesonide 0.83 0.12-5.80 0.05-13.04 - - - -
Indacaterol vs Formoterol 0.96 0.29-3.15 0.18-5.16 - - - -
Salmeterol vs Formoterol 0.66 0.19-2.30 0.11-3.87 - - - -
Aclidinium vs Formoterol 0.75 0.22-2.60 0.13-4.36 - - - -
Glycopyrronium vs Formoterol 1.01 0.30-3.34 0.18-5.50 - - - -
Tiotropium vs Formoterol 0.78 0.30-2.04 0.20-3.05 - - - -
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 - - - -
Indacaterol/Glycopyrronium vs Formoterol 1.08 0.33-3.59 0.20-5.92 - - - -
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
Tiotropium vs Indacaterol 0.81 0.35-1.87 0.25-2.65 0.87 0.24-3.08 0.02 2 4395
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 - - - -
Indacaterol/Glycopyrronium vs Indacaterol 1.13 0.41-3.10 0.27-4.72 0.67 0.11-4.02 -- 1 950
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 - - - -
Glycopyrronium vs Aclidinium 1.35 0.38-4.83 0.22-8.21 - - - -
Tiotropium vs Aclidinium 1.04 0.36-3.00 0.23-4.66 - - - -
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 - - - -
Indacaterol/Glycopyrronium vs Aclidinium 1.45 0.40-5.19 0.24-8.83 - - - -
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 - - - -
Indacaterol/Glycopyrronium vs Glycopyrronium 1.08 0.50-2.31 0.37-3.18 1.10 0.50-2.42 0.00 2 2416
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
Common within-network heterogeneity variance 0.00
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity variance)
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
Indacaterol/Glycopyrronium vs
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
Tiotropium/Fluticasone/Salmeterol vs
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
Indacaterol/Glycopyrronium vs
Umeclidinium 0.46 0.23-0.90
Indacaterol/Glycopyrronium vs
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
Design-by-treatment interaction model
for inconsistency χ² (d.f., P-value,
heterogeneity 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
Indacaterol/Glycopyrronium vs
Budesonide/Formoterol 0.12 0.02-0.91
Indacaterol/Glycopyrronium vs
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
Design-by-treatment interaction model
for inconsistency χ² (d.f., P-value,
heterogeneity variance)
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
Mortality, Pneumonia,
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
Mortality, Pneumonia,
Serious arrhythmia, CVM
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
Mod/severe exacerbation, Mortality,
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
Mod/severe exacerbation, Mortality,
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
Mortality, Pneumonia,
Serious arrhythmia, CVM
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
Mortality, Pneumonia,
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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