1 APPENDICES Appendix 1. Inhalers Included in The

Home , Arformoterol, Fenoterol, Levosalbutamol, Oxitropium bromide, Triamcinolone, Tulobuterol

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

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

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.

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.

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

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)

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.

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/

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-

9 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.

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.

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.

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.

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

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].

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].

Appendix 7. Characteristics of the randomized controlled trials

Author, year Country of conduct Setting Study Treatme # of Overall conduct nt treatme Sample period duration nt size (weeks) (weeks) groups Aalbers, 2002[96] Australia, Belgium, multi-center 12 12 4 687 Denmark, Germany, Hungary, The Netherlands, Norway, Poland, UK Aaron, 2007[167] Canada multi-center 52 52 3 449 Abrahams, 10 countries multi-center 24 24 2 856 2013[133] Agusti, 2014[178] Europe, Asia (not specified) multi-center 12 12 2 528 Ambrosino, Italy multi-center 25 25 2 234 2008[164] 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] 31 countries multi-center 52 48 2 3917 CR:[210] Bateman, 2012[83] NR multi-center 4 4 6 576 Bateman, 2013[174] NR multi-center 30 26 5 2144 Bedard, 2012[166] Canada single center 3 3 2 36 Beier, 2007[136] Belgium, Germany, France, multi-center 5 4 3 163 the Netherlands, Slovakia Beier, 2013[70] Czech Republic, Germany, multi-center 6 6 3 414 Hungary, Poland Bogdan, 2011[77] Japan, Romania, Russia, multi-center 12 12 3 613 Ukraine Bolukbas, 2011[142] Germany multi-center 12 1 2 46 Bourbeau, Canada single center 26 26 2 79 1998[128] 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, multi-center 12 12 2 653 Portugal, Sweden, Turkey, UK, USA Buhl, 2011[27] USA, Austria, Belgium, multi-center 12 12 2 1598 Canada, Columbia, Denmark, Finland, France, Germany, Greece, Hungary, Israel, Italy, Mexico, Norway, Poland, Russia, Slovakia, Spain, Switzerland, Turkey, UK Burge, 2000 [129] UK multi-center 156.53 156.53 2 751 CR:[204-208] Caillaud, 2007[4] France multi-center 3 3 8 202

Calverley, 2003[34] 25 countries multi-center 54 52 4 1465 CR:[214-216, 261] Calverly, 2003[53] NR multi-center 6 6 3 121 Calverly, 2003[119] NR (15 countries) multi-center 52 52 4 1022 Calverley, 42 countries (not specified) multi-center 158 156 4 6112 2007[138] CR: [234- 242] 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] USA multi-center 25 25 2 108 CR:[243] 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, Canada, Denmark, The multi-center 26 24 2 408 2002[147] Netherlands, Russia, Sweden, UK Chapman, USA, Argentina, Canada, multi-center 52 52 3 414 2011[115] CR: [249- Germany, India, Italy, 251] Spain, Sweden, Turkey Choudhury, UK multi-center 52 52 2 260 2007[173] 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, multi-center 52 52 4 1732 Czech, Denmark, Ecuador, Egypt, Estonia, France, Germany, Hungary, Israel, Italy, Korea, Latvia, Lithuania, Netherlands, Peru, Romania, Russia, Slovakia, Spain, Switzerland, Turkey, UK Dahl, 2013[82] Denmark multi-center 4 4 2 193 Dahl, 2013[131] Europe (not specified), multi-center 52 52 2 338 Canada, India, Korea, South Africa Dal Negro, Italy single center 52 52 3 18 2003[137] Decramer, Argentina, Australia, multi-center 52 52 2 3439 2013[122] Austria, Belgium, Brazil, Canada, China, Columbia,

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, Germany, Italy, Mexico, multi-centre 25 24 4 843 2014[183]a Peru, Poland, Romania, Russia, Ukraine, USA Decramer, Argentina, Australia, multi-centre 25 24 4 869 2014[183]b Canada, Chile, Germany, Mexico, Romania, South Africa, South Korea, USA Doherty, 2012 North, Central and South multi-center 52 26 5 1196 America, Europe, Africa, Asia (not specified) Donohue, 2002[3] 12 countries multi-center 24 24 3 623 CR:[257, 258] Donohue, 2013[81] USA, Bulgaria, Canada, multi-center 24 24 4 1532 Chile, Czech Republic, Greece, Japan, Mexico, Poland, Russia, South Africa, Spain, Thailand Dransfield, 2011[47] USA multi-center 16 16 2 249 Dransfield, 15 countries multi-center 52 52 4 1622 2013[180]a Dransfield, 15 countries multi-center 52 52 4 1633 2013[180]b Dusser, 2006[154] France multi-center 50 48 2 1010 Engel, 1989[12] Denmark single center 12 12 2 18 Feldman, 2010[76] USA, New Zealand, multi-center 12 12 2 416 Belgium Feldman, 2012[1] USA multi-center 5 4 2 51 Ferguson, 2008[45] USA, Canada multi-center 52 52 2 782 Freeman, 2007[84] UK multi-center 12 12 2 374 Fukuchi, 2013[31] Japan, Korea, Taiwan, multi-center 12 12 2 1293 Philippines, Vietnam, India, Russia, Poland, Ukraine Gelb, 2013[179] USA, Canada multi-center 54 52 2 602 Gupta, 2002[20] India single center 8 8 2 33 Hagedorn, Germany multi-center 52 52 2 212 2013[109] 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

Hattotuwa, UK single center 12 12 2 37 2002[157] CR:[260] 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, multi-center 16 16 3 283 Belgium, France, Germany, Italy, The Netherlands, New Zealand Jones, 2011[176]a NR - 16 European countries multi-center 52 52 2 843 Jones, 2011[176]b NR - 7 mostly North multi-center 52 52 2 804 American countries Jones, 2012[85] 9 European countries (not multi-center 24 24 3 819 specified), South Africa Jung, 2012[39] Republic of Korea multi-center 24 24 2 479 Kardos, 2007[101] Germany multi-center 44 44 2 994 Kaushik, 1999[57] India NR 1 1 2 30 Kerwin, 2011[177]a USA multi-center 12 12 2 323 Kerwin, 2011[177]b USA multi-center 12 12 2 318 Kerwin, 2012[68] USA, Canada multi-center 12 12 3 560 CR:[244] Kerwin, 2012[78] USA, Argentina, Canada, multi-center 52 52 3 1066 Chile, France, Germany, Hungary, Israel, Italy, Korea, Mexico, Netherlands, New Zealand, Peru, Poland, Russia Kerwin, 2013[10] Chile, Estonia, Germany, multi-center 24 24 5 1030 Japan, Korea, Philippines, Poland, Russian Federation, USA Kinoshita, 2012[75] Hong Kong, India, Japan, multi-center 12 12 3 347 CR: [253] Korea, Singapore, Taiwan Korn, 2011[108] USA, Czech, Germany, multi-center 12 12 2 1123 Hungary, India, Slovakia, Spain, Turkey Kornmann, 15 countries (not specified) multi-center 27 26 3 998 2011[123] Koser, 2010[132] USA multi-center 12 12 2 247 Kuna, 2013[71] Bulgaria, Canada, Japan, multi-center 4 4 5 329 Poland, Russia Lapperre, 2009[49] The Netherlands multi-center 120 (24 120 (24 4 75 CR:[252] weeks weeks for one for one group) group) Littner, 2000[112] USA multi-center 7.14 4.14 5 169 Llewellyn-Jones, UK NR 14 8 2 16 1996[44] Lomas, 2012[21] Estonia, Finland, Germany, multi-center 12 12 2 197 South Korea, Latvia, Lithuania, The Netherlands, New Zealand, Russia,

Slovenia, South Africa, UK Lötvall, 2012[67] Norway, Sweden multi-center 4 4 2 60 Magnussen, Belgium, Canada, Germany, multi-center 12 12 2 472 2008[106] Denmark, France, Italy, the Netherlands, South Africa Mahler, 1999[91] USA multi-center 12 12 2 278 Mahler, 2002[56] Lebanon multi-center 24 24 4 645 Mahler, 2012[175]a Argentina, Australia, multi-center 12 12 2 1131 Colombia, Denmark, Germany, Greece, Guatemala, Mexico, Peru, Philippines, South Africa, Spain, Turkey, USA Mahler, 2012[175]b Argentina, Canada, multi-center 12 12 2 1142 Colombia, Czech Republic, Hungary, India, Netherlands, Philippines, Slovakia, Spain, USA Maltais, 2005[105] NR multi-center 6 6 2 261 Maltais, 2011[14] Canada, USA multi-center 6 6 2 181 Mansori, 2010[152] Iran single center 24 12 2 40 Martinez, 2013[94] Czech Republic, Germany, multi-center 24 24 6 1224 Japan, Poland, Romania, Russian Federation, Ukraine, USA Mathioudakis, Greece single center 208 208 5 564 2013[100] McNicholas, UK, Ireland, The multi-center 4 4 3 95 2004[113] Netherlands Mirici, 2001[50] Turkey single center 12 12 2 50 Moita, 2008[165] Portugal multi-center 12 12 2 304 Mroz, 2013[107] Poland single center 12 12 2 34 Nicolini, 2012[140] Italy single center 0.14 0.14 2 100 Niewoehner, USA multi-center 26 24 2 1829 2005[126] CR:[211, 212] O'Donnell, 2004[65] Canada, USA, Germany multi-center 6 6 2 187 O'Donnell, 2006[48] USA, Canada multi-center 8 8 3 185 Ozol, 2005[150] Turkey NR 24 24 2 26 Paggiaro, 1998[120] 13 European countries (not multi-center 24 24 2 281 specified), New Zealand, South Africa Pasqua, 2010[35] Italy NR 4 4 2 22 Pauwels, 1999[117] Belgium, Denmark, Finland, multi-center 156 144 2 1277 CR:[245, 246] Italy, the Netherlands, Norway, Spain, Sweden, UK Perng, 2009[24] Taiwan multi-center 12 12 3 99 Powrie, 2007[55] UK single center 52 52 2 142 Pukhta, 2010[9] India single center 2 2 2 60

Rabe, 2008[37] Austria, Belgium, Denmark, multi-center 6 6 2 605 France, Germany, Netherlands, South Africa, Sweden Reid, 2008[29] Australia NR 24 24 2 34 Renkema, 1996[62] The Netherlands NR 104 104 2 39 Rennard, 2001[171] USA multi-center 12 12 2 267 Rennard, 2009[87] USA, Mexico, Europe (not multi-center 56 52 4 1964 specified) Rossi, 2002[38] Austria, Belgium, Czech multi-center 52 52 3 854 Republic, France, Germany, Greece, Hungary, Italy, Slovakia, South Africa, Spain, USA Rubin, 2008[99] Brazil single center 0.14 0.003 2 40 (30 minutes) Rutgers, 1998[143] The Netherlands single center 6 6 2 44 Rutten-van, The Netherlands multi-center 12 12 2 97 1999[18] Santus, 2012[30] Italy NR 4 4 2 24 Schermer, The Netherlands multi-center 12 12 2 40 2007[118] Scherr, 2012[130] Switzerland single center 12 12 2 68 Sechaud, 2012[125] Germany, Denmark multi-center 2 2 5 41 Senderovitz, Denmark multi-center 24 24 2 26 1999[144] Shaker, 2009[151] Denmark single center 208 104 -208 2 254 CR:[256] Sharafkhaneh, USA, Central and South multi-center 54 52 3 1219 2012[42] America, South Africa Sin, 2008[156] Canada multi-center 4 4 3 224 Sposato, 2008[139] Italy single center 0.05 0.34 2 37 Sridevi, 2012[134] India single center 14 14 2 60 Stahl, 2001[98] Sweden multi-center 12 12 2 121 Stockley, 2006[16] Austria, Bulgaria, Belgium, multi-center 52 52 2 634 Croatia, Czech Republic, Denmark, Ireland, Estonia, France, Germany, Holland, Hungary, Latvia, Poland, Spain, Slovak Republic, Slovenia, Ukraine, UK Struijs, 1997[158] The Netherlands NR 52 52 2 33 Sugiura, 2003[40] Japan single center 4 4 2 18 Suzuki, 2010[90] Japan single center 52 52 2 20 Szafranski, 2003[73] Argentina, Brazil, Denmark, multi-center 52 52 4 812 CR:[259] Finland, UK, Italy, Mexico, Poland, Portugal, South Africa, Spain Tashkin, 2008 [2] 37 countries multi-center 208 208 2 5992 CR: [217-224, 227-

232] Tashkin, 2008[72] USA, Czech Republic, The multi-center 28 26 6 1704 Netherlands, Poland, South Africa Tashkin, 2009[95] USA multi-center 12 12 2 255 Tashkin, 2012[69] South America, Asia, multi-center 52 26 5 1055 Africa, Europe, North America (not specified) The Lung Health NR multi-center 208 mean 2 1116 Study Research 160 Group, 2000 [51] CR: [209] Tonnel, 2008 France multi-center 36 36 2 554 Troosters, 2014[182] Belgium, Canada, Czech multi-center 24 24 2 457 Republic, Germany, Great Britain, Greece, the Netherlands, Portugal, Ukraine, USA Tzani, 2011[58] Italy multi-center 12 12 2 18 Ulubay, 2005[163] Turkey single center 4 4 2 25 Um, 2007[148] Korea single center 6 6 2 81 Van de Maele, Belgium multi-center 2 2 5 255 2010[33] van Den Boom, The Netherlands single center 52 52 2 74 2001[149] CR: [247, 248] van den Broek, Netherlands single center 104 0.006 2 77 2008[89] van der Valk, The Netherlands single center 24 24 2 244 2002[43] van Noord, The Netherlands multi-center 14 12 2 97 2000[116] Verhoeven, The Netherlands NR 24 24 2 23 2002[59] CR: [254, 255] Verkindre, France multi-center 14 12 2 100 2006[155] Vestbo, 1999[114] Denmark single center 144 144 2 290 Vogelmeier, 8 countries multi-center 24 24 4 847 2008[97] Vogelmeier, Germany, France, the multi-center 4 4 3 281 2010[135] Netherland, Spain, Turkey, USA Vogelmeier, 25 countries multi-center 52 52 2 7376 2011[169] CR: [213] Vogelmeier, Belgium, Czech, Estonia, multi-center 26 26 2 523 2013[80] Germany, Hungary, Korea, efficacy, Lithuania, Norway, Spain, 30 safety South Africa Wadbo, 2002[60] Sweden multi-center 12 12 2 121 Watkins, 2013[141] USA single center 6 6 3 365 Wedzicha, 2008[22] Austria, Belgium, Czech multi-center 104 104 2 1323 CR:[233] Republic, Denmark, 23

Estonia, Germany, Greece, Italy, Latvia, Lithuania, the Netherlands, Norway, Romania, Russia, Slovakia, Slovenia, Spain, Sweden, Ukraine, UK Wedzicha, 27 countries (not specified) multi-center 80 64 - 76 3 2206 2013[162] 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, The Netherlands single center 6 6 2 35 1991[110] Wielders, 2013[6] 9 countries multi-center 5 4 8 436 Wise, 2013[168] USA, UK, France, multi-center mean median 3 17135 Denmark, Germany and 119.6 119.28 other countries not specified Woolhouse, UK NR 2 2 2 23 2001[145] 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, 52 52 2 631 2003†[186] USA NR Cheng, 2012†[198] Taiwan NR 52 52 2 78 da Fonseca Reis, 12 12 2 18 2010†[200] NR NR Dawber, 2005†[189] NR single center 3 3 2 59 Australia, Bulgaria, Croatia, Czech Republic, France, Germany, Greece, Italy, Latvia, Lithuania, Netherlands, Philippines, 24 24 2 1050 Poland, Romania, Russian GlaxoSmithKline, Federation, Slovakia, 2005 Slovenia, Sweden, Thailand, (SCO100470)†[193] UK multi-center GlaxoSmithKline, 2005 12 12 2 125 (SCO40034)†[195] The Netherlands multi-center GlaxoSmithKline, 2005 (SLMF 24 24 2 34 4010)†[187] France multi-center GlaxoSmithKline, 2005 16 16 2 347 (SMS40298)†[197] Canada multi-center GlaxoSmithKline, 4 8 2 316 2005 USA multi-center

(SMS40315)†[196] GlaxoSmithKline, 2005 ,SFCT01 54 52 3 387 (SCO30002)†[192] Italy, Poland multi-center GlaxoSmithKline, 2006 24 24 2 445 (SCO100540)†[194] China multi-center GlaxoSmithKline, 2007 Russian Federation, USA, 12 12 4 161 (SCO104925)†[185] Chile, Estonia multi-center GlaxoSmithKline, 2008 156 156 2 186 (SCO40041)†[184] USA multi-center Kelleher, 1 1 3 38 2011†[201] NR NR Canada, Germany, USA, 4 4 4 360 Maltais, 2010†[202] France NR Belgium, Canada, Denmark, France, Germany, Italy, the Novartis, 2006 Netherlands, Norway, Peru, 2 2 6 635 (CQAB149B2205)† Russia, Sweden, [191] Switzerland, USA multi-center Ohar, 2013†[199] USA multi-center 26 26 2 639 Sekiya, 2012†[203] Japan multi-center 52 52 2 163 Sricharoenchai, NR 0.012 2 15 2008†[190] Thailand NR 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

Appendix 8. Patient characteristics

Author, year Age category % Female COPD Definition Diagnosis of COPD Severity COPD COPD (GOLD duration criteria) 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 NA moderate to very severe† NR emphysema 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, Adult & elderly (≥18) 22.45 COPD NR moderate to severe† NR 2010[7]CR:[210] 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 No moderate to severe† NR (salbutamol 400 mg)

forced expiratory volume in 1 s (FEV1) ,<80% and ≥30% predicted, FEV1/forced vital capacity (FVC),<70%) Burge, 2000[129] Adult & elderly (≥18) 25.43 COPD NR mild to very severe† NR CR: [204-208] Caillaud, 2007 Adult & elderly (≥18) 14.4 COPD NR moderate to severe† NR Calverley, 2003[34] Adult & elderly (≥18) 27.65 COPD NR moderate to very severe† NR CR:[214-216, 261] 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, Adult & elderly (≥18) 24.23 COPD NR moderate to very severe† NR 2007[138] CR: [234-242] Calverly, 2008 Adult & elderly (≥18) 31.72 COPD I-IV mild to very severe† NR Calverley, 2010 Adult & elderly (≥18) 19.35 COPD severe stable COPD severe† >24 according to the GOLD guidelines Campbell, 2007 Adult & elderly (≥18) 48.04 COPD NR moderate to very severe† NR Casaburi, 2005[103] Adult & elderly (≥18) 43.5 COPD NR moderate to very severe† NR CR:[243] Cazzola, 2000 Adult & elderly (≥18) 8.75 COPD NR mild to very severe† NR Cazzola, 2007 Adult & elderly (≥18) 11.11 COPD a baseline FEV1 of severe to very severe NR less than 50% of predicted, and a post-bronchodilator FEV1/ FVC<70% following salbutamol 400 mg according with the GOLD criteria of severity 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

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, Adult & elderly (≥18) 39 COPD Yes moderate to severe† NR 2011[115] CR: [249-251] 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 moderate to severe† NR guidelines 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 Yes severe† NR airflow limitations 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 moderate to very severe† NR diagnoses Donohue, 2002[3] Adult & elderly (≥18) 25 COPD NR moderate† NR CR:[257, 258] 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 NR mild to moderate† at least the for at least three months preceding 2 a year during at least the years

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 NR mild to very severe† NR symptoms/events of >3days in duration requiring a change in treatment 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 NR moderate to very severe† 12-636 dyspnea 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, Adult & elderly (≥18) 13.33 COPD NR mild to very severe† NR 2002[157] CR:[260] 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

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 severe to very severe† NR and IV 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] Adult & elderly (≥18) 47 COPD NR moderate to severe† NR CR:[244] 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] Adult & elderly (≥18) 3.47 COPD II, III moderate to severe† NR CR: [253] 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] Adult & elderly (≥18) 13.86 non-asthmatic COPD II-III moderate to severe NR CR:[252] Littner, 2000 Adult & elderly (≥18) 43.19 COPD NR moderate to severe† NR Llewellyn-Jones, Adult & elderly (≥18) 50 chronic bronchitis and NR moderate to severe† >24 1996 emphysema 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

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 II and III NR NR emphysematic" and "predominantly bronchitic patients." 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 NR NR 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. Nanshan/Zhong, Adult & elderly (≥18) 4.87 COPD NR moderate to very severe† NR 2012 Nicolini, 2012 Adult & elderly (≥18) 32 COPD stages 2, 3, 4 stable NR Niewoehner, Adult & elderly (≥18) 1.48 COPD NR moderate to very severe† NR 2005[126] CR:[211, 212] O'Donnell, 2004 Adult & elderly (≥18) 26.2 COPD NR moderate to very severe† NR O'Donnell, 2006 Adult & elderly (≥18) 30.12 COPD NR moderate to very severe† NR Ozol, 2005 Adult & elderly (≥18) 18.18 COPD NR mild to moderate NR Paggiaro, 1998 Adult & elderly (≥18) 22.78 COPD: "as a disorder NR mild to severe† NR characterised by decreased maximum

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] Adult (18-64) 27.15 COPD NR mild to moderate† NR CR:[245, 246] 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] Adult & elderly (≥18) 42 COPD is defined as a NR moderate to severe† ≥24 CR:[256] "preventable and treatable disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is

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 NR moderate to very severe† NR exacerbation for at least 4 weeks) Sposato, 2008 Adult & elderly (≥18) 32.43 COPD moderate-to-severe moderate to severe, stable NR COPD as per GOLD Sridevi, 2012 Adult & elderly (≥18) stable or exacerbated NR moderate to very severe† NR COPD Stahl, 2001 Adult & elderly (≥18) 46.99 COPD NR moderate to severe NR Stockley, 2006 Adult & elderly (≥18) 24.04 COPD NR moderate to very severe† NR Struijs, 1997 Adult & elderly (≥18) 39.39 COPD NR NR NR Sugiura, 2002 Adult & elderly (≥18) 11.11 COPD NR NR NR Suzuki, 2010 Adult & elderly (≥18) 10 COPD I; II-III moderate to severe NR Szafranski, Adult & elderly (≥18) 21.26 COPD moderate-to-severe moderate to very severe† ≥24 2003[73] CR:[259] Tashkin DP, 2012 Adult & elderly (≥18) 22.46 COPD NR moderate to very severe† ≥24 Tashkin, 2008[2] Adult & elderly (≥18) 25 COPD II (44.5%); III moderate to very severe† NR CR: [217-224, 227- (44%); IV (8.5%) 232] Tashkin, 2008[72] Adult & elderly (≥18) 31.87 COPD who had previous NR moderate to verey severe† >24 exacerbations Tashkin, 2009 Adult & elderly (≥18) 33.73 COPD NR severe to very severe† NR The Lung Health Adult & elderly (≥18) 36.95 COPD NR mild to severe† NR Study Research Group, 2000[51] CR: [209] 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

Tzani, 2011 Adult & elderly (≥18) 16.67 COPD confirmed NR NR diagnosis according to GOLD guidelines 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, Adult & elderly (≥18) 58.1 Obstructive airway NA moderate to severe† NR 2001[149] CR: disease [247, 248] van den Broek, Adult & elderly (≥18) 33.77 COPD NR NR ≥6 2008 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 NR mild to moderate† NR 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." Verhoeven, Adult & elderly (≥18) 17.39 COPD NR mild to moderate NR 2002[59] CR: [254, 255] 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 moderate to severe moderate to severe† NR COPD according to 2006 GOLD guidelines Vogelmeier, Adult & elderly (≥18) 25.35 COPD II, III, IV moderate to very severe† NR 2011[169] CR:[213] Vogelmeier, 2013 Adult & elderly (≥18) 29 COPD II or III moderate to severe† NR

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] Adult & elderly (≥18) 17.49 COPD III-IV moderate to very severe† NR CR:[233] 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 NR NR NR without marked airflow obstruction (FEV ~70% predicted) 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 NA NR NR defined by daily sputum production for at least 3 months of 2 consecutive years 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 NR moderate to very severe† NR Society and GOLD guidelines Unpublished Studies (n=20) Calverley, 2003*[186] NR NR COPD NR moderate to very severe† NR Cheng, 2012* NR NR COPD NR NR NR da Fonseca Reis, 2010* NR NR COPD III Severe NR Dawber, 2005* NR NR COPD NR moderate to severe NR GlaxoSmithKline, 2005 (SCO100470)* Adult & elderly (≥18) 22.19 COPD II NR† NR

GlaxoSmithKline, NR 2005 (SCO40034)* Adult & elderly (≥18) 25.6 COPD NR moderate to very severe† GlaxoSmithKline, NR 2005 (SLMF 4010)* Adult (18-64) 11.76 COPD NR moderate to severe† GlaxoSmithKline, NR 2005 (SMS40298)* Adult & elderly (≥18) 41.21 COPD NR moderate to very severe† GlaxoSmithKline, NR 2005 (SMS40315)* Adult & elderly (≥18) 39.18 COPD NR moderate to severe† GlaxoSmithKline, NR 2005 ,SFCT01 (SCO30002)* Adult & elderly (≥18) 17.57 COPD NR moderate to very severe† GlaxoSmithKline, NR 2006 (SCO100540)* Adult & elderly (≥18) 10.79 COPD NR moderate to very severe† GlaxoSmithKline, NR 2007 (SCO104925)* Adult & elderly (≥18) 23.6 bronchitis and COPD NR moderate to severe† GlaxoSmithKline, NR 2008 (SCO40041)* Adult & elderly (≥18) 38.71 COPD NR moderate to very severe† Kelleher, 2011* NR NR COPD NR NR† NR Maltais, 2010* NR 45.5 COPD NR NR NR Novartis, 2006 NR (CQAB149B2205)* Adult & elderly (≥18) 33.23 COPD NR moderate to severe† 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, NR 2008* NR NR COPD 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

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

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 Unclear Unclear Low Low Low Unclear Unclear (SMS40298) GlaxoSmithKline, 2005 Unclear Unclear Low Low Low Unclear Unclear (SMS40315) GlaxoSmithKline, Unclear Unclear Low Low Low Unclear Unclear 2005(SCO40034) GlaxoSmithKline, 2005 Unclear Unclear Low Low Low Low High (SCO100470) GlaxoSmithKline, 2005 Unclear Unclear Low Low Low Low High (SCO30002) GlaxoSmithKline, 2005 Unclear Unclear Low Low Low Unclear High (SLMF4010) GlaxoSmithKline, 2006 Unclear Unclear Low Low Low Unclear Unclear (SCO100540)

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

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 Low Unclear Low Low Low Low Low N,2012 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

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 Unclear Unclear Low Low Low Unclear Unclear Research Group, 2000 To, 2011 Unclear Unclear Low Unclear Low Unclear Unclear Tonnel, 2008 Low Unclear Low Low High Unclear High Troosters, 2014 Low Unclear Low Low Low Low Unclear Tzani, 2011 Low Unclear Low Low Low Low High Ulubay, 2005 Unclear Unclear Low Low Unclear Unclear Unclear Um, 2007 Low Unclear High Low High Unclear Low Van de Maele, 2010 Low Unclear Low Low Low Unclear Unclear van Den Boom, 2001 Unclear Unclear Low Low Low Unclear Low van den Broek , 2008 Low Unclear Low Low Low Unclear Unclear van der Valk, 2002 Low Unclear Low Low Low Unclear Unclear van Noord, 2000 Unclear Unclear Low Low Low Unclear High Verhoeven, 2002 Unclear Unclear Low Low Low Low Unclear Verkindre, 2006 Unclear Unclear Low Low Low Unclear High Vestbo, 1999 Low Low Low Low Low Unclear Unclear Vogelmeier, 2008 Unclear Unclear Low Low Low Low High Vogelmeier, 2010 Unclear Unclear Low Low Low Low High Vogelmeier, 2011 Low Low Low Low Low Low High Vogelmeier, 2013 Low Low Low Low Low Low High Wadbo, 2002 Unclear Unclear Low Low High Unclear Unclear Watkins, 2013 Unclear Unclear Low Low Low Low High Wedzicha, 2008 Low Low Low Low Low Low Unclear Wedzicha, 2013 Low Low Low Low Low Low High Weir, 1999 Unclear Unclear Low Low High Unclear Unclear Welte, 2008 Unclear Unclear Low Low Low Unclear High Welte, 2009 Low Unclear Low Low Low Low High Wesseling, 1991 Unclear Unclear Low Low Low Unclear Unclear Wielders, 2013 Unclear Unclear Low Low Low Low High Wise, 2013 Unclear Unclear Low Low Low Low Low Woolhouse, 2001 Unclear Unclear Low Low Low Unclear Unclear Wouters, 2005 Low Unclear Low Low High Unclear High

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

Appendix 10. Network Meta-analysis Results Outcome

Network Meta-analysis Results Pairwise Meta-analysis Treatment Comparison Odds CI PrI Odds CI Heteroge # studies # patients Ratio Ratio neity Variance 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 43

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 - - - - -

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 - - - - -

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 0.65 0.37-1.15 - - - - - Beclomethasone/Formoterol Tiotropium/Fluticasone/Salmeterol vs 0.78 0.39-1.58 - - - - - Beclomethasone/Formoterol Tiotropium/Budesonide/Formoterol vs 0.32 0.15-0.65 - - - - - Beclomethasone/Formoterol Fluticasone/Vilanterol vs Budesonide/Formoterol 0.88 0.27-2.88 - - - - -

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 0.90 0.49-1.66 - - - - - Budesonide/Formoterol Tiotropium/Budesonide/Formoterol vs 0.36 0.19-0.69 - - - - - Budesonide/Formoterol 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 1.02 0.30-3.41 - - - - - Fluticasone/Vilanterol Tiotropium/Budesonide/Formoterol vs 0.41 0.12-1.39 - - - - - Fluticasone/Vilanterol 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 0.86 0.52-1.40 - - - - - Fluticasone/Salmeterol Tiotropium/Budesonide/Formoterol vs 0.35 0.21-0.58 - - - - - Fluticasone/Salmeterol Indacaterol/Glycopyrronium vs Tiotropium/Salmeterol 0.68 0.41-1.13 - - - - - Tiotropium/Fluticasone/Salmeterol vs 0.81 0.51-1.31 - 0.81 0.51-1.30 -- 1 293 Tiotropium/Salmeterol Tiotropium/Budesonide/Formoterol vs 0.33 0.17-0.65 - - - - - Tiotropium/Salmeterol Tiotropium/Fluticasone/Salmeterol vs 1.20 0.72-2.00 - - - - - Indacaterol/Glycopyrronium Tiotropium/Budesonide/Formoterol vs 0.48 0.28-0.83 - - - - - Indacaterol/Glycopyrronium Tiotropium/Budesonide/Formoterol vs 0.40 0.21-0.80 - - - - - Tiotropium/Fluticasone/Salmeterol Common within-network heterogeneity variance 0.00 Design-by-treatment interaction model for 3.37 (4,0.498,0.00) inconsistency χ² (d.f., P-value, heterogeneity variance) 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 47

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- 0.00 2 1044 11.24 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- -- 1 698 91.84 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- -- 1 693 92.96 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 - - - -

Formoterol/Budesonide/Tiotropium vs AZD3199 (Ultra 6.39 0.07-561.41 0.06-683.41 - - - - LABA) 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 3.46 0.12-101.64 0.10-118.04 - - - - LABA) 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 - - - -

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- -- 1 470 10.84 Formoterol/Budesonide/Tiotropium vs 3.82 0.11-138.30 0.09-162.06 - - - - Beclomethasone/Formoterol Fluticasone vs Beclomethasone/Formoterol 1.36 0.27-6.88 0.25-7.42 - - - - Salmeterol/Fluticasone vs Beclomethasone/Formoterol 1.02 0.20-5.17 0.19-5.58 - - - - Salmeterol/Fluticasone/Tiotropium vs 2.07 0.26-16.35 0.24-17.96 - - - - Beclomethasone/Formoterol 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 - - - -

Indacaterol vs Beclomethasone/Formoterol 1.07 0.20-5.69 0.19-6.15 - - - - Indacaterol/Glycopyrronium vs 1.12 0.20-6.08 0.19-6.58 - - - - Beclomethasone/Formoterol 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 - - - -

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 2.75 0.11-71.01 0.09-82.01 - - - - Formoterol/Budesonide 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 1.49 0.37-6.02 0.35-6.44 - - - - Formoterol/Budesonide 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 - - - -

Salmeterol/Fluticasone vs 0.27 0.01-6.68 0.01-7.71 - - - - Formoterol/Budesonide/Tiotropium Salmeterol/Fluticasone/Tiotropium vs 0.54 0.02-17.20 0.01-20.04 - - - - Formoterol/Budesonide/Tiotropium Fluticasone/Tiotropium vs 0.31 0.01-17.58 0.00-21.00 - - - - Formoterol/Budesonide/Tiotropium Vilanterol/Fluticasone vs 0.42 0.01-12.34 0.01-14.33 - - - - Formoterol/Budesonide/Tiotropium Formoterol vs Formoterol/Budesonide/Tiotropium 0.44 0.02-11.23 0.01-12.97 - - - - Formoterol/Tiotropium vs 0.23 0.01-10.28 0.00-12.16 - - - - Formoterol/Budesonide/Tiotropium 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 0.29 0.01-7.54 0.01-8.71 - - - - Formoterol/Budesonide/Tiotropium Indacaterol/Tiotropium vs 0.37 0.01-12.96 0.01-15.17 - - - - Formoterol/Budesonide/Tiotropium Mometasone vs Formoterol/Budesonide/Tiotropium 0.48 0.02-13.21 0.01-15.31 - - - - Formoterol/Mometasone vs 0.24 0.01-7.57 0.01-8.82 - - - - Formoterol/Budesonide/Tiotropium Salmeterol vs Formoterol/Budesonide/Tiotropium 0.31 0.01-7.62 0.01-8.79 - - - - Salmeterol/Tiotropium vs 0.53 0.02-16.83 0.01-19.61 - - - - Formoterol/Budesonide/Tiotropium Tiotropium vs Formoterol/Budesonide/Tiotropium 0.33 0.01-8.16 0.01-9.41 0.33 0.01-8.14 -- 1 660 Tiotropiumropium Respimat vs 0.33 0.01-8.30 0.01-9.57 - - - - Formoterol/Budesonide/Tiotropium Triamcinoloneacetonide vs 0.27 0.01-7.16 0.01-8.29 - - - - Formoterol/Budesonide/Tiotropium Umeclidinium vs Formoterol/Budesonide/Tiotropium 0.39 0.01-12.95 0.01-15.12 - - - - Vilanterol vs Formoterol/Budesonide/Tiotropium 0.51 0.02-14.56 0.02-16.88 - - - - Vilanterol/Umeclidinium vs 0.44 0.01-13.54 0.01-15.75 - - - - Formoterol/Budesonide/Tiotropium 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- 1.163 2 820 19.56 Formoterol vs Fluticasone 1.23 0.76-2.01 0.73-2.09 - - - -

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- 0.00 2 818 16.33 Vilanterol/Umeclidinium vs Fluticasone 1.24 0.37-4.14 0.35-4.40 - - - - Salmeterol/Fluticasone/Tiotropium vs 2.02 0.54-7.54 0.51-8.04 - - - - Salmeterol/Fluticasone Fluticasone/Tiotropium vs Salmeterol/Fluticasone 1.16 0.10-13.41 0.09-14.97 1.03 0.06- -- 1 65 17.24 Vilanterol/Fluticasone vs Salmeterol/Fluticasone 1.57 0.54-4.58 0.51-4.84 2.97 0.12- -- 1 528 73.14 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- -- 1 605 15.90 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 - - - -

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 0.58 0.04-9.14 0.03-10.34 - - - - Salmeterol/Fluticasone/Tiotropium Vilanterol/Fluticasone vs 0.78 0.15-4.14 0.13-4.48 - - - - Salmeterol/Fluticasone/Tiotropium Formoterol vs Salmeterol/Fluticasone/Tiotropium 0.81 0.21-3.21 0.19-3.43 - - - - Formoterol/Tiotropium vs 0.42 0.04-4.77 0.03-5.32 - - - - Salmeterol/Fluticasone/Tiotropium 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 0.54 0.13-2.18 0.12-2.33 - - - - Salmeterol/Fluticasone/Tiotropium Indacaterol/Tiotropium vs 0.68 0.09-5.11 0.08-5.60 - - - - Salmeterol/Fluticasone/Tiotropium Mometasone vs Salmeterol/Fluticasone/Tiotropium 0.88 0.18-4.18 0.17-4.50 - - - - Formoterol/Mometasone vs 0.44 0.07-2.76 0.06-3.01 - - - - Salmeterol/Fluticasone/Tiotropium Salmeterol vs Salmeterol/Fluticasone/Tiotropium 0.57 0.15-2.10 0.14-2.23 - - - - Salmeterol/Tiotropium vs 0.98 0.31-3.13 0.29-3.32 0.98 0.31-3.11 -- 1 293 Salmeterol/Fluticasone/Tiotropium Tiotropium vs Salmeterol/Fluticasone/Tiotropium 0.61 0.17-2.22 0.16-2.36 0.61 0.17-2.21 -- 1 301 Tiotropiumropium Respimat vs 0.62 0.17-2.28 0.16-2.43 - - - - Salmeterol/Fluticasone/Tiotropium Triamcinoloneacetonide vs 0.49 0.11-2.17 0.11-2.33 - - - - Salmeterol/Fluticasone/Tiotropium Umeclidinium vs Salmeterol/Fluticasone/Tiotropium 0.72 0.10-4.89 0.10-5.34 - - - - Vilanterol vs Salmeterol/Fluticasone/Tiotropium 0.94 0.19-4.74 0.17-5.12 - - - - Vilanterol/Umeclidinium vs 0.82 0.14-4.74 0.13-5.14 - - - - Salmeterol/Fluticasone/Tiotropium 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 - - - -

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- -- 1 66 15.68 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

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 - - - -

Indacaterol vs Glycopyrronium 1.09 0.57-2.10 0.54-2.19 1.99 0.18- -- 1 431 22.04 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 - - - -

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 - - - -

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- -- 1 417 74.07 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

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 31.44 (50,0.982,0.00) inconsistency χ² (d.f., P-value, heterogeneity variance) 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- -- 1 542 75.35 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- -- 1 581 112.46 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- -- 1 1116 14.98 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- -- 1 693 50.25 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 - - - -

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 - - - -

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- -- 1 556 103.12 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- -- 1 559 71.87 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 - - - -

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- -- 1 818 74.80 Vilanterol/Fluticasone vs Salmeterol/Fluticasone 1.17 0.19-7.38 0.06-23.26 2.97 0.12- -- 1 528 73.14 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 - - - -

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- -- 1 818 74.80 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- -- 1 871 73.51 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 65

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- -- 1 1593 73.38 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 7.55 0.16-357.46 0.01- - - - - Indacaterolacaterol/Glycopyrronium 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 - - - -

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- -- 1 852 73.01 Vilanterol vs Tiotropium 1.28 0.29-5.64 0.11-14.26 3.00 0.12- -- 1 417 74.07 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- -- 1 1270 74.93 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 11.79 (27,0.995,0.00) inconsistency χ² (d.f., P-value, heterogeneity variance) 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

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- 2.81 2 1044 26.65 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 - - - -

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- 1.55 2 915 18.09 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 - - - -

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- -- 1 474 44.24 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

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- -- 1 408 22.56 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 - - - -

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

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 0.75 0.20-2.80 0.15-3.71 - - - - Beclomethasone/Formoterol Umeclidinium/Vilanterol vs Beclomethasone/Formoterol 0.54 0.07-4.26 0.05-6.55 - - - - Tiotropium/Fluticasone/Salmeterol vs 1.38 0.17-10.93 0.11-16.87 - - - - Beclomethasone/Formoterol Tiotropium/Budesonide/Formoterol vs 0.83 0.11-6.37 0.07-9.77 - - - - Beclomethasone/Formoterol 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 - - - -

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 1.24 0.22-7.00 0.15-10.09 - - - - Budesonide/Formoterol Tiotropium/Budesonide/Formoterol vs 0.75 0.14-4.05 0.10-5.79 - - - - Budesonide/Formoterol Fluticasone/Salmeterol vs Fluticasone/Vilanterol 0.89 0.41-1.96 0.34-2.34 2.04 0.18- -- 1 528 22.62 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 0.73 0.12-4.60 0.08-6.76 - - - - Fluticasone/Vilanterol Tiotropium/Budesonide/Formoterol vs 0.44 0.07-2.67 0.05-3.89 - - - - Fluticasone/Vilanterol 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 0.82 0.15-4.41 0.11-6.29 - - - - Fluticasone/Salmeterol Tiotropium/Budesonide/Formoterol vs 0.50 0.10-2.55 0.07-3.60 - - - - Fluticasone/Salmeterol 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 1.78 0.25-12.79 0.16-19.35 - - - - Mometasone/Formoterol Tiotropium/Budesonide/Formoterol vs 1.07 0.15-7.44 0.10-11.18 - - - - Mometasone/Formoterol Umeclidinium/Vilanterol vs Indacaterol/Glycopyrronium 0.72 0.13-3.97 0.09-5.68 - - - - Tiotropium/Fluticasone/Salmeterol vs 1.84 0.33-10.21 0.23-14.66 - - - - Indacaterol/Glycopyrronium Tiotropium/Budesonide/Formoterol vs 1.11 0.21-5.90 0.15-8.41 - - - - Indacaterol/Glycopyrronium Tiotropium/Fluticasone/Salmeterol vs 2.54 0.25-26.17 0.15-42.60 - - - - Umeclidinium/Vilanterol Tiotropium/Budesonide/Formoterol vs 1.53 0.15-15.30 0.09-24.76 - - - - Umeclidinium/Vilanterol Tiotropium/Budesonide/Formoterol vs 0.60 0.06-6.09 0.04-9.87 - - - - Tiotropium/Fluticasone/Salmeterol 74

Common within-network heterogeneity variance 0.01 Design-by-treatment interaction model for 34.33 (31,0.311,0.00) inconsistency χ² (d.f., P-value, heterogeneity variance) 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- 0.00 2 1522 24.37 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- 1.50 2 1556 32.10 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- -- 1 706 51.45 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 - - - -

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

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- -- 1 522 75.99 Common within-network heterogeneity variance 0.00 Design-by-treatment interaction model for 3.06 (11,0.9899,0.36) inconsistency χ² (d.f., P-value, heterogeneity variance) 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

Appendix 11. Sensitivity Network Meta-analysis results (only statistically significant results are presented)

Network Meta-analysis Results Pairwise Meta-anlaysis Results Odds Odds Treatment Comparison CI CI # studies # patients Ratio Ratio 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 0.62 0.47-0.82 0.63 0.51-0.77 1.00 1469.00 Glycopyrronium Indacaterol/Glycopyrronium vs Tiotropium 0.73 0.57-0.94 0.74 0.60-0.91 1.00 1466.00 0.67 0.46-0.98 Indacterol/Tiotropium vs Placebo 0.60 0.43-0.84 Indacaterol/Glycopyrronium vs Placebo 3.30 1.44-7.55 Indacaterol vs Fluticasone 3.40 1.49-7.72 Salmeterol vs Fluticasone 3.44 1.47-8.07 Glycopyrronium vs Fluticasone 2.93 1.30-6.57 Tiotropium vs Fluticasone 4.71 1.71-12.96 Umeclidinium vs Fluticasone Fluticasone/Salmeterol vs Fluticasone 3.14 1.37-7.20 1.19 0.31-4.59 1.00 179.00 3.20 1.23-8.29 Tiotropium/Salmeterol vs Fluticasone 2.41 1.02-5.73 Indacterol/Tiotropium vs Fluticasone 4.37 1.73-11.05 Umeclidinium/Vilanterol vs Fluticasone Tiotropium/Fluticasone/Salmeterol vs 2.60 1.00-6.73 Fluticasone 0.65 0.47-0.90 Indacaterol/Glycopyrronium vs Indacaterol 0.63 0.46-0.86 Indacaterol/Glycopyrronium vs Salmeterol 0.55 0.33-0.92 Indacaterol/Glycopyrronium vs Vilanterol Indacaterol/Glycopyrronium vs 0.46 0.23-0.90 Umeclidinium Indacaterol/Glycopyrronium vs 0.68 0.50-0.93 0.67 0.44-1.03 1.00 522.00 Fluticasone/Salmeterol Umeclidinium/Vilanterol vs 1.81 1.00-3.27 Indacterol/Tiotropium Common within-network heterogeneity 0.01 variance Design-by-treatment interaction model 13.51(12,0.333,0.00) for inconsistency χ² (d.f., P-value, heterogeneity variance) 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 78 variance Design-by-treatment interaction model 9.51 (12, 0.659,0.00) for inconsistency χ² (d.f., P-value, heterogeneity variance) Pneumonia: 19 studies (2 four-arm, 4 three-arm, 13 two-arm), 18 treatments, 28763 patients 8.39 1.16-60.69 Budesonide/Formoterol vs Placebo 2.45 1.48-4.07 Fluticasone/Salmeterol vs Placebo 2.15 1.00-4.61 Salmeterol vs Budesonide 1.05- 11.02 Beclomethasone/Formoterol vs Budesonide 116.02 1.66- 13.42 Budesonide/Formoterol vs Budesonide 108.72 3.92 1.68-9.15 Fluticasone/Salmeterol vs Budesonide 1.24- 25.06 Budesonide/Formoterol vs Mometasone 506.42 Budesonide/Formoterol vs Formoterol 2.72 1.38-5.37 2.72 1.38-5.37 2.00 1290.00 2.08 1.10-3.93 Fluticasone/Salmeterol vs Indacaterol 1.82 1.02-3.26 Fluticasone/Salmeterol vs Salmeterol Fluticasone/Vilanterol vs Vilanterol 2.06 1.27-3.34 2.10 1.28-3.44 3.00 2031.00 2.24 1.14-4.41 Fluticasone/Salmeterol vs Glycopyrronium 7.97 1.10-57.95 Budesonide/Formoterol vs Tiotropium Fluticasone/Salmeterol vs Tiotropium 2.33 1.43-3.78 2.20 1.33-3.62 1.00 1323.00 Mometasone/Formoterol vs 0.12 0.02-0.88 Budesonide/Formoterol Indacaterol/Glycopyrronium vs 0.12 0.02-0.91 Budesonide/Formoterol Indacaterol/Glycopyrronium vs 0.41 0.21-0.80 0.11 0.01-2.09 1.00 522.00 Fluticasone/Salmeterol Common within-network heterogeneity 0.00 variance Design-by-treatment interaction model 4.88 (7, 0.675, 0.00) for inconsistency χ² (d.f., P-value, heterogeneity variance) Abbreviations: CI, Confidence Interval; d.f., degrees of freedom

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

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).

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

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).

Appendix 14. Included studies in our review versus previous Cochrane reviews Kew KM, Seniukovich A, 2014 Kew KM, Dias S, Cates CJ, 2014 Study [43 studies] [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

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

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

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

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

Appendix 15. Characteristics of new studies published since our search date Year Citation Trial Name/NCT Interventions Outcomes* Celli B, Crater G, Kilbride S, Mehta R, Tabberer M, Kalberg C et umeclidinium/vilanterol vs. 2014 al. Once-daily umeclidinium/vilanterol 125/25 mcg in COPD: a NCT01313637 umeclidinium vs. vilanterol vs. Mortality, Pneumonia, CVM randomized, controlled study. Chest. 2014; 145(5):981-991. placebo Chapman KR, Beeh K-M, Beier J, Bateman ED, D’Urzo A, Nutbrown R et al. A blinded evaluation of the efficacy and safety glycopyrronium+placebo vs. Mod/severe exacerbation, 2014 of glycopyrronium, a once-daily long-acting muscarinic GLOW5 tiotropium (HandiHaler)+placebo Serious arrhythmia antagonist, versus tiotropium, in patients with COPD: the GLOW5 study. BMC pulmonary medicine. 2014; 14(1):4. 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 umeclidinium/vilanterol vs. Mod/severe exacerbation, Mortality, 2014 NCT01316887 obstructive pulmonary disease: results from a 52-week, umeclidinium vs. placebo Pneumonia, Serious arrhythmia, CVM randomized, double-blind, placebo-controlled study. Respiratory research. 2014; 15(1):78. Dransfield MT, Feldman G, Korenblat P, LaForce CF, Locantore N, Pistolesi M et al. Efficacy and safety of once-daily fluticasone (NCT01323634, fluticasone/vilanterol vs. 2014 furoate/vilanterol (100/25 mcg) versus twice-daily fluticasone NCT01323621, Pneumonia, Serious arrhythmia fluticasone/salmeterol propionate/salmeterol (250/50 mcg) in COPD patients. Respiratory NCT01706328) medicine. 2014; 108(8):1171-1179. D’Urzo AD, Rennard SI, Kerwin EM, Mergel V, Leselbaum A, Caracta C. Efficacy and safety of fixed-dose combinations of aclidinium/formoterol (400/12 AUGMENT COPD Mortality, Pneumonia, 2014 aclidinium bromide/formoterol fumarate: the 24-week, μg) vs. aclidinium vs. formoterol (NCT01437397) Serious arrhythmia, CVM randomized, placebo-controlled AUGMENT COPD study. Respir vs. placebo Res. 2014; 15(1):123. Ferguson GT, Feldman GJ, Hofbauer P, Hamilton A, Allen L, Olodaterol Phase III Korducki L et al. Efficacy and safety of olodaterol once daily clinical program in COPD; olodaterol (5 μg Respimat) vs. Mortality, Pneumonia, 2014 delivered via Respimat® in patients with GOLD 2–4 COPD: NCT00782210, placebo CVM (for NCT00782210 only) results from two replicate 48-week studies. International journal of NCT00782509 chronic obstructive pulmonary disease. 2014; 9:629. Koch A, Pizzichini E, Hamilton A, Hart L, Korducki L, De Salvo MC et al. Lung function efficacy and symptomatic benefit of Olodaterol Phase III olodaterol once daily delivered via Respimat® versus placebo and clinical program in COPD; olodaterol (5 μg Respimat) vs. 2014 Mortality, Pneumonia formoterol twice daily in patients with GOLD 2–4 COPD: results NCT00793624, formoterol vs. placebo from two replicate 48-week studies. International journal of NCT00796653 chronic obstructive pulmonary disease. 2014; 9:697.. Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A. umeclidinium/vilanterol vs. Mortality, Pneumonia, 2014 Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and NCT01777334 tiotropium Serious arrhythmia, CVM tiotropium 18 mcg in chronic obstructive pulmonary disease:

results of a 24-week, randomized, controlled trial. Respiratory medicine. 2014; 108(12):1752-1760. Pepin J-L, Cockcroft JR, Midwinter D, Sharma S, Rubin DB, Andreas S. Long-acting bronchodilators and arterial stiffness in fluticasone/vilanterol vs. 2014 NCT01395888 Mortality, Pneumonia patients with COPD: a comparison of fluticasone furoate/vilanterol tiotropium (HandiHaler) with tiotropium. CHEST Journal. 2014; 146(6):1521-1530. 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 indacaterol vs. Mod/severe exacerbation, Mortality, 2014 INSTEAD; NCT01555138 salmeterol/fluticasone in moderate COPD. European Respiratory salmeterol/fluticasone Pneumonia, Serious arrhythmia Journal. 2014; 44(6):1548-1556. Singh D, Jones PW, Bateman ED, Korn S, Serra C, Molins E et al. Efficacy and safety of aclidinium bromide/formoterol fumarate aclidinium/formoterol (400/12 fixed-dose combinations compared with individual components ACLIFORM-COPD; Mod/severe exacerbation, Mortality, 2014 μg) vs. aclidinium vs. formoterol and placebo in patients with COPD (ACLIFORM-COPD): a NCT01462942 Pneumonia, Serious arrhythmia, CVM vs. placebo multicentre, randomised study. BMC pulmonary medicine. 2014; 14(1):178. Singh D, Nicolini G, Bindi E, Corradi M, Guastalla D, extrafine Kampschulte J et al. Extrafine Beclomethasone/formoterol FUTURE; Mortality, Pneumonia, 2014 beclomethasone/formoterol vs. compared to Fluticasone/salmeterol Combination Therapy in NCT01245569 Serious arrhythmia, CVM fluticasone/salmeterol COPD. BMC pulmonary medicine. 2014; 14(1):43. Trivedi R, Richard N, Mehta R, Church A. Umeclidinium in umeclidinium (125 μg) vs. 2014 patients with COPD: a randomised, placebo-controlled study. NCT01387230 Serious arrhythmia placebo European Respiratory Journal. 2014; 43(1):72-81. Wedzicha J, Singh D, Vestbo J, Paggiaro P, Jones P, Bonnet- extrafine Gonod F et al. Extrafine beclomethasone/formoterol in severe Mortality, Pneumonia, 2014 FORWARD beclomethasone/formoterol vs. COPD patients with history of exacerbations. Respiratory Serious arrhythmia formoterol medicine. 2014; 108(8):1153-1162. ZuWallack R, Allen L, Hernandez G, Ting N, Abrahams R. ANHELTO 1 and tiotropium (HandiHaler)+ Efficacy and safety of combining olodaterol Respimat® and ANHELTO 2 ; olodaterol (Respimat) vs. 2014 tiotropium HandiHaler® in patients with COPD: results of two Mortality NCT01694771, tiotropium (HandiHaler)+ randomized, double-blind, active-controlled studies. International NCT01696058 placebo (Respimat) journal of chronic obstructive pulmonary disease. 2014; 9:1133. Rennard SI, Scanlon PD, Ferguson GT, Rekeda L, Maurer BT, Gil EG et al. ACCORD COPD II: a randomized clinical trial to ACCORD COPD II; 2013 evaluate the 12-week efficacy and safety of twice-daily aclidinium placebo vs. aclidinium (400 μg) Mortality, Serious arrhythmia NCT01045161 bromide in chronic obstructive pulmonary disease patients. Clinical drug investigation. 2013; 33(12):893-904. Notes: *Outcomes from our NMA that were assessed as outcomes in the trial Abbreviations: CVM, Cardiovascular related mortality; Mod/severe, Moderate/severe

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