bmj open€¦ · journal: bmj open manuscript id: bmjopen-2015-009183 article type: research date...

For peer review only

Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease:

A systematic review and network meta-analysis

Journal: BMJ Open

Manuscript ID: bmjopen-2015-009183

Article Type: Research

Date Submitted by the Author: 23-Jun-2015

Complete List of Authors: Tricco, Andrea; Li Ka Shing Knowledge Institute of St Michael's Hospital Strifler, Lisa; Li Ka Shing Knowledge Institute of St Michael's Hospital Veroniki, Areti Angeliki; Li Ka Shing Knowledge Institute of St Michael's

Hospital Yazdi, Fatemeh; Ottawa Hospital Research Institute, Center for Practice Changing Research Khan, Paul; Li Ka Shing Knowledge Institute of St Michael's Hospital Scott, Alistair; Li Ka Shing Knowledge Institute of St Michael's Hospital Ng, Carmen; Li Ka Shing Knowledge Institute of St Michael's Hospital Antony, Jesmin; Li Ka Shing Knowledge Institute of St Michael's Hospital Mrklas, Kelly; Alberta Health Services, ; Li Ka Shing Knowledge Institute of St Michael's Hospital D'Souza, Jennifer; Li Ka Shing Knowledge Institute of St. Michael's Hospital, Cardoso, Roberta; Li Ka Shing Knowledge Institute of St. Michael's

Hospital, Straus, Sharon; Li Ka Shing Knowledge Institute of St. Michael's Hospital,

<b>Primary Subject Heading</b>:

Respiratory medicine

Secondary Subject Heading: Evidence based practice, Research methods, Pharmacology and therapeutics

Keywords: Pulmonary Disease, Chronic Obstructive , Emphysema < THORACIC MEDICINE, Pulmonary Emphysema, Network Meta-analysis, Systematic Review

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Comparative safety and effectiveness of long-acting inhaled agents for treating chronic 1

obstructive pulmonary disease: A systematic review and network meta-analysis 2

Andrea C Tricco1,2

; Lisa Strifler1; Areti-Angeliki Veroniki

1; Fatemeh Yazdi

3; Paul A. Khan

1; 3

Alistair Scott1; Carmen Ng

1; Jesmin Antony

1; Kelly Mrklas

1,4; Jennifer D’Souza

1; Roberta 4

Cardoso1; Sharon E Straus

*1,5 5

6

1Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, 209 7

Victoria Street, East Building. Toronto, Ontario, M5B 1T8, Canada 8

2Epidemiology Division, Dalla Lana School of Public Health, University of Toronto, 155 9

College Street, 6th floor, Toronto, Ontario, M5T 3M7, Canada 10

3Ottawa Hospital Research Institute, Center for Practice Changing Research Building, The 11

Ottawa Hospital- General Campus, 501 Smyth Road/PO Box 201B, Ottawa, Ontario, K1H 8L6, 12

Canada 13

4Alberta Health Services, Seventh Street Plaza, 10030 – 107 Street NW, Edmonton, Alberta, T5J 14

3E4, Canada 15

5Department of Geriatric Medicine, University of Toronto, 27 Kings College Circle. Toronto, 16

Ontario M5S 1A1, Canada 17

18

Word count: 299 (abstract), 3670 (main text), 3 figures, 3 tables, 14 appendices. 19

20

Corresponding Author: 21

Dr. Sharon E. Straus, MSc, MD 22

Director, Knowledge Translation program, 23

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Li Ka Shing Knowledge Institute, St. Michael’s Hospital 24

209 Victoria Street, East Building, Room 716, Toronto, Ontario, M5B 1T8, Canada 25

Email: [email protected] 26

Phone: 416-864-3068, fax: 416-864-5805 27

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ABSTRACT 28

Objective: To compare the safety and effectiveness of long-acting beta-antagonists (LABA), 29

long-acting anti-muscarinic agents (LAMA), and inhaled corticosteroids (ICS) for managing 30

chronic obstructive pulmonary disease (COPD). 31

Setting: Systematic review and network meta-analysis (NMA). 32

Participants: 208 studies including 134,692 adults with COPD. 33

Interventions: LABA, LAMA, and/or ICS versus each other or placebo. 34

Primary and secondary outcomes: The proportion of patients with moderate-to-severe 35

exacerbations was the primary outcome, while the number of patients experiencing mortality, 36

pneumonia, arrhythmia, and cardiovascular-related mortality were secondary outcomes. 37

Results: NMA was conducted including 20 RCTs for moderate-to-severe exacerbations for 38

26,141 patients with an exacerbation in the past year. Thirty-two treatments were effective, 39

including the following for reducing exacerbations versus placebo: tiotropium, 40

budesonide/formoterol, salmeterol, indacaterol, fluticasone/salmeterol, 41

indacaterol/glycopyrronium, tiotropium/fluticasone/salmeterol, and 42

tiotropium/budesonide/formoterol. The most effective was tiotropium/budesonide/formoterol 43

(99.2% probability of being the most effective according to the Surface Under the Cumulative 44

RAnking [SUCRA] curve). 45

A NMA was conducted on mortality (88 RCTs, 97,526 patients); fluticasone/salmeterol was 46

more effective in reducing mortality than placebo, formoterol, and fluticasone alone, and was the 47

most effective (SUCRA=71%). 48

A NMA was conducted on cardiovascular-related mortality (CVM, 37 RCTs, 55,156 patients). 49

The following were the safest in reducing CVM: salmeterol versus each placebo, tiotropium, and 50

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tiotropium (Soft Mist Inhaler [SMR]); fluticasone versus tiotropium (SMR); and 51

salmeterol/fluticasone versus tiotropium and tiotropium (SMR). Triamcinolone acetonide was 52

the most harmful (SUCRA=81% for CVM harm). 53

A NMA was conducted on pneumonia occurrence (54 RCTs, 61,551 patients). Twenty-four 54

treatments were more harmful, including two that increased risk of pneumonia versus placebo; 55

fluticasone and fluticasone/salmeterol. The most harmful agent was fluticasone/salmeterol 56

(SUCRA=89% for pneumonia harm). 57

A NMA was conducted for arrhythmia presence; no differences between the agents were 58

identified. 59

Conclusions: Many inhaled agents are available for COPD, some are more effective than others 60

and some may increase the risk of harm. 61

Protocol registration number: PROSPERO # CRD42013006725 62

Keywords: Pulmonary Disease, Chronic Obstructive; Emphysema; Pulmonary Emphysema; 63

Systematic Review; Network Meta-analysis. 64

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STRENGTHS AND LIMITATIONS OF THIS STUDY: 65

• We included >200 randomized trials and this is one of the most comprehensive 66

systematic reviews in this area 67

• We follow the methodologically rigourous guidelines put forth by the Cochrane 68

Collaboration 69

• We conducted a network meta-analysis in accordance with guidance put forth by the 70

International Society For Pharmacoeconomics and Outcomes Research 71

• Many of the included randomized trials were at a high risk of bias for many of the 72

Cochrane risk-of-bias criteria 73

• We were unable to explore other important effect modifiers, such as duration of treatment 74

administration, as this was inconsistently reported across the included randomized trials 75

76

BACKGROUND 77

Evidence from previous systematic reviews and network meta-analyses suggests that inhaled 78

therapy with inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting 79

muscarinic antagonists (LAMA) for patients with chronic obstructive pulmonary disease 80

(COPD) is promising.[1-9] However, to date, it is not clear which combinations of inhaled 81

therapies are the safest and most effective for these patients for all relevant outcomes. In order to 82

examine this issue further, we conducted a systematic review and network meta-analysis. This 83

work is part of a Drug Class Review conducted by the Ontario Drug Policy Research Network 84

(ODPRN) that was funded by the Ontario Ministry of Health and Long-Term Care Health 85

System Research Fund. Our research question was “what is the comparative safety and 86

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effectiveness of long-acting inhaled agents (ICS, LABA, LAMA), alone or in any combination, 87

for patients with COPD?” 88

89

METHODS 90

Protocol 91

Our systematic review protocol was drafted using the Preferred Reporting Items for Systematic 92

reviews and Meta-analyses for Protocols (PRISMA-P) guidance.[10] The protocol was revised 93

based on feedback from various stakeholders, including policy makers from the Ontario Public 94

Drug Programs, industry stakeholders, patients, researchers within the ODPRN, and health care 95

professionals. The final protocol was registered with the PROSPERO registry 96

(CRD42013006725) and posted on the ODPRN website.[11] Since our full methods have been 97

posted online, they are summarized briefly here. 98

Eligibility criteria 99

Parallel-group randomized clinical trials (RCTs) including adults with COPD administered long-100

acting inhaled agent in any combination compared with each other or placebo were eligible for 101

inclusion. Concomitant COPD medications were included if both groups received the same 102

interventions (e.g., rescue medication with a short-acting beta-agonist). A list of included agents 103

can be found in Supplementary File: Appendix 1. A list of the excluded medications can be 104

found in Supplementary File: Appendix 2. 105

The primary outcome of interest was the proportion of patients with moderate-to-severe 106

exacerbations (i.e., worsening of COPD symptoms that may require hospitalization, emergency 107

department visits, treatment with oral steroids and/or antibiotics, use of rescue medication, or 108

unscheduled visits to a walk-in clinic or to a healthcare provider). Secondary outcomes included 109

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the number of patients experiencing mortality, pneumonia, arrhythmia, and cardiovascular-110

related mortality. Outcomes were selected based on feedback from patients with COPD and other 111

stakeholders through a survey (Supplementary File: Appendix 3). The results of the survey 112

appear in Supplementary File: Appendix 4; these have been disseminated online.[12] 113

RCTs were included regardless of duration of follow-up, date of dissemination, or publication 114

status. Due to feasibility constraints, we limited inclusion to English language articles; this has 115

not been shown to bias meta-analysis estimates in the past.[13] Due to the large number of 116

unpublished citations conference abstracts identified, we limited inclusion of unpublished data to 117

abstracts from 2004 onwards because this is more likely to capture unreported data given the 118

greater than the average time it takes for a RCT to be published.[14] 119

Information sources and literature search 120

An experienced librarian conducted comprehensive literature searches in MEDLINE, EMBASE, 121

and the Cochrane Central Register of Controlled Trials from inception until December 2013. The 122

MEDLINE search was peer-reviewed by another experienced librarian using the Peer Review of 123

Electronic Search Strategies (PRESS) checklist,[15] and revised as necessary (Supplementary 124

File: Appendix 5). This was supplemented by manual searching of the reference lists of included 125

studies and relevant reviews.[1-9, 16] 126

Study selection process 127

Only when >90% agreement was achieved through a training exercise, pairs of reviewers 128

screened citations for inclusion, independently. The same process was followed for screening 129

potentially relevant full-text articles. Conflicts were resolved by discussion or the involvement of 130

a third reviewer (ACT or SES). 131

Data items and data abstraction process 132

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After a calibration exercise, study characteristics (e.g., year of conduct, sample size, setting) 133

patient characteristics (e.g., number of patients, age mean age and standard deviation) and the 134

definitions of outcome definitions (e.g., exacerbations [i.e., number of patients with at least 1 135

exacerbation in the past year]) were abstracted independently by pairs of reviewers, 136

independently. To ensure data integrity for the abstracted data, all data were verified by a third 137

reviewer (LS, FY, or AS). Since the Global Initiative for Chronic Obstructive Lung Disease 138

(GOLD) criteria have changed over time, a clinician (SES) reviewed all of the included studies 139

to ascertain the average COPD severity of the patients included in each RCT. 140

Risk of bias and methodological quality appraisal process 141

After a calibration exercise, pairs of reviewers independently assessed each of the included RCTs 142

using the 7-item Cochrane Risk-of-Bias tool.[17] 143

Synthesis 144

A restricted maximum likelihood (REML) method [18] and the I2 statistic [19] were used to 145

estimate the magnitude and measure the between-study heterogeneity variance in meta-analysis, 146

respectively. A random-effects network meta-analysis was conducted because we anticipated 147

that the treatment effects were heterogeneous across the included RCTs. We assumed common 148

heterogeneity across treatment comparisons. As the included treatments are of the same nature, it 149

is clinically reasonable to share a common heterogeneity parameter. Treatment nodes of the 150

network were selected based on input from clinicians, methodologists, and statisticians on the 151

team. 152

Before conducting the analyses, we assessed the transitivity assumption by exploring whether 153

any systematic differences were prevalent in the distribution of potential treatment effect 154

modifiers across treatment comparisons in the network. For each outcome, we examined the 155

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percentage of female participants in the RCTs and the risk of bias results. For the moderate-to-156

severe exacerbations outcome, we also examined RCTs with eligibility criteria focusing on 157

patients who experienced an exacerbation in the past year and severity of COPD. 158

To evaluate the consistency assumption, we evaluated the network as a whole using the design-159

by-treatment interaction model.[20] If inconsistency was prevalent, the loop-specific method was 160

used to identify local inconsistency in parts of the network.[21-23] When important 161

inconsistency and/or heterogeneity were observed, we assessed for potential data abstraction 162

errors, and if none were identified, we conducted a sub-group network meta-analysis on the 163

potential treatment effect modifiers. We explored the effect of study duration in a random-effects 164

meta-regression analysis for mortality and exacerbation outcomes, assuming a common fixed 165

coefficient across treatment comparisons. To assess the robustness of our results, we conducted a 166

sensitivity analysis limiting all of the analyses to studies with a low risk of bias according to the 167

randomization and allocation concealment components. 168

Summary treatment effects (odds ratios [ORs]) from the network meta-analysis are presented, 169

along with their respective 95% confidence intervals (CI) and 95% predictive intervals (PrI). The 170

PrI is more conservative than the CI and indicates the possible treatment effects, should an 171

additional study become available.[24, 25] It should be noted that a PrI is available only when 172

the difference between the number of studies in the network and the number of available direct 173

comparisons is greater than 2. A comparison-adjusted funnel plot was used to investigate the 174

association between effect size and its standard error (the latter is closely related to study size). If 175

a relationship exists, this can be due to publication or related biases or due to systematic 176

differences between small and large studies.[26] A treatment hierarchy was also obtained using 177

the SUrface under the Cumulative RAnking (SUCRA) curve analysis which allows the ranking 178

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of interventions according to the probability of being the most effective for each outcome (e.g., 179

most effective at reducing the risk of exacerbations, most harmful at increasing the risk of 180

cardiovascular-related mortality) .[27] 181

Model fit 182

Random-effects meta-analyses were undertaken in R 3.1.2 using the meta package,[28, 29] while 183

random-effects network meta-analyses were conducted in STATA 13.1 using the mvmeta 184

command.[30, 31] We implemented network meta-regression analyses in OpenBUGS 3.2.3,[32] 185

using 100,000 simulations with a thinning rate of 10 after discarding the first 30,000 iterations. 186

Convergence was assessed by visual inspection of the mixing of 2 chains with different initial 187

values. We assumed a vague prior for the coefficient parameter (�(0,10�)) and an informative 188

prior for the between-study variance, as suggested by Turner et al. [33] 189

(�~�� (−2.13,1.58)). 190

191

RESULTS 192

Literature search 193

The literature search yielded a total of 2,447 titles and abstracts (Figure 1). Of these, 980 articles 194

were potentially relevant and their full-text was reviewed. Subsequently, 203 RCTs providing 195

data on 208 RCTs (some trials reported the results from more than one study) plus 58 companion 196

reports fulfilled our eligibility criteria and were included. The list of the included studies can be 197

found in Supplementary File: Appendix 6. Twenty of the included studies were unpublished. 198

Study and patient characteristics 199

The year of publication ranged from 1989 to 2014 (Table 1, Supplementary File: Appendix 7). 200

Most RCTs were multi-center trials conducted across numerous countries. The duration of 201

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treatment with long-acting inhaled agents ranged from 9 hours to almost 4 years. Most of the 202

RCTs reported moderate-to-severe COPD exacerbations (54%) and mortality (46%). The 203

presence of arrhythmia was the least frequently reported outcome (15% of studies). 204

The total number of patients across the RCTs was 134,692, with an average of 648 patients per 205

trial (Table 2, Supplementary File: Appendix 8). The severity of COPD was most commonly 206

moderate-to-severe or moderate-to-very severe (61%) in nature. The percentage of females in the 207

included studies ranged from 0 to 58%. 208

Risk of bias 209

Across the included RCTs, the majority had an unclear random sequence generation (63%) and 210

unclear allocation concealment (84%) risk of bias (Figure 2, Supplementary File: Appendix 9). 211

In addition, the majority had an unclear risk of bias (55%) related to selective outcome reporting, 212

as the outcomes reported in the trial protocols differed from those reported in the final 213

publication. Finally, many of the RCTs had a high (52%) or unclear (39%) risk of bias due to the 214

‘other bias’ item, mainly owing to the potential for funding bias as many studies were funded by 215

a pharmaceutical company and included study authors who were employed by the drug 216

manufacturer. Finally, visual inspection of the comparison adjusted funnel plots showed that 217

there was no evidence for small-study effects and publication bias across all analyses. 218

Moderate-to-severe exacerbations 219

A network meta-analysis was attempted with 112 RCTs including 77,749 patients and 26 inhaled 220

treatments for patients presenting with moderate-to-severe exacerbations (i.e., worsening of 221

COPD symptoms that may require hospitalization, emergency department visits, treatment with 222

oral steroids and/or antibiotics, use of rescue medication, unscheduled walk-in clinic/healthcare 223

provider visits). However, significant inconsistency was observed between direct and indirect 224

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evidence (χ2=80.74, degrees of freedom=51, P-value=0.005, heterogeneity variance=0.01). As 225

such, a sub-group network meta-analysis was conducted including only those trials with patients 226

who had experienced an exacerbation in the past year (Figure 3: Panel A). For this analysis, 20 227

RCTs were included with 26,141 patients and 17 treatments; there was no evidence of statistical 228

inconsistency (χ2=3.37, degrees of freedom=4, P-value=0.50, heterogeneity variance=0.00). Of 229

the 136 treatment comparisons in the network meta-analysis model, 32 were statistically 230

significant (Table 3, Supplementary File: Appendices 10 and 11) and eight of these were more 231

effective than placebo in reducing the risk of moderate-to-severe exacerbations: tiotropium, 232

salmeterol, indacaterol, budesonide/formoterol, fluticasone/salmeterol, 233


tiotropium/budesonide/formoterol. The most effective were tiotropium/budesonide/formoterol 235

(99% probability of being the most effective in reducing exacerbations) and 236

indacaterol/glycopyrronium (86%) according to the SUCRA curves (Supplementary File: 237

Appendix 12). 238

A sensitivity analysis was conducted with studies at a low risk of randomization and allocation 239

concealment biases. Based on 25 RCTs, 20 treatments, and 33,211 patients meeting these 240

criteria, 190 treatment comparisons were made in the network meta-analysis model. Twenty-four 241

of these were statistically significant, including three that reduced the risk of moderate-to-severe 242

exacerbations compared to placebo; fluticasone, indacaterol/tiotropium, and 243

indacaterol/glycopyrronium (Supplementary File: Appendix 13). The most effective agent was 244

fluticasone according to the SUCRA curves (96%), which was followed by 245

indacaterol/glycopyrronium (80%), and mometasone/formoterol (80%). A statistically significant 246

association was not observed in our meta-regression analysis conducted using the study duration 247

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as a covariate (estimated coefficient: 1.01 (95% credible interval (CrI): 0.41, 2.41), heterogeneity 248

variance=0.02). 249

Mortality 250

Six studies were excluded from the analysis because they reported 0 events in all relevant 251

treatment arms.[34-39] As such, a network meta-analysis was conducted with 88 RCTs, 28 252

treatments, and 97,526 patients (Figure 3: Panel B). There was no evidence of statistical 253

inconsistency (χ2=31.44, degrees of freedom=50, P-value=0.98, heterogeneity variance=0.00). 254

Of the 378 treatment comparisons in the network meta-analysis model, only 3 were statistically 255

significant. Fluticasone/salmeterol combination therapy resulted in a reduced risk of mortality 256

compared with placebo, formoterol, and fluticasone alone (Table 3, Supplementary File: 257

Appendices 10 and 11). The most effective agent in having a reduced risk of mortality was 258

fluticasone/salmeterol as determined by the SUCRA curves (71%) (Supplementary File: 259

Appendix 12). 260

A sensitivity analysis was conducted with studies at a low risk of randomization generation and 261

allocation concealment biases. Based on 23 RCTs, 21 treatments, and 33,624 patients, 210 262

treatment comparisons were made in the network meta-analysis model. Four of these were 263

statistically significant, as follows: fluticasone/salmeterol was superior to placebo, salmeterol 264

alone, tiotropium, and vilanterol (Supplementary File: Appendix 13). The most effective agent 265

was the inhaled combination of fluticasone/salmeterol (90%) according to the SUCRA curves. A 266

statistically significant association was not observed in our meta-regression analysis conducted 267

using the study duration as a covariate (estimated coefficient 1.00 (95% CrI: 0.88, 1.14), 268

heterogeneity variance=0.03). 269

Cardiovascular-related mortality 270

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Nine studies were excluded from the analysis because they reported 0 events in all relevant 271

treatment arms.[34-42] As such, a network meta-analysis was conducted including 37 RCTs, 20 272

treatments, and 55,156 patients (Figure 3: Panel C). There was no evidence of statistical 273

inconsistency (χ2=13.05, degrees of freedom=24, P-value=0.97, heterogeneity variance=0.00). A 274

total of 190 treatment comparisons were made in the network meta-analysis model and the 275

following six were statistically significant: salmeterol had a decreased risk of cardiovascular-276

related mortality versus placebo, tiotropium (Handihaler), and tiotropium (Soft Mist Inhaler). In 277

addition, fluticasone was superior to tiotropium (Soft Mist Inhaler); and the 278

salmeterol/fluticasone combination was superior to both tiotropium (Handihaler) and tiotropium 279

(Soft Mist Inhaler) (Table 3, Supplementary File: Appendices 10 and 11). None of these 280

treatment comparisons remained statistically significant according to the PrI, except for 281

salmeterol versus tiotropium (Soft Mist Inhaler). According to the SUCRA curves 282

(Supplementary File: Appendix 12), the following were the most harmful: triamcinolone 283

acetonide (81% probability of being the most harmful because of a greater risk of cardiovascular-284

related mortality), formoterol/budesonide (73%), and vilanterol/umeclidinium (73%). However, 285

these particular SUCRA results should be interpreted with caution, as some of these 286

interventions were not statistically different from the other agents according to the effect sizes 287

and 95% CIs. 288

A sensitivity analysis was conducted including only studies with a low risk of bias for 289

cardiovascular-related mortality with 11 RCTs, 12 treatments, 16,443 patients, and 66 treatment 290

comparisons; none of the results were statistically significant. 291

Pneumonia 292

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One study was excluded from the analysis for reporting 0 events in all treatment arms.[39] As 293

such, 54 RCTs including 21 treatments, and 61,551 patients were included in a network meta-294

analysis for pneumonia (Figure 3: Panel D). There was no evidence of statistical inconsistency 295

(χ2=34.33, degrees of freedom=31, P-value=0.31, heterogeneity variance=0.00). A total of 210 296

treatment comparisons were made in the network meta-analysis model; 24 were statistically 297

significant (Table 3, Supplementary File: Appendices 11 and 12). Of these, two agents had a 298

greater risk of pneumonia versus placebo; fluticasone and fluticasone/salmeterol. The following 299

were the most harmful agents because they had a greater risk of pneumonia; 300

fluticasone/salmeterol (SUCRA=89%), fluticasone/vilanterol (SUCRA=88%), and fluticasone 301

(SUCRA=82%) (Supplementary File: Appendix 12). 302

A sensitivity analysis was conducted including only studies with a low risk of bias with 19 303

RCTs, 18 treatments, and 28,763 patients. There were 153 treatment comparisons in the network 304

meta-analysis model and 17 were statistically significant (Supplementary File: Appendix 13) 305

including two that were more harmful than placebo because they had a greater risk of 306

pneumonia; budesonide/formoterol and fluticasone/salmeterol. The most harmful agents were 307

budesonide/formoterol (SUCRA=94%), beclomethasone/formoterol (SUCRA=89%), and 308

fluticasone/salmeterol (SUCRA=78%). 309

Arrhythmia 310

Five studies were excluded from the analysis because they reported 0 events in all treatment 311

arms.[39, 43-46] As such, a network meta-analysis was conducted including 26 RCTs, 12 312

treatments, and 27,407 patients (Figure 3: Panel E). None of the 66 treatment comparisons were 313

statistically significant (Supplementary File: Appendices 11 and 12) and no evidence of 314

statistical inconsistency was observed (χ2=3.06, degrees of freedom=11, P-value=0.99, 315

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heterogeneity variance=0.36). The same results were observed in a sensitivity analysis involving 316

6 studies at low risk of bias with 7 treatments, 13,060 patients, and 22 treatment comparisons. 317

318

DISCUSSION 319

For risk of a moderate-to-severe COPD exacerbation, we could not complete a network meta-320

analysis overall because the data were inconsistent. Here we were able to present results of our 321

network meta-analysis for moderate-to-severe COPD exacerbation amongst patients who had 322

experienced an exacerbation in the past year. We found that tiotropium/budesonide/formoterol 323

and indacaterol/glycopyrronium combinations were the most effective inhaled agents at 324

minimizing the risk of a moderate-to-severe COPD exacerbation. Furthermore, we performed 325

sensitivity analysis for moderate-to-severe exacerbations which included all studies rated as 326

scoring a low risk of bias on the randomization and allocation concealment components. For this 327

network meta-analysis, fluticasone, indacaterol/glycopyrronium, and mometasone/formoterol 328

were the most effective agents at reducing the risk of moderate-to-severe COPD exacerbations. 329

Our results are similar to a previously published network meta-analysis funded by industry 330

(Merck, Dhome, and Nycomed) that included 35 RCTs with 26,786 patients concluded that 331

combination therapy with an ICS and LABA is likely superior to single therapy regarding 332

exacerbations.[9] A second network meta-analysis of inhaled drugs for COPD concluded that 333

ICS/LABA combination therapy reduced exacerbations only in patients with low forced 334

expiratory volume.[8] 335

We also analyzed all-cause mortality in a network meta-analysis and found that the most 336

effective agent was fluticasone/salmeterol because it had a decreased risk of mortality compared 337

with the other agents. These results were consistent when we limited the analysis to those studies 338

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with a low risk of bias. We also conducted a network meta-analysis on cardiovascular-related 339

mortality and found that use of tiotropium Handihaler and/or tiotropium Soft Mist Inhalers 340

increased the risk compared to some of the other agents. However, in our sensitivity analysis 341

including only studies with a low risk of allocation concealment or randomization bias no 342

statistically significant results were observed, suggesting that these particular results should be 343

interpreted with caution. 344

Our mortality results are different, yet the cardiovascular-related mortality results are similar to a 345

previously published network meta-analysis including 42 trials (52,516 patients) involving 346

patients allocated to tiotropium Soft Mist Inhalers, tiotropium HandiHalers, ICS+LABA, LABA, 347

ICS or placebo.[47] Patients receiving the tiotropium Soft Mist Inhalers had the greatest risk of 348

mortality overall, as well as cardiovascular-related mortality. 349

A recent Cochrane review and network meta-analysis compared four classes of long acting 350

inhalers for COPD (ICS, LABA, ICS/LABA combination, and LAMA) for 2 efficacy outcomes: 351

mean trough forced expiratory volume in one second (FEV1) and mean total score on the St 352

George’s Respiratory Questionnaire (SGRQ).[48] In their review, 71 RCTs with 73,062 patients 353

were included. As this recent Cochrane review and network meta-analysis did not examine 354

outcomes pertaining to either exacerbations or mortality, there is no overlap in results with our 355

review. 356

We found that the following were the most harmful agents for being associated with increasing 357

risk of pneumonia: fluticasone/salmeterol, fluticasone/vilanterol, and fluticasone according to the 358

SUCRA. These results are consistent with a recent Cochrane review on ICS, LABA and 359

ICS/LABA combination which looked at pneumonia in patients with COPD.[49] Those study 360

authors found an increased risk of pneumonia with fluticasone use versus placebo and for any 361

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fluticasone/LABA combination versus LABA alone. However, our pneumonia sensitivity 362

analysis including studies with a low risk of bias found that the most harmful agents that 363

increased the risk of pneumonia were budesonide/formoterol, beclomethasone/formoterol, and 364

fluticasone/salmeterol. Of note, we included 132 more studies comprising 56,727 more patients 365

than the previous Cochrane reviews (Supplementary File: Appendix 14). 366

We found no differences in risks of arrhythmia across any of the compared agents in our rapid 367

review. This finding is clinically important as clinicians have raised concerns about increasing 368

risk of arrhythmia with use of LABA.[50-52] We are unaware of any other network meta-369

analysis that examines this outcome for patients with COPD. We also attempted a network meta-370

analysis for the dyspnea outcome, yet the results were unreliable so are not presented here, 371

despite numerous sub-group and sensitivity analyses. Such an analysis should be attempted in the 372

future, perhaps utilizing advanced individual patient data network meta-analysis techniques that 373

are currently emerging. 374

There are some limitations of our systematic review that are worth noting. First, we are aware of 375

a handful of new trials that have been presented or published since our original literature search 376

in December of 2013. This is particularly apparent for the LABA/LAMA combinations. 377

However, the current review is one of the largest published network meta-analyses [53] and we 378

have included 208 RCTs and 134,692 patients and we believe that our results for the other agents 379

are valid. Second, many of the included RCTs were at a high risk of bias for many of the 380

Cochrane risk-of-bias criteria, especially for important items such as random sequence 381

generation and allocation concealment, which are imperative for the internal validity of a RCT. 382

In order to address this limitation, we conducted a sensitivity analysis for all outcomes, which 383

focused on inclusion of studies with a low risk of bias in the analysis. Third, we were unable to 384

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explore other important effect modifiers, such as duration of treatment administration, as this 385

was inconsistently reported across the included RCTs. Fourth, given the inconsistency across the 386

data, we could not complete a network meta-analysis for risk of moderate-to-severe 387

exacerbations overall. Fifth, we limited inclusion to RCTs published in English, yet this has not 388

been shown to bias meta-analysis results in the past.[13] Finally, we were unable to calculate the 389

PrI for all outcomes, due to the small number of studies included in the exacerbations and 390

sensitivity analyses. 391

In conclusion, tiotropium/budesonide/formoterol inhaled combination therapy reduces risk of 392

moderate-to-severe exacerbations in patients having already experienced a COPD-related 393

exacerbation in the past year. Inhaled fluticasone/salmeterol reduces risk of mortality, yet may 394

increase risk of pneumonia. Tiotropium may increase risk of cardiovascular-related mortality. 395

These agents likely do not increase risk of arrhythmia. Future research should update our review 396

to include studies examining the LABA/LAMA combination, as well as the dyspnea outcome, as 397

we were presently unable to conduct a network meta-analysis on this. 398

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SUPPLEMENTARY FILES 399

File name: Supplementary File.pdf 400

File format: Adobe Acrobat Document (.pdf) 401

Title of the Data: Appendix 1-14 402

403

Description of Data: Protocol 404

File name: Protocol.pdf 405


Title of the Data: Study Protocol 407

408

ACKNOWLEDGEMENTS 409

We thank Becky Skidmore for conducting the literature search and Heather McDonald for peer 410

reviewing the search, Inthuja Selvaratnam for formatting the paper, and Alissa Epworth for 411

obtaining the full-text articles. We also thank Sandra Knowles for all of her support and useful 412

feedback on the draft manuscript. 413

414

AUTHORS’ CONTRIBUTIONS 415

ACT conceived and designed the study, helped obtain funding for the study, screened citations, 416

abstracted data, guided the analysis, interpreted the results, and drafted the manuscript. LS 417

coordinated the review, screened citations and full-text articles, abstracted data, cleaned the data, 418

wrote sections of the manuscript, and edited the manuscript. AAV analyzed and interpreted the 419

data, wrote sections of the manuscript, and edited the manuscript. FY screened citations and full-420

text articles, abstracted data, appraised quality, cleaned the data, and edited the manuscript. PAK 421

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abstracted data, appraised quality, cleaned the data, and edited the manuscript. AS screened 422

citations and full-text articles, abstracted data, helped clean the data, and edited the manuscript. 423

CN screened full-text articles, abstracted data, and edited the manuscript. JA screened citations 424

and full-text articles, abstracted data, and edited the manuscript. KM abstracted data, and edited 425

the manuscript. JD screened citations and full-text articles, and edited the manuscript. RC 426

abstracted data, helped clean the data, and edited the manuscript. SES conceived and designed 427

the study, helped obtain funding for the study, guided the analysis, interpreted the results, and 428

edited the manuscript. All authors read and approved the final paper. 429

430

FUNDING 431

This study was funded by the Ontario Ministry of Health and Long-Term Care Health System 432

Research Fund. ACT is funded by a Canadian Institutes of Health Research (CIHR)/Drug Safety 433

and Effectiveness Network New Investigator Award in Knowledge Synthesis. SES is funded by 434

a Tier 1 Canada Research Chair in Knowledge Translation. AAV is funded by the CIHR Banting 435

Postdoctoral Fellowship Program. 436

437

COMPETING INTERESTS 438

None. 439

440

DATA SHARING STATEMENT 441

The full data set is available, including data from the 20 included unpublished studies, on request 442

from the corresponding author (SES, [email protected]).443

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444

Table 1. Study characteristics

Characteristic No. of studies* (n=208) % of studies

Year of publication

1989–1994 3 1.4

1995–1999 15 7.2

2000–2004 35 16.8

2005–2009 68 32.7

2010–2014 87 41.8

Geographic region

Europe 72 34.6%

Multi-continent 44 21.2%

North America 36 17.3%

Multi-country (not specified) 24 11.5%

Asia 20 9.6%

Not reported 9 4.3%

Africa 1 0.5%

Australia 1 0.5%

South America 1 0.5%

Setting

Single centre 32 15.4

Multi-centre 152 73.1

Not reported 24 11.5

Duration of follow-up†

0 to ≤ 6 45 21.6

> 6 to ≤ 12 52 25

> 12 to ≤ 24 35 16.8

> 24 to ≤ 48 19 9.1

> 48 to ≤ 72 39 18.8

> 72 to ≤ 96 2 1

>96 to ≤ 120 6 2.9

> 120 weeks 9 4.3

Not reported 1 0.5

Outcomes examined: frequency§

Efficacy - Exacerbations 112 53.8

Efficacy - Mortality 95 45.7

Harm - Cardiovascular –related mortality 46 22.1

Harm - Pneumonia 54 26.0

Harm - Arrhythmia 32 15.4 *Includes unpublished data

†Duration is in weeks unless otherwise noted; §Multiple interventions and outcomes

reported per study.

Abbreviations: NR; not reported

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445

Table 2. Patient characteristics

Total number of patients 134692

Mean sample size 648

Mean % female 27.7%

Characteristic No. of studies* (n=) % of studies

Age Category

Adult & Elderly ( ≥18) 195 93.8

Adult (18-64) 4 1.9

Elderly ( ≥65) 0 0.0

NR 9 4.3

Severity of COPD

Mild to moderate 10 4.8

Mild to severe 9 4.3

Mild to very severe 8 3.8

Moderate 7 3.4

Moderate to severe 60 28.9

Moderate to very severe 67 32.2

Severe 5 2.4

Severe to very severe 6 2.9

Stable (severity NR) 5 2.4

NR 31 14.9

% Female

0-25% 90 43.3

26%-50% 104 50

51-100% 4 1.9

Not reported 10 4.8

Note: *Includes unpublished studies. Abbreviation: NR; not reported

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Table 3. Statistically Significant Network Meta-analysis Results

Treatment

Comparison

NMA

estimate OR

(95 % CI) CI

MA estimate

OR (95 %

CI) CI

# studies

(# patients) Heterogeneity

Variance

Exacerbation Past year – 20 studies, 17 treatments, 26141 patients

FLUT/SALM vs SALM 0.85 0.75-0.97 0.82 0.70-0.95 4 (2784) 0.00

TIOT vs INDAC 0.83 0.72-0.96 0.83 0.72-0.96 1 (3439) --

TIOT vs SALM 0.82 0.73-0.93 0.84 0.76-0.92 1 (7376) --

SALM vs Placebo 0.79 0.64-0.97 0.80 0.58-1.09 1 (634) --

INDAC vs Placebo 0.78 0.61-1.00 . . . .

BUDE/FORM vs FORM 0.76 0.64-0.91 0.76 0.62-0.93 4 (3080) 0.01

FLUT/F vs VILA 0.75 0.62-0.92 0.75 0.61-0.94 2 (1624) 0.00

INDAC/GLYC vs TIOT 0.74 0.60-0.91 0.74 0.60-0.91 1 (1466) --

INDAC/GLYC vs

FLUT/SALM 0.71 0.55-0.92 . . . .

FLUT/SALM vs Placebo 0.67 0.53-0.85 . . . .

TIOT vs Placebo 0.65 0.53-0.79 0.64 0.50-0.83 1 (1003) --

BUDE/FORM vs

Placebo 0.64 0.45-0.91 0.55 0.36-0.83 1 (519) --

INDAC/GLYC vs GLYC 0.63 0.51-0.78 0.63 0.51-0.77 1 (1469) --

INDAC/GLYC vs

INDAC 0.62 0.48-0.79 . . . .

INDAC/GLYC vs SALM 0.61 0.48-0.78 . . . .

TIOT/FLUT/SALM vs

Placebo 0.58 0.35-0.96 . . . .

INDAC/GLYC vs

FORM 0.57 0.36-0.90 . . . .

TIOT/BUDE/FORM vs

INDAC/GLYC 0.48 0.28-0.83 . . . .

INDAC/GLYC vs

Placebo 0.48 0.36-0.64 . . . .

TIOT/BUDE/FORM vs

TIOT/FLUT/SALM 0.40 0.21-0.80 . . . .

TIOT/BUDE/FORM vs

BUDE/FORM 0.36 0.19-0.69 . . . .

TIOT/BUDE/FORM vs

TIOT 0.36 0.22-0.59 0.36 0.22-0.59 1 (660) --

TIOT/BUDE/FORM vs

FLUT/SALM 0.35 0.21-0.58 . . . .

TIOT/BUDE/FORM vs

TIOT/SALM 0.33 0.17-0.65 . . . .

TIOT/BUDE/FORM vs

BECL/FORM 0.32 0.15-0.65 . . . .

TIOT/BUDE/FORM vs

BUDE 0.31 0.16-0.60 . . . .

TIOT/BUDE/FORM vs

GLYC 0.30 0.18-0.52 . . . .

TIOT/BUDE/FORM vs

INDAC 0.30 0.18-0.50 . . . .

TIOT/BUDE/FORM vs

SALM 0.30 0.18-0.49 . . . .

TIOT/BUDE/FORM vs

FLUT 0.29 0.14-0.60 . . . .

TIOT/BUDE/FORM vs

FORM 0.28 0.15-0.52 . . . .

TIOT/BUDE/FORM vs

Placebo 0.23 0.14-0.40 . . . .

Between –study heterogeneity 0.00

Design-by-treatment interaction model for 3.37 (4,0.498,0.00)

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

Mortality Overall – 88 studies, 28 treatments, 97526 patients

FORM vs FLUT/SALM 1.64 1.01-2.67 . . . 0.00

FLUT/SALM vs Placebo 0.78 1.04-1.57 0.81 0.66-1.00 6 (4852) 0.00

FLUT/SALM vs FLUT 0.75 1.07-1.65 0.76 0.62-0.93 3 (3752) 0.00


Design-by-treatment interaction model for

inconsistency χ² (d.f., P-value, heterogeneity) 31.46 (50,0.981,0.00)

Cardiovascular-related Mortality – 37 studies, 20 treatments, 55156 patients

TIOT+Resp vs SALM 2.32 1.38-3.88 . . . .

TIOT vs SALM 2.00 1.23-3.26 1.32 0.46-3.81 1 (7798) --

TIOT+Resp vs

FLUT/SALM 1.87 1.14-3.06 . . . .

TIOT+Resp vs FLUT 1.75 1.04-2.94 . . . .

TIOT vs FLUT/SALM 1.61 1.02-2.56 2.12 0.95-4.72 1 (1448) --

SALM vs Placebo 0.63 0.45-0.88 0.60 0.42-0.87 4 (5171) 0.00




Pneumonia – 54 studies, 21 treatments, 61551 patients

FLUT/VILA vs ACLI 3.15 1.07-9.24 . . . .

FLUT/VILA vs BUDE 2.83 1.10-7.25 . . . .

FLUT/SALM vs ACLI 2.81 1.30-6.07 . . . .

FLUT/VILA vs GLYC 2.59 1.09-6.18 . . . .

FLUT/SALM vs BUDE 2.52 1.44-4.43 . . . .

FLUT/SALM vs GLYC 2.31 1.47-3.64 . . . .

FLUT/VILA vs TIOT 2.25 1.02-4.96 . . . .

FLUT vs BUDE 2.21 1.25-3.92 . . . .

FLUT/SALM vs FORM 2.09 1.29-3.37 . . . .

FLUT/SALM vs TIOT 2.00 1.52-2.64 2.20 1.33-3.62 1 (1323) --

FLUT/SALM vs. INDAC 1.95 1.20-3.17 . . . .

FLUT/SALM vs. Placebo 1.90 1.53-2.34 1.75 1.44-2.13 4 (3872) <0.0001

FLUT/VILA vs. VILA 1.87 1.18-2.96 1.90 1.20-3.01 4 (2442) 0.00

FLUT/SALM vs. SALM 1.70 1.38-2.09 1.69 1.40-2.04 8 (7613) 0.00

FLUT vs. Placebo 1.66 1.32-2.08 1.60 1.32-1.95 5 (4258) 0.00

SALM vs. FLUT 0.67 0.54-0.84 0.68 0.56-0.83 2 (3174) 0.00

INDAC vs. FLUT 0.58 0.36-0.95 . . . .

TIOT vs. FLUT 0.57 0.43-0.75 . . . .

FORM vs. FLUT 0.55 0.33-0.90 . . . .

INDAC/GLYC vs. FLUT 0.51 0.31-0.85 . . . .

GLYC vs. FLUT 0.49 0.31-0.78 . . . .

INDAC/GLYC vs.

FLUT/SALM 0.45 0.27-0.75 0.11 0.01-2.09 1 (522) --

ACLI vs. FLUT 0.41 0.19-0.88 . . . .

INDAC/GLYC vs.

FLUT/VILA 0.40 0.16-0.98 . . . .



inconsistency χ² (def., P-value, heterogeneity) 34.33 (31,0.311,0.00)

Abbreviations: OR: Odds Ratio, NMA: Network Meta-analysis, MA: Meta-analysis, CI: Confidence Interval, def.: Degrees of

freedom, vs.: Versus

Treatment Abbreviations: BECL, beclomethasone; BUDE, budesonide; FLUT, fluticasone; FORM, formoterol; INDAC,

indacaterol ; SALM, salmeterol; VILA, vilanterol; ACLI, aclidinium bromide; GLYC, glycopyrronium bromide; TIOT, tiotropium;

TIOT+Resp, Tiotropium Respimat (Soft Mist Inhaler).

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FIGURES 446

Figure 1. Study Flow Diagram Details the flow of information through the different phases of 447

the review; maps out the number of records identified, included and excluded, and the reasons 448

for their exclusion. 449

450

Figure 2. Risk of Bias Appraisal Results 451

Abbreviations: High, High risk of bias; Low, Low risk of bias; Unclear, Unclear risk of bias. 452

Items: 453

1. Random sequence generation 454

2. Allocation concealment 455

3. Blinding of participants and personnel 456

4. Blinding of outcome assessment 457

5. Incomplete outcome data 458

6. Selective reporting 459

7. Other bias 460

Figure 3. Network Meta-analysis Plots. Panel A: Exacerbation, Panel B: Mortality, Panel C: 461

Cardiovascular-related Mortality, Panel D: Pneumonia, and Panel E: Arrhythmia. Nodes are proportional to the 462

number of patients included in the corresponding treatments, and edges are weighted according to the number of 463

studies included in the respective comparisons. Abbreviations: BECL, beclomethasone; BUDE, budesonide; FLUT, 464

fluticasone; MOME, mometasone; TRIAM, triamcinolone acetonide; AZD3199, AZD3199 (ultra LABA); FORM, 465

formoterol; INDAC, indacaterol ; SALM, salmeterol; VILA, vilanterol; ACLI, aclidinium bromide; GLYC, 466

glycopyrronium bromide; DAROT, darotropium bromide; TIOT, tiotropium; UMEC, umeclidinium; 467

FORM/BECLO, formoterol/beclomethasone; FORM/BUDE, formoterol/budesonide; VILA/FLUT, 468

vilanterol/fluticasone; SALM/FLUT, salmeterol/fluticasone/; FORM/MOME, formoterol/mometasone; 469

TIOT/BUDE, tiotropium/budesonide; TIOT/FLUT, tiotropium/fluticasone; TIOT/FORM, tiotropium/formoterol; 470

TIOT/SALM, tiotropium/salmeterol; IND/TIOT, indacaterol/tiotropium; INDA/GLYC, indacaterol/glycopyrronium; 471

VILA/UMEC, vilanterol/umeclidinium; GSK961081, GSK961081; FORM/IPRATR, formoterol + ipratropium 472

bromide; TIOT/FLUT/SALM, tiotropium/ fluticasone /salmeterol; TIOT/BUDE/FORM, 473

tiotropium/budesonide/formoterol; BUDE/FORM/IPRATR, budesonide/formoterol/ipratropium bromide; 474

TIOT+Resp, Tiotropium Respimat (Soft Mist Inhaler). 475

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609

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Figure 1. Study Flow Diagram. Details the flow of information through the different phases of the review; maps out the number of records identified, included and excluded, and the reasons for their exclusion.

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Figure 2. Risk of bias Appraisal Results. Abbreviations: High, High risk of bias; Low, Low risk of bias; Unclear, Unclear risk of bias.

Items: 1. Random sequence generation

2. Allocation concealment 3. Blinding of participants and personnel

4. Blinding of outcome assessment 5. Incomplete outcome data

6. Selective reporting 7. Other bias

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Figure 3. Network Meta-analysis Plots. Panel A: Exacerbation, Panel B: Mortality, Panel C: Cardiovascular-related Mortality, Panel D: Pneumonia, and Panel E: Arrhythmia. Nodes are proportional to the number of patients included in the corresponding treatments, and edges are weighted according to the number of

studies included in the respective comparisons. 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).

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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 .................................................. 33

Appendix 8. Patient characteristics .............................................................................................. 41

Appendix 9: Risk of bias results for the included studies ............................................................. 52

Appendix 10. Network Meta-analysis results Outcome: .............................................................. 57

Appendix 11. Sensitivity Network Meta-analysis results (only significant) ................................ 92

Appendix 12. SUCRA Values ...................................................................................................... 94

Appendix 13. Forest Plots ............................................................................................................. 97

Appendix 14. Included studies in our review versus previous Cochrane reviews...................... 100

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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

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3

Combo LABA plus Short-acting muscarinic anticholinergic (SAMA)

formoterol/ipratropium bromide

Combo LAMA plus LABA in one inhaler**

vilanterol/umeclidinium AnoroEllipta

indacaterol/glycopyrronium QVA149, Ultibro

tiotropium/formoterol

indacterol/tiotropium

tiotropium/salmeterol

Combo LAMA plus LABA in one inhaler (MABA)

GSK961081 (formerly TD5959)

Combo ICS plus LABA plus LAMA in one inhaler

tiotropium/fluticasone/salmeterol

tiotropium/budesonide/formoterol

Combo ICS plus LABA plus SAMA

budesonide/formoterol/ipratropium bromide

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

inhalers.

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Appendix 2. Full list of excluded medications


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.

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5

Appendix 3. All efficacy and safety outcomes considered

Efficacy outcomes:

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

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

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

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

5. Forced expiratory volume (FEV)

6. Quality of life

7. Mortality

Safety outcomes:

1. All harms

2. Serious harms

3. Withdrawals due to lack of efficacy

4. Treatment-related withdrawals

5. Cardiovascular-related mortality

6. Bone mineral density

7. Dyspnea

8. Ischemic heart disease

9. Heart failure

10. Arrhythmia

11. Pneumonia

12. Cataracts

13. Oral thrush

14. Palpitations

15. Headache

16. Constipation

17. Dry mouth

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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)

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Appendix 5. Final MEDLINE Search

1 exp Pulmonary Disease, Chronic Obstructive/

2 exp Emphysema/ or exp Pulmonary Emphysema/

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

air flow*)).tw.

4 (COPD or COAD).tw.

5 (chronic adj2 bronchitis).tw.

6 emphysema*.tw.

7 or/1-6

8 Formoterol*.tw,rn.

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

10 (eformoterol or Foradil).tw.

11 73573-87-2.rn.)

12 Indacaterol.tw,rn.

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

14 312753-06-3.rn.

15 Salmeterol*.tw,rn.

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

UNII-2I4BC502BT).tw.

17 89365-50-4.rn.

18 Salmeterolxinafoate.tw,rn.

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

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

20 94749-08-3.rn.

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

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

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


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

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


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

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

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

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

adrenoceptor agonist*")).tw.


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

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


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

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

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


ultralong-acting) and bronchodilator*).tw.


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

30 exp Adrenergic beta-Agonists/ or Bronchodilator Agents/

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

ultralong-acting).tw.

32 30 and 31

33 or/21-29,32

34 Administration, Inhalation/

35 exp Aerosols/

36 (inhal* or aerosol*).tw.

37 or/34-36

38 33 and 37

39 or/8-20,38 )

40 Beclomethasone/

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

AsmabecClickhaler).tw.

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

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

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

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

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

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

45 4419-39-0.rn.

46 Budesonide/

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

Spirocort or Uceris or UNII-Q3OKS62Q6X).tw.

48 51333-22-3.rn.

49 Fluticasone.tw,rn.

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

UNII-CUT2W21N7U).tw.

51 Glucocorticoids/

52 glucocorticoid*.tw.

53 Adrenal Cortex Hormones/

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

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

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

57 or/51-56

58 57 and 37

59 or/40-50,58

60 (Fluticasone adj3 salmeterol).tw,rn.

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

62 (formoterol adj3 mometasone).tw,rn.

63 (Zenhale or Dulera).tw.

64 (formoterol adj3 budesonide).tw,rn.

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

66 (vilanterol adj3 fluticasone).tw,rn.

67 Breo Ellipta.tw.

68 or/60-67

69 tiotropium.tw,rn.

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

XX112XZP0J).tw.

71 aclidiniumbromide.tw,rn.

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

UNII-UQW7UF9N91).tw.

73 glycoyrroniumbromide.tw,rn.

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


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

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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/


air flow*)).tw.



105 emphysema*.tw.

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11

106 or/100-105

107 formoterol/ or formoterolfumarate/


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/


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

119 94749-08-3.rn.










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












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



131 129 and 130

132 or/120-128,131

133 inhalational drug administration/

134 aerosol/


136 or/133-135

137 132 and 136

138 or/107-119,137

139 beclometasone/









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/



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

151 glucocorticoid/


153 corticosteroid/


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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/


161 (fluticasone adj3 salmeterol).tw.

162 136112-01-1.rn.

163 formoterolfumarate plus mometasonefuroate/

164 (formoterol adj3 mometasone).tw.


166 budesonide plus formoterol/

167 (formoterol adj3 budesonide).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/


XX112XZP0J).tw.

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

177 aclidinium bromide/



179 320345-99-1.rn.

180 glycoyrronium bromide.tw.







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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

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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].

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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].

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179. Gelb AF, Tashkin DP, Make BJ, Zhong X, Garcia Gil E, Caracta C et al. Long-term safety and efficacy of twice-daily aclidinium bromide in patients with COPD. Respir Med. 2013; 107(12):1957-1965.

180. Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. The Lancet Respiratory Medicine. 2013; 1(3):210-223.

181. Yao W, Wang C, Zhong N, Han X, Wu C, Yan X et al. Effect of once-daily indacaterol in a predominantly Chinese population with chronic obstructive pulmonary disease: a 26-week Asia-Pacific study. Respirology. 2014; 19(2):231-238.

182. Troosters T, Sciurba FC, Decramer M, Siafakas NM, Klioze SS, Sutradhar SC et al. Tiotropium in patients with moderate COPD naive to maintenance therapy: a randomised placebo-controlled trial. NPJ Prim Care Respir Med. 2014; 24:14003.

183. Decramer M, Anzueto A, Kerwin E, Kaelin T, Richard N, Crater G et al. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. The Lancet Respiratory Medicine. 2014; 2(6):472-486.

184. Study No. SCO40041: Randomized, Double-Blind, Parallel-Group Clinical Trial Evaluating the Effect of the Fluticasone Propionate/Salmeterol Combination Product 250/50mcg BID via DISKUS versus Salmeterol 50mcg BID via DISKUS on Bone Mineral Density in Subjects with Chronic Obstructive Pulmonary Disease (COPD).

185. Study No. SCO104925: Evaluation of Novel Endpoints in Subjects with Chronic Obstructive Pulmonary Disease (COPD) in a Randomized, Double-Blind, Placebo-Controlled Study of Treatment with Fluticasone Propionate/Salmeterol 500/50mcg combination and its individual components, Fluticasone Propionate 500mcg and Salmeterol 50mcg http://www.gsk-clinicalstudyregister.com/files2/21078.pdf. Accessed: January 2015.

186. Calverley PMA, Pauwels R, Nieminem M, Stryszak P, Staudinger H, T L. Once-daily mometasone furoate dry powder inhaler preserves lung function, reduces symptoms, and delays

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exacerbations in patients with COPD previously maintained on ICS. 2003. https://www.ersnetsecure.org/public/prg_congres.abstract?ww_i_presentation=11322. Accessed: January 2015.

187. Study No. SLMF 4010: Multicentre, randomised, parallel group, placebo-controlled, double-blind, study, stratified on tobacco status at enrollment, evaluating during 6 months the efficacy of salmeterol powder for inhalation, 50 µg two times per day for the reduction of thoracic distension in subjects with chronic obstructive pulmonary disease (COPD). http://www.gsk-clinicalstudyregister.com/files2/2577.pdf. Accessed: January 2015.

188. To Y NM, Fukuchi Y, Kitawaki T, Okino N,, Lassen C LD, Kramer D. Long-term safety and tolerability of indacaterol versus Salmeterol in Japanese COPD patients: a 52-week open-labeled study. Respirology 2011:16 (Suppl. 12), 11–326.

189. Dawber F TD, Häussermann S, Betzfigure R Efficacy of salmeterol/fluticasone propionate 50/500mcg bd versus tiotropium on lung function and mucociliary clearance in COPD patients In: 10th Congress of the Asian Pacific Society of Respirology. A99: 394.

190. Sricharoenchai T WA. Effect of Salmeterol/Fluticasone on Acute Exacerbation of COPD. Asian Pacific Society of Respirology.Suppl: A167; P162-193.

191. Study No. CQAB149B2205: A randomized, double-blind, placebo-controlled, parallel group, multi-center, multiple dose (7 days) dose-ranging study, to assess the efficacy and safety of 4 doses of QAB149 (50, 100, 200 & 400 µg) delivered via a multiple dose inhaler (MDDPI) and 1 dose of QAB149 (400 µg) delivered via a single dose inhaler (SDDPI) in patients with chronic obstructive pulmonary disease (COPD). Accessed:

192. Study No. SCO30002: A Multicentre, Randomised, Double-Blind, Parallel Group, Placebo-Controlled Study to Compare the Efficacy and Safety of Inhaled Salmeterol/Fluticasone Propionate Combination Product 25/250 μg Two Puffs Bd and Fluticasone Propionate 250μg Two Puffs Bd Alone, All Administered Via Metered Dose Inhalers (MDI), in the Treatment of Subjects with Chronic Obstructive Pulmonary Disease (COPD) for 52 Weeks.

193. Study No: SCO100470: A multicentre, randomised, double-blind, parallel group, 24-week study to compare the effect of the salmeterol/fluticasone propionate combination product 50/250mcg, with salmeterol 50mcg both delivered twice daily via the DISKUS/ACCUHALER inhaler on lung function and dyspnoea in subjects with Chronic Obstructive Pulmonary Disease (COPD).

194. Study No. SCO100540: A multi-centre, randomised, double-blind, parallel group study to investigate the efficacy and safety of the Salmeterol/fluticasone propionate combination at a strength of 50/500µg BD, compared with placebo via Accuhaler™, added to usual chronic obstructive pulmonary disease (COPD) therapy, in subjects with COPD for 24 weeks. http://www.gsk-clinicalstudyregister.com/files2/23672.pdf. Accessed: January 2015.

195. Study No. SCO40034: A multicentre, randomised, double-blind, double dummy, parallel group 12-week exploratory study to compare the effect of the salmeterol/fluticasone propionate combination product (SERETIDE™) 50/500mcg bd via the DISKUS™/ACCUHALER™ inhaler with tiotropium bromide 18 mcg od via the Handihaler inhalation device on efficacy and safety in patients with Chronic Obstructive Pulmonary Disease (COPD). http://www.gsk-clinicalstudyregister.com/files2/23678.pdf. Accessed: January 2015.

196. Study No. SMS40315: A Multicenter, Randomized, Double-Blind, Double-Dummy, Parallel Group, 8-Week Comparison of Salmeterol Xinafoate Versus Ipratropium Bromide Versus Salmeterol Xinafoate Plus Ipratropium Bromide Versus Placebo in Subjects With Chronic Obstructive Pulmonary Disease. http://www.gsk-clinicalstudyregister.com/files2/2981.pdf. Accessed: January 2015.

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197. Study No. SMS40298 : A multi-centre, randomized, double-blind, parallel group study to evaluate the impact on Quality of Life (QOL) of adding Serevent 50ug bid via MDI to patients’ existing therapy in patients with chronic obstructive pulmonary disease (COPD). http://www.gsk-clinicalstudyregister.com/files2/2647.pdf. Accessed: January 2015.

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201. Kelleher D, Preece A, Mehta R, Donald A, Hardes K, Cahn A et al. Phase II study of once-daily GSK573719 inhalation powder, a new long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD). European Respiratory Journal. 2011; 38(Suppl 55):p834.

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214. Calverley P, Pauwels RA, Jones PW, Anderson JA, Vestbos J. The severity of airways obstruction as a determinant of treatment response in COPD. Int J Chron Obstruct Pulmon Dis. 2006; 1(3):209-218.

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216. Vestbo J, Soriano JB, Anderson JA, Calverley P, Pauwels R, Jones P. Gender does not influence the response to the combination of salmeterol and fluticasone propionate in COPD. Respir Med. 2004; 98(11):1045-1050.

217. Kesten S, Celli B, Decramer M, Liu D, Tashkin D. Adverse health consequences in COPD patients with rapid decline in FEV1-evidence from the UPLIFT trial. Respir Res. 2011; 12:129.

218. Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. The Lancet. 2009; 374(9696):1171-1178.

219. Tashkin DP, Celli BR, Decramer M, Lystig T, Liu D, Kesten S. Efficacy of tiotropium in COPD patients with FEV1≥ 60% participating in the UPLIFT® trial. Copd: Journal of Chronic Obstructive Pulmonary Disease. 2012; 9(3):289-296.

220. Hanania NA, Sharafkhaneh A, Celli B, Decramer M, Lystig T, Kesten S et al. Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial. Respiratory research. 2011; 12(1):6.

221. Morice A, Celli B, Kesten S, Lystig T, Tashkin D, Decramer M. COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT). Respiratory medicine. 2010; 104(11):1659-1667.

222. Tashkin D, Celli B, Kesten S, Lystig T, Decramer M. Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial. Respir Med. 2010; 104(10):1495-1504.

223. Fukuchi Y, Fernandez L, Kuo HP, Mahayiddin A, Celli B, Decramer M et al. Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial. Respirology. 2011; 16(5):825-835.

224. Halpin DM, Decramer M, Celli B, Kesten S, Liu D, Tashkin DP. Exacerbation frequency and course of COPD. International journal of chronic obstructive pulmonary disease. 2012; 7:653-661.

225. Tashkin DP. Impact of tiotropium on the course of moderate-to-very severe chronic obstructive pulmonary disease: the UPLIFT® trial. Expert Review of Respiratory Medicine. 2010; 4.3:279.

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227. Tashkin D, Celli B, Kesten S, Lystig T, Mehra S, Decramer M. Long-term efficacy of tiotropium in relation to smoking status in the UPLIFT trial. European Respiratory Journal. 2010; 35(2):287-294.

228. Rutten-van Molken MP, Oostenbrink JB, Tashkin DP, Burkhart D, Monz BU. Does quality of life of COPD patients as measured by the generic EuroQol five-dimension questionnaire differentiate between COPD severity stages? CHEST Journal. 2006; 130(4):1117-1128.

229. Celli B, Decramer M, Kesten S, Liu D, Mehra S, Tashkin DP. Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009; 180(10):948-955.

230. Decramer M, Molenberghs G, Liu D, Celli B, Kesten S, Lystig T et al. Premature discontinuation during the UPLIFT study. Respir Med. 2011; 105(10):1523-1530.

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232. Troosters T, Celli B, Lystig T, Kesten S, Mehra S, Tashkin D et al. Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT® trial. European Respiratory Journal. 2010; 36(1):65-73.

233. Calverley PM, Stockley RA, Seemungal TA, Hagan G, Willits LR, Riley JH et al. Reported pneumonia in patients with COPD: findings from the INSPIRE study. CHEST Journal. 2011; 139(3):505-512.

234. Celli BR, Thomas NE, Anderson JA, Ferguson GT, Jenkins CR, Jones PW et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. American journal of respiratory and critical care medicine. 2008; 178(4):332-338.

235. Jenkins CR, Jones PW, Calverley P, Celli B, Anderson JA, Ferguson GT et al. Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir Res. 2009; 10(59):1465-9921.

236. Jones PW, Anderson JA, Calverley PM, Celli BR, Ferguson GT, Jenkins C et al. Health status in the TORCH study of COPD: treatment efficacy and other determinants of change. Respir Res. 2011; 12(1):71-78.

237. Ferguson GT, Calverley PM, Anderson JA, Jenkins CR, Jones PW, Willits LR et al. Prevalence and progression of osteoporosis in patients with COPD: results from the Towards a Revolution in COPD Health study. CHEST Journal. 2009; 136(6):1456-1465.

238. Vestbo J, Anderson JA, Calverley PM, Celli B, Ferguson GT, Jenkins C et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax. 2009; 64(11):939-943.

239. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW et al. Cardiovascular events in patients with COPD: TORCH study results. Thorax. 2010; 65(8):719-725.

240. Corhay J-L, Louis R. L'etude clinique du mois. L'etude TORCH (TOwards a Revolution in COPD Health): vers une revolution de la sante des patients souffrant de BPCO. Revue Médicale de Liège. 2007; 62(4):230-234.

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242. Crim C, Calverley P, Anderson J, Celli B, Ferguson G, Jenkins C et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. European Respiratory Journal. 2009; 34(3):641-647.

243. Kesten S, Casaburi R, Kukafka D, Cooper CB. Improvement in self-reported exercise participation with the combination of tiotropium and rehabilitative exercise training in COPD patients. International journal of chronic obstructive pulmonary disease. 2008; 3(1):127-136.

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245. Löfdahl C-G, Postma DS, Pride NB, Boe J, Thorén A. Possible protection by inhaled budesonide against ischaemic cardiac events in mild COPD. European Respiratory Journal. 2007; 29(6):1115-1119.

246. Johnell O, Pauwels R, Löfdahl C-G, Laitinen L, Postma D, Pride N et al. Bone mineral density in patients with chronic obstructive pulmonary disease treated with budesonide Turbuhaler®. European Respiratory Journal. 2002; 19(6):1058-1063.

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Appendix 7. Characteristics of the randomized controlled trials

Author, year Country of conduct Setting Study

conduct

period

(weeks)

Treatme

nt

duration

(weeks)

# of

treatme

nt

groups

Overall

Sample

size

Aalbers, 2002 Australia, Belgium,

Denmark, Germany,

Hungary, The Netherlands,

Norway, Poland, UK

multi-center 12 12 4 687

Aaron, 2007 Canada multi-center 52 52 3 449

Abrahams, 2013 10 countries multi-center 24 24 2 856

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

Ambrosino, 2008 Italy multi-center 25 25 2 234

Anzueto, 2009 USA, Canada multi-center 52 52 2 797

Auffarth, 1991 Netherlands NR 8 8 2 24

Barnes, 2006 NR multi-center 13 13 2 140

Bateman, 2008 South Africa multi-center 6 6 2 107

Bateman, 2010 31 countries multi-center 52 48 2 3917

Bateman, 2012 NR multi-center 4 4 6 576

Bateman, 2013 NR multi-center 30 26 5 2144

Bedard, 2012 Canada single center 3 3 2 36

Beier, 2007 Belgium, Germany, France,

the Netherlands, Slovakia


Beier, 2013 Czech Republic, Germany,

Hungary, Poland


Bogdan, 2011 Japan, Romania, Russia,

Ukraine


Bolukbas, 2010 Germany multi-center 12 1 2 46

Bourbeau, 1998 Canada single center 26 26 2 79

Bourbeau, 2007 Canada multi-center 12 12 3 60

Boyd, 1997 18 countries multi-center 18 16 3 674

Briggs, 2005 Finland, Greece, Italy,

Portugal, Sweden, Turkey,

UK, USA


Buhl, 2011 USA, Austria, Belgium,

Canada, Columbia,

Denmark, Finland, France,

Germany, Greece, Hungary,

Israel, Italy, Mexico,

Norway, Poland, Russia,

Slovakia, Spain,

Switzerland, Turkey, UK


Burge, 2000 UK multi-center 156.53 156.53 2 751

Caillaud, 2007 France multi-center 3 3 8 202

Calverley, 2003 25 countries multi-center 54 52 4 1465

Calverly, 2003 NR multi-center 6 6 3 121

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

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Calverley, 2007 42 countries (not specified) multi-center 158 156 4 6112

Calverly, 2008 11 countries multi-center 52 52 3 911

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

Campbell, 2007 USA multi-center 8 8 2 204

Casaburi, 2005 USA multi-center 25 25 2 108

Cazzola, 2000 Italy NR 12 12 3 69

Cazzola, 2007 Italy NR 12 12 3 90

Celli, 2003 USA NR 5 4 2 81

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

Chan, 2007 Canada multi-center 48 48 2 913

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

Chapman, 2002 Canada, Denmark, The

Netherlands, Russia,

Sweden, UK


Chapman, 2011 USA, Argentina, Canada,

Germany, India, Italy,

Spain, Sweden, Turkey


Choudhury, 2007 UK multi-center 52 52 2 260

Cooper, 2012 11 countries multi-center 96 96 2 519

Cote, 2009 USA multi-center 4 4 2 266

Covelli, 2005 USA multi-center 12 12 2 196

Criner, 2008 USA multi-center 8 8 2 166

D’Urzo, 2011 NR NR 30.29 26 2 822

Dahl, 2001 8 countries multi-center 12 12 3 586

Dahl, 2010 Argentina, Chile, Columbia,

Czech, Denmark, Ecuador,

Egypt, Estonia, France,

Germany, Hungary, Israel,

Italy, Korea, Latvia,

Lithuania, Netherlands,

Peru, Romania, Russia,

Slovakia, Spain,



Dahl, 2013 Denmark multi-center 4 4 2 193

Dahl, 2013 Europe (not specified),

Canada, India, Korea, South

Africa


Dal Negro, 2003 Italy single center 52 52 3 18

Decramer, 2013 Argentina, Australia,

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,


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Slovakia, South Africa,

Spain, Sweden, Switzerland,

Taiwan, Thailand, Turkey,

UK, Venzuela

Decramer, 2014 Germany, Italy, Mexico,

Peru, Poland, Romania,

Russia, Ukraine, USA

multi-centre 25 24 4 843

Decramer, 2014 Argentina, Australia,

Canada, Chile, Germany,

Mexico, Romania, South

Africa, South Korea, USA


Doherty, 2012 North, Central and South

America, Europe, Africa,

Asia (not specified)


Donohue, 2002 12 countries multi-center 24 24 3 623

Donohue, 2013 USA, Bulgaria, Canada,

Chile, Czech Republic,

Greece, Japan, Mexico,

Poland, Russia, South

Africa, Spain, Thailand


Dransfield, 2011 USA multi-center 16 16 2 249

Dransfield, 2013 15 countries multi-center 52 52 4 1622

Dransfield, 2013 15 countries multi-center 52 52 4 1633

Dusser, 2006 France multi-center 50 48 2 1010

Engel, 1989 Denmark single center 12 12 2 18

Feldman, 2010 USA, New Zealand,

Belgium


Feldman, 2012 USA multi-center 5 4 2 51

Ferguson, 2008 USA, Canada multi-center 52 52 2 782

Freeman, 2007 UK multi-center 12 12 2 374

Fukuchi, 2013 Japan, Korea, Taiwan,

Philippines, Vietnam, India,

Russia, Poland, Ukraine


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

Gupta, 2002 India single center 8 8 2 33

Hagedorn, 2013 Germany multi-center 52 52 2 212

Hanania, 2003 USA multi-center 24 24 4 723

Hanania, 2012 USA multi-center 24 24 2 342

Hanania, 2012 NR multi-center 4 4 6 602

Hasani, 2004 UK single center 3 3 2 34

Hattotuwa, 2002 UK single center 12 12 2 37

Hoshino, 2011 Japan NR 12 12 2 30

Hoshino, 2013 Japan NR 16 16 4 60

Johansson, 2008 Sweden multi-center 12 12 2 224

Jones, 1997 17 countries including: UK,

Belgium, France, Germany,

Italy, The Netherlands, New

Zealand


Jones, 2011 NR - 16 European countries multi-center 52 52 2 843

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Jones, 2011 NR - 7 mostly North

American countries


Jones, 2012 9 European countries (not

specified), South Africa


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

Kardos, 2007 Germany multi-center 44 44 2 994

Kaushik, 1999 India NR 1 1 2 30

Kerwin, 2011 USA multi-center 12 12 2 323

Kerwin, 2011 USA multi-center 12 12 2 318

Kerwin, 2012 USA, Canada multi-center 12 12 3 560

Kerwin, 2012 USA, Argentina, Canada,

Chile, France, Germany,

Hungary, Israel, Italy,

Korea, Mexico,

Netherlands, New Zealand,

Peru, Poland, Russia


Kerwin, 2013 Chile, Estonia, Germany,

Japan, Korea, Philippines,

Poland, Russian Federation,

USA


Kinoshita, 2012 Hong Kong, India, Japan,

Korea, Singapore, Taiwan


Korn, 2011 USA, Czech, Germany,

Hungary, India, Slovakia,

Spain, Turkey


Kornmann, 2011 15 countries (not specified) multi-center 27 26 3 998

Koser, 2010 USA multi-center 12 12 2 247

Kuna, 2013 Bulgaria, Canada, Japan,

Poland, Russia


Lapperre, 2009 The Netherlands multi-center 120 (24

weeks

for one

group)

120 (24

weeks

for one

group)

4 75

Littner, 2000 USA multi-center 7.14 4.14 5 169

Llewellyn-Jones,

1996

UK NR 14 8 2 16

Lomas, 2012 Estonia, Finland, Germany,

South Korea, Latvia,

Lithuania, The Netherlands,

New Zealand, Russia,

Slovenia, South Africa, UK


L'tvall, 2012 Norway, Sweden multi-center 4 4 2 60

Magnussen, 2008 Belgium, Canada, Germany,

Denmark, France, Italy, the

Netherlands, South Africa


Mahler, 1999 USA multi-center 12 12 2 278

Mahler, 2002 Lebanon multi-center 24 24 4 645

Mahler, 2012 Argentina, Australia,

Colombia, Denmark,

Germany, Greece,

Guatemala, Mexico, Peru,

Philippines, South Africa,


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Spain, Turkey, USA

Mahler, 2012 Argentina, Canada,

Colombia, Czech Republic,

Hungary, India,

Netherlands, Philippines,

Slovakia, Spain, USA


Maltais, 2005 NR multi-center 6 6 2 261

Maltais, 2011 Canada, USA multi-center 6 6 2 181

Mansori, 2010 Iran single center 24 12 2 40

Martinez, 2013 Czech Republic, Germany,

Japan, Poland, Romania,

Russian Federation,

Ukraine, USA


Mathioudakis, 2013 Greece single center 208 208 5 564

McNicholas, 2004 UK, Ireland, The

Netherlands


Mirici, 2001 Turkey single center 12 12 2 50

Moita, 2008 Portugal multi-center 12 12 2 304

Mroz, 2013 Poland single center 12 12 2 34

Nicolini, 2012 Italy single center 0.14 0.14 2 100

Niewoehner, 2005 USA multi-center 26 24 2 1829

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

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

Ozol, 2005 Turkey NR 24 24 2 26

Paggiaro, 1998 13 European countries (not

specified), New Zealand,

South Africa


Pasqua, 2010 Italy NR 4 4 2 22

Pauwels, 1999 Belgium, Denmark, Finland,

Italy, the Netherlands,

Norway, Spain, Sweden,

UK


Perng, 2009 Taiwan multi-center 12 12 3 99

Powrie, 2007 UK single center 52 52 2 142

Pukhta, 2010 India single center 2 2 2 60

Rabe, 2008 Austria, Belgium, Denmark,

France, Germany,

Netherlands, South Africa,

Sweden


Reid, 2008 Australia NR 24 24 2 34

Renkema, 1996 The Netherlands NR 104 104 2 39

Rennard, 2001 USA multi-center 12 12 2 267

Rennard, 2009 USA, Mexico, Europe (not

specified)


Rossi, 2002 Austria, Belgium, Czech

Republic, France, Germany,

Greece, Hungary, Italy,


Spain, USA


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Rubin, 2008 Brazil single center 0.14 0.003

(30

minutes)

2 40

Rutgers, 1998 The Netherlands single center 6 6 2 44

Rutten-van, 1999 The Netherlands multi-center 12 12 2 97

Santus, 2012 Italy NR 4 4 2 24

Schermer, 2007 The Netherlands multi-center 12 12 2 40

Scherr, 2012 Switzerland single center 12 12 2 68

Sechaud, 2012 Germany, Denmark multi-center 2 2 5 41

Senderovitz, 1999 Denmark multi-center 24 24 2 26

Shaker, 2009 Denmark single center 208 104 -208 2 254

Sharafkhaneh, 2012 USA, Central and South

America, South Africa


Sin, 2008 Canada multi-center 4 4 3 224

Sposato, 2008 Italy single center 0.05 0.34 2 37

Sridevl, 2012 India single center 14 14 2 60

Stahl, 2001 Sweden multi-center 12 12 2 121

Stockley, 2006 Austria, Bulgaria, Belgium,

Croatia, Czech Republic,

Denmark, Ireland, Estonia,

France, Germany, Holland,

Hungary, Latvia, Poland,

Spain, Slovak Republic,

Slovenia, Ukraine, UK


Struijs, 1997 The Netherlands NR 52 52 2 33

Sugiura, 2002 Japan single center 4 4 1 18

Suzuki, 2010 Japan single center 52 52 2 20

Szafranski, 2003 Argentina, Brazil, Denmark,

Finland, UK, Italy, Mexico,

Poland, Portugal, South

Africa, Spain


Tashkin, 2008 37 countries multi-center 208 208 2 5992

Tashkin, 2008 USA, Czech Republic, The

Netherlands, Poland, South

Africa


Tashkin, 2009 USA multi-center 12 12 2 255

Tashkin, 2012 South America, Asia,

Africa, Europe, North

America (not specified)


The Lung Health

Study Research

Group, 2000

NR multi-center 208 mean

160

2 1116

Tonnel, 2008 France multi-center 36 36 2 554

Troosters, 2014 Belgium, Canada, Czech

Republic, Germany, Great

Britain, Greece, the

Netherlands, Portugal,

Ukraine, USA


Tzani, 2011 Italy multi-center 12 12 2 18

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Ulubay, 2005 Turkey single center 4 4 2 25

Um, 2007 Korea single center 6 6 2 81

Van de Maele, 2010 Belgium multi-center 2 2 5 255

van Den Boom,

2001

The Netherlands single center 52 52 2 74

van den Broek, 2008 Netherlands single center 104 0.006 2 77

van der Valk, 2002 The Netherlands single center 24 24 2 244

van Noord, 2000 The Netherlands multi-center 14 12 2 97

Verhoeven, 2002 The Netherlands NR 24 24 2 23

Verkindre, 2006 France multi-center 14 12 2 100

Vestbo, 1999 Denmark single center 144 144 2 290

Vogelmeier, 2008 8 countries multi-center 24 24 4 847

Vogelmeier, 2010 Germany, France, the

Netherland, Spain, Turkey,

USA


Vogelmeier, 2011 25 countries multi-center 52 52 2 7376

Vogelmeier, 2013 Belgium, Czech, Estonia,

Germany, Hungary, Korea,

Lithuania, Norway, Spain,

South Africa

multi-center 26

efficacy,

30 safety

26 2 523

Wadbo, 2002 Sweden multi-center 12 12 2 121

Watkins, 2013 USA single center 6 6 3 365

Wedzicha, 2008 Austria, Belgium, Czech

Republic, Denmark,

Estonia, Germany, Greece,

Italy, Latvia, Lithuania, the

Netherlands, Norway,

Romania, Russia, Slovakia,

Slovenia, Spain, Sweden,

Ukraine, UK


Wedzicha, 2013 27 countries (not specified) multi-center 80 64 - 76 3 2206

Weir, 1999 UK multi-center 104 104 2 98

Welte, 2008 Germany multi-center 13 12 2 321

Welte, 2009 9 countries multi-center 12 12 2 660

Wesseling, 1991 The Netherlands single center 6 6 2 35

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

Wise, 2013 USA, UK, France,

Denmark, Germany and

other countries not specified

multi-center mean

119.6

median

119.28

3 17135

Woolhouse, 2001 UK NR 2 2 2 23

Wouters, 2005 The Netherlands multi-center 52 52 2 373

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

Yildiz, 2004 Turkey single center 12 12 2 38

Zheng, 2007 China multi-center 26 24 2 445

Zhong, 2012 China multi-center 24 24 2 308

Unpublished Studies (n= 20)

Calverley, 2003† USA NR 52 52 2 631

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Cheng, 2012† Taiwan NR 52 52 2 78

da Fonseca Reis,

2010† NR NR 12 12 2 18

Dawber, 2005† NR single center 3 3 2 59

GlaxoSmithKline,

2005 (SCO100470)†

Australia, Bulgaria, Croatia,

Czech Republic, France,

Germany, Greece, Italy,

Latvia, Lithuania,


Poland, Romania, Russian

Federation, Slovakia,

Slovenia, Sweden, Thailand,

UK multi-center

24 24 2 1050

GlaxoSmithKline,

2005 (SCO40034)† The Netherlands multi-center 12 12 2 125

GlaxoSmithKline,

2005 (SLMF 4010)† France multi-center 24 24 2 34

GlaxoSmithKline,

2005 (SMS40298)† Canada multi-center 16 16 2 347

GlaxoSmithKline,

2005 (SMS40315)† USA multi-center 4 8 2 316

GlaxoSmithKline,

2005 ,SFCT01

(SCO30002)† Italy, Poland multi-center

54 52 3 387

GlaxoSmithKline,

2006 (SCO100540)† China multi-center 24 24 2 445

GlaxoSmithKline,

2007 (SCO104925)†

Russian Federation, USA,

Chile, Estonia multi-center 12 12 4 161

GlaxoSmithKline,

2008 (SCO40041)† USA multi-center 156 156 2 186

Kelleher, 2011† NR NR 1 1 3 38

Maltais, 2010†

Canada, Germany, USA,

France NR 4 4 4 360

Novartis, 2006

(CQAB149B2205)†

Belgium, Canada, Denmark,

France, Germany, Italy, the

Netherlands, Norway, Peru,

Russia, Sweden,

Switzerland, USA multi-center

2 2 6 635

Ohar, 2013† USA multi-center 26 26 2 639

Sekiya, 2012† Japan multi-center 52 52 2 163

Sricharoenchai,

2008† Thailand NR NR 0.012 2 15

To, 2011† Japan NR 52 52 2 186

Note: †Unpublished data (n=20 studies)

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

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Appendix 8. Patient characteristics

Author, year Age category % Female COPD Definition Diagnosis of

COPD (GOLD

criteria)

COPD Severity COPD

duration

range

(mos)

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

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

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

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

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

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

emphysema

NA moderate to very severe† NR

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

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

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

Bateman, 2010 Adult & elderly (≥18) 22.45 COPD NR moderate to severe† NR

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

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

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

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

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

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

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

diagnosed

patients

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

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

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

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

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

(salbutamol 400 mg)

forced expiratory volume

No moderate to severe† NR

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in 1 s (FEV1) ,<80% and

≥30% predicted,

FEV1/forced vital

capacity (FVC),<70%)

Burge, 2000 Adult & elderly (≥18) 25.43 COPD NR mild to very severe† NR

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

Calverley, 2003 Adult & elderly (≥18) 27.65 COPD NR moderate to very severe† NR

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

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

Calverley, 2007 Adult & elderly (≥18) 24.23 COPD NR moderate to very severe† NR

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

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

according to the

GOLD guidelines

severe† >24

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

Casaburi, 2005 Adult & elderly (≥18) 43.5 COPD NR moderate to very severe† NR

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

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

less than 50% of

predicted, and a

post-bronchodilator

FEV1/ FVC<70%

following

salbutamol 400 mg

according with the

GOLD criteria of

severity

severe to very severe NR

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

Celli, 2003 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, 2011 Adult & elderly (≥18) 39 COPD Yes moderate to severe† NR

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

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Cooper, 2012 Adult & elderly (≥18) 23 COPD II/III/IV moderate to very severe† NR

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

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

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

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

guidelines

moderate to severe† NR

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

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

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

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

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

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

airflow limitations

Yes severe† NR

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

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

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

diagnoses

moderate to very severe† NR

Donohue, 2002 Adult & elderly (≥18) 25 COPD NR moderate† NR

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

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

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

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

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

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

for at least three months

a year during at least the

preceding 2 years, and

moderate to severe

bronchial

hyperresponsiveness as

judged by a bronchial

histamine challenge

(provocative

concentration producing

NR mild to moderate† at least the

preceding 2

years

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a 20% fall in FEV1

≤2.0mg/ histamine ml)

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

240

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

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

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

symptoms/events of

>3days in duration

requiring a change in

treatment

NR mild to very severe† NR

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

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

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

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

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

dyspnea

NR moderate to very severe† 12-636

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

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

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

Hattotuwa, 2002 Adult & elderly (≥18) 13.33 COPD NR mild to very severe† NR

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

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

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

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

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

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

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

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

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

and IV

severe to very severe† NR

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

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

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

Kerwin, 2012 Adult & elderly (≥18) 47 COPD NR moderate to severe† NR

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

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

Kinoshita, 2012 Adult & elderly (≥18) 3.47 COPD II, III moderate to severe† NR

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

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

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

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

Lapperre, 2009 Adult & elderly (≥18) 13.86 non-asthmatic COPD II-III moderate to severe NR

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

Llewellyn-Jones,

1996

Adult & elderly (≥18) 50 chronic bronchitis and

emphysema

NR moderate to severe† >24

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

L'tvall, 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, 2012 Adult & elderly (≥18) 31.49 COPD II moderate to severe† NR

Mahler, 2012 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

emphysematic" and

"predominantly

bronchitic patients."

II and III NR NR

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

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

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

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

in the appendix but

linked only to the

introduction section

that describes

COPD as a

progressive,

inflammatory

condition leading to

airflow limitation,

pulmonary

hyperinflation,

resulting in

dyspnea, decreased

exercise tolerance

and impaired QoL.

NR NR

Nanshan/Zhong,

2012

Adult & elderly (≥18) 4.87 COPD NR moderate to very severe† NR

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

Niewoehner, 2005 Adult & elderly (≥18) 1.48 COPD NR moderate to very severe† NR

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


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

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

characterised by

decreased maximum

expiratory flow and slow

forced emptying of the

lungs, which is slowly

progressive, irreversible,

and does not change

markedly over several

months."

NR mild to severe† NR

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

Pauwels, 1999 Adult (18-64) 27.15 COPD NR mild to moderate† NR

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

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

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

"preventable and

treatable disease state

characterised by airflow

limitation that is not

fully reversible. The

airflow limitation is

usually progressive and

is associated with an

abnormal inflammatory

response of the lungs to

noxious particles or

gases, primarily caused

by cigarette smoking."

NR moderate to severe† ≥24

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

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

exacerbation for at least

4 weeks)

NR moderate to very severe† NR

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

COPD as per

moderate to severe, stable NR

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GOLD

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

COPD


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

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

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

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

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

Szafranski, 2003 Adult & elderly (≥18) 21.26 COPD moderate-to-severe moderate to very severe† ≥24

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

Tashkin, 2008 Adult & elderly (≥18) 25 COPD II (44.5%); III

(44%); IV (8.5%)


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

exacerbations

NR moderate to verey severe† >24

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

The Lung Health

Study Research

Group, 2000

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

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

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

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

diagnosis according

to GOLD

guidelines

NR NR

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

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

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

van Den Boom,

2001

Adult & elderly (≥18) 58.1 Obstructive airway

disease

NA moderate to severe† NR

van den Broek,

2008

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

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

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

according to ATS.

COPD is "defined as a

NR mild to moderate† NR

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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, 2002 Adult & elderly (≥18) 17.39 COPD NR mild to moderate NR

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

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

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

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

COPD according to 2006

GOLD guidelines

moderate to severe moderate to severe† NR

Vogelmeier, 2011 Adult & elderly (≥18) 25.35 COPD II, III, IV moderate to very severe† NR

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

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

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

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

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

years

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

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

without marked airflow

obstruction (FEV ~70%

predicted)

NR NR NR

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

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

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

defined by daily sputum

production for at least 3

NA NR NR

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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

Society and GOLD

guidelines


Unpublished Studies (n=20)

Calverley, 2003b* 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,

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

NR

GlaxoSmithKline,

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

NR

GlaxoSmithKline,

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

NR

GlaxoSmithKline,

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

NR

GlaxoSmithKline,

2005 ,SFCT01

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

NR

GlaxoSmithKline,


NR

GlaxoSmithKline,

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

NR

GlaxoSmithKline,


NR

Kelleher, 2011* NR NR COPD NR NR† NR

Maltais, 2010* NR 45.5 COPD NR NR NR

Novartis, 2006 Adult & elderly (≥18) 33.23 COPD NR moderate to severe† NR

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(CQAB149B2205)*

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

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

Sricharoenchai,

2008* NR NR COPD NR NR

NR

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

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

Abbreviations: NR, not reported; 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

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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 Unclear Unclear Low Low Unclear Unclear Unclear

Calverley, 2003 Low Low Low Low Low Low High

Calverly, 2003 Unclear Unclear Low Low Unclear Unclear High

Calverly, 2003 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


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 Unclear Unclear Low Low Low Unclear High

Celli, 2003 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

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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, 2012 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 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 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, 2014 Low Low Low Low Low Low High

Decramer, 2014 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, 2013 Low Low Low Low Low Low High

Dransfield, 2013 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



GlaxoSmithKline, 2005 Unclear Unclear Low Low Low Low High

GlaxoSmithKline, 2005 Unclear Unclear Low Low Low Low High

GlaxoSmithKline, 2005 Unclear Unclear Low Low Low Unclear High


Glaxo 2007 (SCO104925) 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

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Hanania, 2003 Unclear Unclear Low Low Unclear Unclear Unclear

Hanania, 2012 Unclear Unclear Low Low Low Low High

Hanania, 2012 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, 2011 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, 2011 Low Low Low Low Low Low High

Kerwin, 2011 Low Low Low Low Low Low High

Kerwin, 2012 Unclear Unclear Low Low Low High High

Kerwin, 2012 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, 2012 Low Low Low Low Low Unclear High

Mahler, 2012 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

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Mirici, 2001 Low High Low Low Low Unclear Unclear

Moita, 2008 Unclear Unclear Low Low Low Unclear Unclear

Mroz, 2013 Unclear Unclear Unclear Low Unclear Unclear Unclear

Nanshan Z/ or Zhong

N,2012

Low Unclear Low Low Low Low Low

Nicolini, 2012 Low Unclear Low Low Low Unclear Low

Niewoehner, 2005 Low Unclear Low Low Low Low High

Novartis, 2006 Unclear Unclear Low Low Low Unclear Unclear

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

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

Ohar, 2013 Unclear Unclear Low Low Low Low High

Ozol, 2005 Low Unclear Low Low High Unclear Unclear

Paggiaro, 1998 Low Unclear Low Low Low Unclear Unclear

Pasqua, 2010 Unclear Unclear Low Low Unclear Unclear Low

Pauwels, 1999 Unclear Unclear Low Low Low Unclear High

Perng, 2009 Low Unclear Low Low Unclear Unclear Low

Powrie, 2007 Unclear Unclear Low Low High Low High

Pukhta, 2010 Unclear Unclear Low Low Low Unclear Unclear

Rabe, 2008 Unclear Unclear Low Low Low Low High

Reid, 2008 Low Unclear Low Low High Unclear Low

Renkema, 1996 Low Unclear Low Low Low Unclear Low

Rennard, 2009 Unclear Unclear Low Low Low Low High

Rennard, 2001 Unclear Unclear Low Low High Unclear High

Rossi, 2002 Unclear Unclear Low Low Low Unclear High

Rubin, 2008 Unclear Unclear Low Low Low Unclear Unclear

Rutgers, 1998 Unclear Unclear Low Low Low Unclear Unclear

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

Santus, 2012 Unclear Unclear Unclear Unclear Unclear Unclear Low

Schermer, 2007 Low Unclear Low Low Low Unclear High

Scherr, 2012 Unclear Unclear Low Low Low High Low

Sechaud, 2012 Unclear Unclear Low Low Low Unclear High

Sekiya, 2012 Unclear Unclear High Low High Unclear Unclear

Senderovitz, 1999 Unclear Unclear Low Low Low Unclear Unclear

Shaker, 2009 Low Unclear Low Low High Low Unclear

Sharafkhaneh, 2012 Low Low Low Low Unclear Low High

Sin, 2008 Low Low Low Low Low Low Low

Sposato, 2008 Unclear Unclear Low Low Unclear Unclear Unclear

Sricharoenchai, 2008 Unclear Unclear Low Low Unclear Unclear Unclear

Sridevl, 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

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Suzuki, 2010 Unclear Unclear Low Low Low Low Unclear

Szafranski, 2003 Unclear Unclear Low Low Low Unclear Unclear

Tashkin, 2008 Low Unclear Low Low Low Low High

Tashkin, 2008 Low Low Low Low Low Low High

Tashkin, 2009 Low Unclear Low Low Low Unclear High

Tashkin, 2012 Low Low Low Low High Low High

The Lung Health Study

Research Group, 2000

Unclear Unclear Low Low Low Unclear Unclear

To, 2011 Unclear Unclear Low Unclear Low Unclear Unclear

Tonnel, 2008 Low Unclear Low Low High Unclear High

Troosters, 2014 Low Unclear Low Low Low Low Unclear

Tzani, 2011 Low Unclear Low Low Low Low High

Ulubay, 2005 Unclear Unclear Low Low Unclear Unclear Unclear

Um, 2007 Low Unclear High Low High Unclear Low

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

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

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

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

van Noord, 2000 Unclear Unclear Low Low Low Unclear High

Verhoeven, 2002 Unclear Unclear Low Low Low Low Unclear

Verkindre, 2006 Unclear Unclear Low Low Low Unclear High

Vestbo, 1999 Low Low Low Low Low Unclear Unclear

Vogelmeier, 2008 Unclear Unclear Low Low Low Low High


Vogelmeier, 2011 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

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Appendix 10. Network Meta-analysis results Outcome

Network Meta-analysis Results Pairwise Meta-analysis

Treatment Comparison Odds

Ratio

CI PrI Odds

Ratio

CI Heteroge

neity

Variance

# studies # patients

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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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 - - - - -

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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 - - - - -

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Indacaterol/Glycopyrronium vs

Beclomethasone/Formoterol

0.65 0.37-1.15 - - - - -

Tiotropium/Fluticasone/Salmeterol vs


0.78 0.39-1.58 - - - - -

Tiotropium/Budesonide/Formoterol vs


0.32 0.15-0.65 - - - - -

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

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

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

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


Budesonide/Formoterol

0.90 0.49-1.66 - - - - -



0.36 0.19-0.69 - - - - -

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

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

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


Fluticasone/Vilanterol

1.02 0.30-3.41 - - - - -



0.41 0.12-1.39 - - - - -

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

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


Fluticasone/Salmeterol

0.86 0.52-1.40 - - - - -



0.35 0.21-0.58 - - - - -

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


Tiotropium/Salmeterol

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



0.33 0.17-0.65 - - - - -


Indacaterol/Glycopyrronium

1.20 0.72-2.00 - - - - -



0.48 0.28-0.83 - - - - -


Tiotropium/Fluticasone/Salmeterol

0.40 0.21-0.80 - - - - -

Common within-network heterogeneity variance 0.00


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

3.37 (4,0.498,0.00)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

11.24

0.00 2 1044

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

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

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

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

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

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

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

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

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

91.84

-- 1 698

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

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

92.96

-- 1 693

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

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

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

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

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Formoterol/Budesonide/Tiotropium vs AZD3199 (Ultra

LABA)

6.39 0.07-561.41 0.06-683.41 - - - -

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

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

Salmeterol/Fluticasone/Tiotropium vs AZD3199 (Ultra

LABA)

3.46 0.12-101.64 0.10-118.04 - - - -

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

10.84

-- 1 470

Formoterol/Budesonide/Tiotropium vs


3.82 0.11-138.30 0.09-162.06 - - - -

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

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

Salmeterol/Fluticasone/Tiotropium vs


2.07 0.26-16.35 0.24-17.96 - - - -

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

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

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

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

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

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



1.12 0.20-6.08 0.19-6.58 - - - -

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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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

2.75 0.11-71.01 0.09-82.01 - - - -

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

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



1.49 0.37-6.02 0.35-6.44 - - - -

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Salmeterol/Fluticasone vs

Formoterol/Budesonide/Tiotropium

0.27 0.01-6.68 0.01-7.71 - - - -



0.54 0.02-17.20 0.01-20.04 - - - -

Fluticasone/Tiotropium vs


0.31 0.01-17.58 0.00-21.00 - - - -

Vilanterol/Fluticasone vs


0.42 0.01-12.34 0.01-14.33 - - - -

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

Formoterol/Tiotropium vs


0.23 0.01-10.28 0.00-12.16 - - - -

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

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



0.29 0.01-7.54 0.01-8.71 - - - -

Indacaterol/Tiotropium vs


0.37 0.01-12.96 0.01-15.17 - - - -

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

Formoterol/Mometasone vs


0.24 0.01-7.57 0.01-8.82 - - - -

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

Salmeterol/Tiotropium vs


0.53 0.02-16.83 0.01-19.61 - - - -

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

Tiotropiumropium Respimat vs


0.33 0.01-8.30 0.01-9.57 - - - -

Triamcinoloneacetonide vs


0.27 0.01-7.16 0.01-8.29 - - - -

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

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

Vilanterol/Umeclidinium vs


0.44 0.01-13.54 0.01-15.75 - - - -

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

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

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

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

19.56

1.163 2 820

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

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

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

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

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

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

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

Formoterol/Mometasone vs Fluticasone 0.66 0.18-2.49 0.17-2.66 - - - -

Salmeterol vs Fluticasone 0.86 0.69-1.07 0.66-1.12 0.81 0.67-0.99 0.00 2 3472

Salmeterol/Tiotropium vs Fluticasone 1.49 0.40-5.56 0.37-5.93 - - - -

Tiotropium vs Fluticasone 0.93 0.71-1.20 0.69-1.25 - - - -

Tiotropium Respimat vs Fluticasone 0.94 0.65-1.34 0.63-1.39 - - - -

Triamcinoloneacetonide vs Fluticasone 0.75 0.36-1.56 0.35-1.63 - - - -

Umeclidinium vs Fluticasone 1.09 0.26-4.55 0.24-4.87 - - - -

Vilanterol vs Fluticasone 1.43 0.54-3.81 0.51-4.01 2.10 0.27-

16.33

0.00 2 818

Vilanterol/Umeclidinium vs Fluticasone 1.24 0.37-4.14 0.35-4.40 - - - -


Salmeterol/Fluticasone

2.02 0.54-7.54 0.51-8.04 - - - -

Fluticasone/Tiotropium vs Salmeterol/Fluticasone 1.16 0.10-13.41 0.09-14.97 1.03 0.06-

17.24

-- 1 65

Vilanterol/Fluticasone vs Salmeterol/Fluticasone 1.57 0.54-4.58 0.51-4.84 2.97 0.12-

73.14

-- 1 528

Formoterol vs Salmeterol/Fluticasone 1.64 1.01-2.67 0.97-2.78 - - - -

Formoterol/Tiotropium vs Salmeterol/Fluticasone 0.85 0.11-6.62 0.10-7.27 0.99 0.06-

15.90

-- 1 605

Glycopyrronium vs Salmeterol/Fluticasone 0.96 0.56-1.66 0.54-1.72 - - - -

Indacaterol vs Salmeterol/Fluticasone 1.05 0.64-1.71 0.62-1.78 - - - -

Indacaterol/Glycopyrronium vs Salmeterol/Fluticasone 1.09 0.61-1.95 0.59-2.03 - - - -

Indacaterol/Tiotropium vs Salmeterol/Fluticasone 1.38 0.29-6.60 0.27-7.10 - - - -

Mometasone vs Salmeterol/Fluticasone 1.77 0.73-4.31 0.70-4.52 - - - -

Formoterol/Mometasone vs Salmeterol/Fluticasone 0.88 0.23-3.32 0.22-3.54 - - - -

Salmeterol vs Salmeterol/Fluticasone 1.14 0.93-1.41 0.88-1.48 1.08 0.89-1.31 0.00 8 8202

Salmeterol/Tiotropium vs Salmeterol/Fluticasone 1.98 0.53-7.38 0.50-7.87 - - - -

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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 - - - -


Salmeterol/Fluticasone/Tiotropium

0.58 0.04-9.14 0.03-10.34 - - - -



0.78 0.15-4.14 0.13-4.48 - - - -

Formoterol vs Salmeterol/Fluticasone/Tiotropium 0.81 0.21-3.21 0.19-3.43 - - - -



0.42 0.04-4.77 0.03-5.32 - - - -

Glycopyrronium vs Salmeterol/Fluticasone/Tiotropium 0.47 0.12-1.90 0.11-2.03 - - - -

Indacaterol vs Salmeterol/Fluticasone/Tiotropium 0.52 0.13-2.03 0.12-2.17 - - - -



0.54 0.13-2.18 0.12-2.33 - - - -



0.68 0.09-5.11 0.08-5.60 - - - -

Mometasone vs Salmeterol/Fluticasone/Tiotropium 0.88 0.18-4.18 0.17-4.50 - - - -



0.44 0.07-2.76 0.06-3.01 - - - -

Salmeterol vs Salmeterol/Fluticasone/Tiotropium 0.57 0.15-2.10 0.14-2.23 - - - -



0.98 0.31-3.13 0.29-3.32 0.98 0.31-3.11 -- 1 293

Tiotropium vs Salmeterol/Fluticasone/Tiotropium 0.61 0.17-2.22 0.16-2.36 0.61 0.17-2.21 -- 1 301



0.62 0.17-2.28 0.16-2.43 - - - -



0.49 0.11-2.17 0.11-2.33 - - - -

Umeclidinium vs Salmeterol/Fluticasone/Tiotropium 0.72 0.10-4.89 0.10-5.34 - - - -

Vilanterol vs Salmeterol/Fluticasone/Tiotropium 0.94 0.19-4.74 0.17-5.12 - - - -



0.82 0.14-4.74 0.13-5.14 - - - -

Vilanterol/Fluticasone vs Fluticasone/Tiotropium 1.35 0.09-19.30 0.08-21.74 - - - -

Formoterol vs Fluticasone/Tiotropium 1.41 0.12-16.90 0.11-18.89 - - - -

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Formoterol/Tiotropium vs Fluticasone/Tiotropium 0.73 0.03-17.70 0.03-20.39 - - - -

Glycopyrronium vs Fluticasone/Tiotropium 0.83 0.07-9.98 0.06-11.16 - - - -

Indacaterol vs Fluticasone/Tiotropium 0.90 0.08-10.78 0.07-12.05 - - - -

Indacaterol/Glycopyrronium vs Fluticasone/Tiotropium 0.94 0.08-11.42 0.07-12.78 - - - -

Indacaterol/Tiotropium vs Fluticasone/Tiotropium 1.18 0.07-21.32 0.06-24.25 - - - -

Mometasone vs Fluticasone/Tiotropium 1.52 0.11-20.37 0.10-22.87 - - - -

Formoterol/Mometasone vs Fluticasone/Tiotropium 0.76 0.05-12.12 0.04-13.71 - - - -

Salmeterol vs Fluticasone/Tiotropium 0.98 0.09-11.35 0.08-12.67 - - - -

Salmeterol/Tiotropium vs Fluticasone/Tiotropium 1.70 0.11-27.00 0.09-30.54 - - - -

Tiotropium vs Fluticasone/Tiotropium 1.06 0.09-12.20 0.08-13.62 0.94 0.06-

15.68

-- 1 66

Tiotropiumropium Respimat vs Fluticasone/Tiotropium 1.07 0.09-12.45 0.08-13.91 - - - -

Triamcinoloneacetonide vs Fluticasone/Tiotropium 0.86 0.07-10.92 0.06-12.24 - - - -

Umeclidinium vs Fluticasone/Tiotropium 1.24 0.07-20.96 0.07-23.77 - - - -

Vilanterol vs Fluticasone/Tiotropium 1.64 0.12-22.60 0.11-25.42 - - - -

Vilanterol/Umeclidinium vs Fluticasone/Tiotropium 1.42 0.09-21.46 0.08-24.23 - - - -

Formoterol vs Vilanterol/Fluticasone 1.05 0.33-3.30 0.31-3.49 - - - -

Formoterol/Tiotropium vs Vilanterol/Fluticasone 0.54 0.05-5.45 0.05-6.05 - - - -

Glycopyrronium vs Vilanterol/Fluticasone 0.61 0.19-1.98 0.18-2.10 - - - -

Indacaterol vs Vilanterol/Fluticasone 0.67 0.21-2.11 0.20-2.24 - - - -

Indacaterol/Glycopyrronium vs Vilanterol/Fluticasone 0.70 0.21-2.28 0.20-2.42 - - - -

Indacaterol/Tiotropium vs Vilanterol/Fluticasone 0.88 0.13-5.75 0.12-6.26 - - - -

Mometasone vs Vilanterol/Fluticasone 1.13 0.29-4.44 0.27-4.74 - - - -

Formoterol/Mometasone vs Vilanterol/Fluticasone 0.56 0.10-3.03 0.10-3.28 - - - -

Salmeterol vs Vilanterol/Fluticasone 0.73 0.25-2.13 0.24-2.25 - - - -

Salmeterol/Tiotropium vs Vilanterol/Fluticasone 1.26 0.24-6.74 0.22-7.29 - - - -

Tiotropium vs Vilanterol/Fluticasone 0.79 0.27-2.29 0.26-2.41 - - - -

Tiotropium Respimat vs Vilanterol/Fluticasone 0.79 0.27-2.36 0.25-2.50 - - - -

Triamcinoloneacetonide vs Vilanterol/Fluticasone 0.64 0.18-2.27 0.17-2.42 - - - -

Umeclidinium vs Vilanterol/Fluticasone 0.92 0.22-3.94 0.20-4.22 - - - -

Vilanterol vs Vilanterol/Fluticasone 1.21 0.59-2.49 0.57-2.60 1.30 0.62-2.74 0.00 4 2442

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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 - - - -

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Indacaterol vs Glycopyrronium 1.09 0.57-2.10 0.54-2.19 1.99 0.18-

22.04

-- 1 431

Indacaterol/Glycopyrronium vs Glycopyrronium 1.14 0.65-1.99 0.62-2.08 1.06 0.59-1.89 0.00 2 428

Indacaterol/Tiotropium vs Glycopyrronium 1.43 0.28-7.28 0.26-7.85 - - - -

Mometasone vs Glycopyrronium 1.85 0.68-5.03 0.64-5.30 - - - -

Formoterol/Mometasone vs Glycopyrronium 0.92 0.23-3.74 0.21-4.00 - - - -

Salmeterol vs Glycopyrronium 1.19 0.70-2.03 0.67-2.11 - - - -

Salmeterol/Tiotropium vs Glycopyrronium 2.06 0.52-8.23 0.48-8.80 - - - -

Tiotropium vs Glycopyrronium 1.28 0.78-2.11 0.75-2.19 1.22 0.71-2.10 0.00 3 3385

Tiotropium Respimat vs Glycopyrronium 1.30 0.75-2.23 0.72-2.32 - - - -

Triamcinoloneacetonide vs Glycopyrronium 1.04 0.44-2.47 0.42-2.60 - - - -

Umeclidinium vs Glycopyrronium 1.51 0.34-6.78 0.31-7.28 - - - -

Vilanterol vs Glycopyrronium 1.98 0.67-5.88 0.63-6.22 - - - -

Vilanterol/Umeclidinium vs Glycopyrronium 1.72 0.47-6.24 0.44-6.65 - - - -

Indacaterol/Glycopyrronium vs Indacaterol 1.04 0.53-2.06 0.51-2.14 0.50 0.05-5.54 -- 1 950

Indacaterol/Tiotropium vs Indacaterol 1.31 0.26-6.57 0.24-7.09 - - - -

Mometasone vs Indacaterol 1.69 0.64-4.49 0.61-4.72 - - - -

Formoterol/Mometasone vs Indacaterol 0.84 0.21-3.36 0.20-3.59 - - - -

Salmeterol vs Indacaterol 1.09 0.68-1.76 0.65-1.83 0.48 0.09-2.51 0.00 3 1970

Salmeterol/Tiotropium vs Indacaterol 1.89 0.48-7.42 0.45-7.92 - - - -

Tiotropium vs Indacaterol 1.18 0.75-1.84 0.72-1.91 1.08 0.65-1.78 0.00 3 5988

Tiotropium Respimat vs Indacaterol 1.19 0.72-1.97 0.69-2.04 - - - -

Triamcinoloneacetonide vs Indacaterol 0.95 0.41-2.20 0.39-2.31 - - - -

Umeclidinium vs Indacaterol 1.38 0.31-6.11 0.29-6.56 - - - -

Vilanterol vs Indacaterol 1.82 0.63-5.27 0.59-5.56 - - - -

Vilanterol/Umeclidinium vs Indacaterol 1.58 0.44-5.61 0.42-5.97 - - - -

Indacaterol/Tiotropium vs Indacaterol/Glycopyrronium 1.26 0.25-6.47 0.23-6.98 - - - -

Mometasone vs Indacaterol/Glycopyrronium 1.63 0.59-4.51 0.56-4.76 - - - -

Formoterol/Mometasone vs Indacaterol/Glycopyrronium 0.81 0.20-3.34 0.18-3.57 - - - -

Salmeterol vs Indacaterol/Glycopyrronium 1.05 0.59-1.85 0.57-1.92 - - - -

Salmeterol/Tiotropium vs Indacaterol/Glycopyrronium 1.81 0.45-7.33 0.42-7.84 - - - -

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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 - - - -

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Umeclidinium vs Formoterol/Mometasone 1.64 0.24-11.34 0.22-12.39 - - - -

Vilanterol vs Formoterol/Mometasone 2.16 0.42-11.00 0.39-11.87 - - - -

Vilanterol/Umeclidinium vs Formoterol/Mometasone 1.87 0.32-11.01 0.29-11.95 - - - -

Salmeterol/Tiotropium vs Salmeterol 1.73 0.47-6.42 0.44-6.84 - - - -

Tiotropium vs Salmeterol 1.08 0.87-1.34 0.83-1.40 0.80 0.58-1.12 <0.0001 3 8451

Tiotropium Respimat vs Salmeterol 1.09 0.79-1.49 0.76-1.56 0.62 0.17-2.25 -- 1 304

Triamcinoloneacetonide vs Salmeterol 0.87 0.42-1.80 0.41-1.88 - - - -

Umeclidinium vs Salmeterol 1.27 0.30-5.28 0.28-5.66 - - - -

Vilanterol vs Salmeterol 1.67 0.63-4.43 0.59-4.66 - - - -

Vilanterol/Umeclidinium vs Salmeterol 1.44 0.43-4.80 0.41-5.10 - - - -

Tiotropium vs Salmeterol/Tiotropium 0.62 0.17-2.27 0.16-2.41 - - - -

Tiotropiumropium Respimat vs Salmeterol/Tiotropium 0.63 0.17-2.33 0.16-2.48 - - - -

Triamcinoloneacetonide vs Salmeterol/Tiotropium 0.51 0.12-2.21 0.11-2.37 - - - -

Umeclidinium vs Salmeterol/Tiotropium 0.73 0.11-4.99 0.10-5.45 - - - -

Vilanterol vs Salmeterol/Tiotropium 0.96 0.19-4.85 0.18-5.23 - - - -

Vilanterol/Umeclidinium vs Salmeterol/Tiotropium 0.83 0.14-4.84 0.13-5.25 - - - -

Tiotropiumropium Respimat vs Tiotropium 1.01 0.82-1.24 0.78-1.30 0.96 0.83-1.10 -- 1 11405

Triamcinoloneacetonide vs Tiotropium 0.81 0.40-1.66 0.38-1.73 - - - -

Umeclidinium vs Tiotropium 1.17 0.28-4.87 0.26-5.21 0.19 0.01-4.02 -- 1 437

Vilanterol vs Tiotropium 1.54 0.58-4.08 0.55-4.30 3.00 0.12-

74.07

-- 1 417

Vilanterol/Umeclidinium vs Tiotropium 1.34 0.41-4.41 0.38-4.68 0.94 0.14-6.45 0.00 2 852

Triamcinoloneacetonide vs Tiotropium Respimat 0.80 0.38-1.70 0.36-1.78 - - - -

Umeclidinium vs Tiotropium Respimat 1.16 0.28-4.90 0.26-5.25 - -

Vilanterol vs Tiotropium Respimat 1.53 0.56-4.15 0.54-4.37 - -

Vilanterol/Umeclidinium vs Tiotropium Respimat 1.33 0.39-4.45 0.37-4.73 - -

Umeclidinium vs Triamcinoloneacetonide 1.45 0.30-7.05 0.28-7.60 - -

Vilanterol vs Triamcinoloneacetonide 1.90 0.58-6.28 0.54-6.66 - -

Vilanterol/Umeclidinium vs Triamcinoloneacetonide 1.65 0.41-6.58 0.39-7.03 - -

Vilanterol vs Umeclidinium 1.32 0.36-4.83 0.34-5.15 0.99 0.20-4.95 -- 1 1270

Vilanterol/Umeclidiniumlidinium vs Umeclidinium 1.14 0.31-4.20 0.29-4.47 1.27 0.30-5.32 0.00 2 839

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Vilanterolnterol/Umeclidinium vs Vilanterol 0.87 0.29-2.59 0.27-2.74 1.01 0.25-4.06 0.00 2 1255




31.44 (50,0.982,0.00)

Cardiovascular Related Mortality: 37 studies (6 four-arm, 6 three-arm, 25 two-arm), 20 treatments, 55156 patients


Aclidinium vs Placebo 3.06 0.12-75.35 0.02-556.25 3.06 0.12-

75.35

-- 1 542

Budesonide vs Placebo 1.07 0.27-4.23 0.12-9.95 1.35 0.30-6.08 -- 1 1852

Formoterol/Budesonide vs Placebo 2.38 0.30-18.87 0.08-68.73 5.38 0.26-

112.46

-- 1 581



Vilanterol/Fluticasone vs Placebo 0.91 0.15-5.73 0.05-18.00 0.33 0.01-8.23 -- 1 822


Glycopyrronium vs Placebo 0.23 0.02-2.83 0.00-13.38 0.16 0.01-3.97 -- 1 817


Indacaterol/Glycopyrronium vs Placebo 0.26 0.01-6.63 0.00-49.40 - - - -




Tiotropium Respimat vs Placebo 1.46 0.93-2.29 0.70-3.03 1.86 0.92-3.76 -- 1 3917

Triamcinolone Acetonide vs Placebo 3.01 0.61-14.98 0.22-40.76 3.01 0.61-

14.98

-- 1 1116

Umeclidinium vs Placebo 1.12 0.09-13.59 0.02-64.54 - - - -


50.25

-- 1 693


Aclidinium vs AZD3199 (Ultra LABA) 7.50 0.08-668.55 0.01-

10996.94

- - - -


Formoterol/Budesonide vs AZD3199 (Ultra LABA) 5.84 0.15-222.91 0.02-

2161.81

- - - -


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Indacaterol/Tiotropium vs AZD3199 (Ultra LABA) 4.90 0.11-219.81 0.01-

2356.05

- - - -




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

- - - -














Triamcinolone Acetonide vs Aclidinium 0.99 0.03-35.50 0.00-331.99 - - - -


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Formoterol/Budesonide vs Budesonide 2.22 0.24-20.44 0.06-81.70 4.93 0.24-

103.12

-- 1 556




Formoterol vs Budesonide 0.76 0.11-5.55 0.03-19.11 2.92 0.12-

71.87

-- 1 559








Triamcinolone Acetonide vs Budesonide 2.81 0.34-23.20 0.09-86.58 - - - -







Formoterol vs Formoterol/Budesonide 0.34 0.05-2.28 0.02-7.39 0.49 0.04-5.47 -- 1 565






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 - - - -

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Vilanterol/Fluticasone vs Fluticasone 1.10 0.17-6.94 0.05-21.94 - - - -









Triamcinolone Acetonide vs Fluticasone 3.62 0.71-18.57 0.25-51.47 - - - -




74.80

-- 1 818


73.14

-- 1 528




Indacaterol/Glycopyrronium vs Salmeterol/Fluticasone 0.34 0.01-8.38 0.00-61.86 0.34 0.01-8.38 -- 1 522



Tiotropium vs Salmeterol/Fluticasone 1.61 1.02-2.56 0.76-3.42 2.12 0.95-4.72 -- 1 1448


Triamcinolone Acetonide vs Salmeterol/Fluticasone 3.87 0.75-19.84 0.27-55.04 - - - -




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Triamcinolone Acetonide vs Vilanterol/Fluticasone 3.30 0.29-37.79 0.06-172.95 - - - -


Vilanterol/Umeclidinium vs Vilanterol/Fluticasone 2.40 0.22-25.69 0.05-112.87 - - - -

Vilanterol vs Vilanterol/Fluticasone 1.76 0.22-14.00 0.06-51.11 3.03 0.12-

74.80

-- 1 818


Indacaterol vs Formoterol 0.93 0.14-6.09 0.04-19.69 2.99 0.12-

73.51

-- 1 871






Triamcinolone Acetonide vs Formoterol 3.68 0.36-37.84 0.08-162.01 - - - -




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

- - - -


Tiotropium vs Glycopyrronium 5.36 0.44-65.17 0.09-309.53 - - - -


Triamcinolone Acetonide vs Glycopyrronium 12.84 0.66-248.48 0.10-

1577.10

- - - -

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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

- - - -


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 - - - -


Tiotropium vs Indacaterol 1.66 0.57-4.81 0.29-9.34 2.99 0.12-

73.38

-- 1 1593


Triamcinolone Acetonide vs Indacaterol 3.97 0.60-26.27 0.18-85.38 - - - -





Indacaterolacaterol/Glycopyrronium

7.55 0.16-357.46 0.01-

3965.59

- - - -


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

- - - -



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 - - - -




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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 - - - -




Tiotropium Respimat vs Tiotropium 1.16 0.89-1.50 0.76-1.76 1.12 0.85-1.47 -- 1 11405

Triamcinolone Acetonide vs Tiotropium 2.40 0.46-12.61 0.16-35.53 - - - -

Umeclidinium vs Tiotropium 0.89 0.07-10.81 0.02-51.35 - - - -

Vilanterol/Umeclidinium vs Tiotropium 1.74 0.31-9.70 0.11-28.34 2.96 0.12-

73.01

-- 1 852


74.07

-- 1 417

Triamcinolone Acetonide vs Tiotropium Respimat 2.07 0.39-10.95 0.14-30.97 - - - -

Umeclidinium vs Tiotropium Respimat 0.77 0.06-9.41 0.01-44.96 - - - -

Vilanterol/Umeclidinium vs Tiotropium Respimat 1.50 0.27-8.48 0.09-24.94 - - - -

Vilanterol vs Tiotropium Respimat 1.10 0.25-4.93 0.10-12.54 - - - -

Umeclidinium vs Triamcinolone Acetonide 0.37 0.02-7.23 0.00-46.05 - - - -

Vilanterol/Umeclidinium vs Triamcinolone Acetonide 0.73 0.07-7.59 0.02-32.81 - - - -

Vilanterol vs Triamcinolone Acetonide 0.53 0.06-4.67 0.02-18.08 - - - -

Vilanterol/Umeclidinium vs Umeclidinium 1.96 0.18-20.93 0.04-91.76 3.04 0.12-

74.93

-- 1 1270

Vilanterol vs Umeclidinium 1.44 0.11-18.58 0.02-91.79 - - - -

Vilanterol vs Vilanterol/Umeclidinium 0.73 0.14-3.79 0.05-10.54 0.62 0.08-5.08 0.00 2 1255




11.79 (27,0.995,0.00)

Pneumonia: 54 studies (1 five-arm, 1 four-arm, 2 three-arm, 23 two-arm), 21 treatments, 61551 patients






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Budesonide/Formoterol vs Placebo 1.26 0.80-2.00 0.70-2.26 1.45 0.50-4.18 0.55 3 2066

Fluticasone/Vilanterol vs Placebo 2.13 0.98-4.64 0.82-5.54 1.87 0.50-6.97 0.00 2 822

Fluticasone/Salmeterol vs Placebo 1.90 1.53-2.34 1.39-2.59 1.75 1.44-2.13 <0.0001 4 3872

Mometasone/Formoterol vs Placebo 0.88 0.31-2.51 0.24-3.16 1.66 0.39-7.11 0.00 2 894


26.65

2.81 2 1044

Umeclidinium/Vilanterol vs Placebo 0.61 0.12-3.21 0.08-4.55 - - - -

Tiotropium/Fluticasone/Salmeterol vs Placebo 1.56 0.29-8.27 0.21-11.75 - - - -

Tiotropium/Budesonide/Formoterol vs Placebo 0.94 0.19-4.78 0.13-6.73 - - - -







Aclidinium vs Budesonide 0.90 0.36-2.23 0.30-2.73 - - - -




Beclomethasone/Formoterol vs Budesonide 1.50 0.42-5.39 0.32-7.09 - - - -

Budesonide/Formoterol vs Budesonide 1.68 0.93-3.03 0.80-3.49 1.51 0.67-3.39 0.00 2 1067

Fluticasone/Vilanterol vs Budesonide 2.83 1.10-7.25 0.90-8.93 - - - -

Fluticasone/Salmeterol vs Budesonide 2.52 1.44-4.43 1.25-5.09 - - - -

Mometasone/Formoterol vs Budesonide 1.17 0.37-3.66 0.29-4.68 - - - -

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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 - - - -





Vilanterol vs Fluticasone 0.69 0.32-1.47 0.27-1.75 1.18 0.39-3.54 0.00 2 818

Aclidinium vs Fluticasone 0.41 0.19-0.88 0.16-1.06 - - - -




Beclomethasone/Formoterol vs Fluticasone 0.68 0.20-2.36 0.15-3.08 - - - -

Budesonide/Formoterol vs Fluticasone 0.76 0.45-1.27 0.40-1.44 - - - -

Fluticasone/Vilanterol vs Fluticasone 1.28 0.59-2.78 0.49-3.32 1.01 0.32-3.24 0.00 2 820

Fluticasone/Salmeterol vs Fluticasone 1.14 0.91-1.43 0.83-1.57 1.08 0.90-1.29 0.00 3 3441

Mometasone/Formoterol vs Fluticasone 0.53 0.18-1.55 0.14-1.96 - - - -


Umeclidinium/Vilanterol vs Fluticasone 0.37 0.07-1.95 0.05-2.77 - - - -

Tiotropium/Fluticasone/Salmeterol vs Fluticasone 0.94 0.18-5.04 0.12-7.18 - - - -

Tiotropium/Budesonide/Formoterol vs Fluticasone 0.57 0.11-2.91 0.08-4.11 - - - -

Formoterol vs Mometasone 0.74 0.30-1.82 0.25-2.22 1.91 0.20-

18.09

1.55 2 915

Indacaterol vs Mometasone 0.79 0.30-2.12 0.24-2.64 - - - -



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 - - - -



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Beclomethasone/Formoterol vs Mometasone 0.92 0.21-4.00 0.16-5.46 - - - -

Budesonide/Formoterol vs Mometasone 1.03 0.40-2.62 0.33-3.23 - - - -

Fluticasone/Vilanterol vs Mometasone 1.74 0.53-5.63 0.41-7.26 - - - -

Fluticasone/Salmeterol vs Mometasone 1.55 0.63-3.82 0.51-4.68 - - - -

Mometasone/Formoterol vs Mometasone 0.72 0.23-2.21 0.18-2.83 1.02 0.30-3.47 0.00 2 909

Indacaterol/Glycopyrronium vs Mometasone 0.69 0.25-1.89 0.20-2.35 - - - -

Umeclidinium/Vilanterol vs Mometasone 0.50 0.08-3.27 0.05-4.84 - - - -

Tiotropium/Fluticasone/Salmeterol vs Mometasone 1.27 0.19-8.40 0.13-12.48 - - - -

Tiotropium/Budesonide/Formoterol vs Mometasone 0.77 0.12-4.88 0.08-7.20 - - - -

Indacaterol vs Formoterol 1.07 0.57-2.01 0.49-2.34 - - - -



Aclidinium vs Formoterol 0.74 0.31-1.76 0.26-2.14 - - - -




Beclomethasone/Formoterol vs Formoterol 1.24 0.38-4.07 0.29-5.26 5.13 0.59-

44.24

-- 1 474

Budesonide/Formoterol vs Formoterol 1.39 0.95-2.03 0.85-2.26 1.49 0.98-2.26 0.04 6 4646

Fluticasone/Vilanterol vs Formoterol 2.34 0.95-5.73 0.78-7.00 - - - -

Fluticasone/Salmeterol vs Formoterol 2.09 1.29-3.37 1.14-3.83 - - - -

Mometasone/Formoterol vs Formoterol 0.96 0.34-2.71 0.27-3.39 0.66 0.18-2.36 0.11 2 898


Umeclidinium/Vilanterol vs Formoterol 0.68 0.12-3.75 0.08-5.38 - - - -

Tiotropium/Fluticasone/Salmeterol vs Formoterol 1.72 0.30-9.65 0.21-13.90 - - - -

Tiotropium/Budesonide/Formoterol vs Formoterol 1.03 0.19-5.59 0.13-7.98 - - - -

Salmeterol vs Indacaterol 1.15 0.73-1.81 0.64-2.05 - - - -


Aclidinium vs Indacaterol 0.70 0.29-1.65 0.24-2.00 - - - -

Glycopyrronium vs Indacaterol 0.84 0.50-1.44 0.43-1.65 1.01 0.20-5.01 -- 1 949


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Beclomethasone/Formoterol vs Indacaterol 1.17 0.32-4.29 0.24-5.68 - - - -

Budesonide/Formoterol vs Indacaterol 1.30 0.68-2.48 0.58-2.89 - - - -

Fluticasone/Vilanterol vs Indacaterol 2.19 0.91-5.30 0.74-6.46 - - - -

Fluticasone/Salmeterol vs Indacaterol 1.95 1.20-3.17 1.06-3.60 - - - -

Mometasone/Formoterol vs Indacaterol 0.90 0.29-2.83 0.23-3.62 - - - -


Umeclidinium/Vilanterol vs Indacaterol 0.63 0.12-3.43 0.08-4.90 - - - -

Tiotropium/Fluticasone/Salmeterol vs Indacaterol 1.61 0.29-8.83 0.20-12.65 - - - -

Tiotropium/Budesonide/Formoterol vs Indacaterol 0.97 0.18-5.11 0.13-7.25 - - - -


Aclidinium vs Salmeterol 0.61 0.28-1.31 0.24-1.56 - - - -

Glycopyrronium vs Salmeterol 0.74 0.48-1.13 0.43-1.27 - - - -



Beclomethasone/Formoterol vs Salmeterol 1.01 0.29-3.51 0.22-4.58 - - - -

Budesonide/Formoterol vs Salmeterol 1.13 0.68-1.88 0.60-2.14 - - - -

Fluticasone/Vilanterol vs Salmeterol 1.91 0.87-4.19 0.73-5.01 - - - -

Fluticasone/Salmeterol vs Salmeterol 1.70 1.38-2.09 1.25-2.31 1.69 1.40-2.04 0.00 8 7613

Mometasone/Formoterol vs Salmeterol 0.79 0.27-2.30 0.21-2.90 - - - -

Indacaterol/Glycopyrronium vs Salmeterol 0.76 0.47-1.25 0.41-1.42 - - - -

Umeclidinium/Vilanterol vs Salmeterol 0.55 0.11-2.89 0.07-4.10 - - - -

Tiotropium/Fluticasone/Salmeterol vs Salmeterol 1.40 0.26-7.45 0.18-10.60 - - - -

Tiotropium/Budesonide/Formoterol vs Salmeterol 0.84 0.17-4.30 0.12-6.08 - - - -

Aclidinium vs Vilanterol 0.59 0.20-1.72 0.16-2.17 - - - -

Glycopyrronium vs Vilanterol 0.72 0.31-1.70 0.25-2.06 - - - -

Tiotropium vs Vilanterol 0.83 0.38-1.81 0.32-2.16 2.03 0.18-

22.56

-- 1 408

Umeclidinium vs Vilanterol 0.65 0.09-4.97 0.06-7.61 - - - -

Beclomethasone/Formoterol vs Vilanterol 0.99 0.23-4.19 0.17-5.70 - - - -

Budesonide/Formoterol vs Vilanterol 1.11 0.45-2.70 0.37-3.29 - - - -

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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 - - - -





Budesonide/Formoterol vs Aclidinium 1.87 0.78-4.47 0.64-5.43 - - - -

Fluticasone/Vilanterol vs Aclidinium 3.15 1.07-9.24 0.85-11.68 - - - -

Fluticasone/Salmeterol vs Aclidinium 2.81 1.30-6.07 1.09-7.24 - - - -

Mometasone/Formoterol vs Aclidinium 1.30 0.36-4.70 0.27-6.19 - - - -


Umeclidinium/Vilanterol vs Aclidinium 0.91 0.15-5.57 0.10-8.15 - - - -

Tiotropium/Fluticasone/Salmeterol vs Aclidinium 2.31 0.37-14.33 0.25-21.03 - - - -

Tiotropium/Budesonide/Formoterol vs Aclidinium 1.39 0.23-8.31 0.16-12.11 - - - -

Tiotropium vs Glycopyrronium 1.15 0.80-1.67 0.71-1.87 1.06 0.71-1.58 <0.0001 4 3385


Beclomethasone/Formoterol vs Glycopyrronium 1.38 0.38-5.02 0.29-6.63 - - - -

Budesonide/Formoterol vs Glycopyrronium 1.54 0.82-2.86 0.71-3.32 - - - -

Fluticasone/Vilanterol vs Glycopyrronium 2.59 1.09-6.18 0.90-7.51 - - - -

Fluticasone/Salmeterol vs Glycopyrronium 2.31 1.47-3.64 1.30-4.11 - - - -

Mometasone/Formoterol vs Glycopyrronium 1.07 0.35-3.31 0.27-4.22 - - - -


Umeclidinium/Vilanterol vs Glycopyrronium 0.75 0.14-4.04 0.10-5.76 - - - -

Tiotropium/Fluticasone/Salmeterol vs Glycopyrronium 1.90 0.35-10.39 0.24-14.87 - - - -

Tiotropium/Budesonide/Formoterol vs Glycopyrronium 1.15 0.22-6.01 0.15-8.52 - - - -


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Beclomethasone/Formoterol vs Tiotropium 1.20 0.35-4.14 0.26-5.41 - - - -

Budesonide/Formoterol vs Tiotropium 1.33 0.80-2.22 0.70-2.53 - - - -

Fluticasone/Vilanterol vs Tiotropium 2.25 1.02-4.96 0.85-5.93 - - - -

Fluticasone/Salmeterol vs Tiotropium 2.00 1.52-2.64 1.38-2.92 2.20 1.33-3.62 -- 1 1323

Mometasone/Formoterol vs Tiotropium 0.93 0.32-2.71 0.25-3.42 - - - -

Indacaterol/Glycopyrronium vs Tiotropium 0.90 0.58-1.40 0.51-1.58 0.98 0.62-1.57 0.00 2 2420

Umeclidinium/Vilanterol vs Tiotropium 0.65 0.13-3.36 0.09-4.75 0.61 0.12-3.20 0.00 2 842

Tiotropium/Fluticasone/Salmeterol vs Tiotropium 1.65 0.31-8.65 0.22-12.27 1.65 0.32-8.61 0.00 2 797

Tiotropium/Budesonide/Formoterol vs Tiotropium 0.99 0.20-4.99 0.14-7.02 0.99 0.20-4.96 -- 1 660

Beclomethasone/Formoterol vs Umeclidinium 1.52 0.16-14.71 0.10-23.63 - - - -

Budesonide/Formoterol vs Umeclidinium 1.70 0.24-12.11 0.16-18.28 - - - -

Fluticasone/Vilanterol vs Umeclidinium 2.87 0.37-22.07 0.24-33.84 - - - -

Fluticasone/Salmeterol vs Umeclidinium 2.56 0.38-17.36 0.25-25.96 - - - -

Mometasone/Formoterol vs Umeclidinium 1.18 0.13-10.44 0.08-16.46 - - - -

Indacaterol/Glycopyrronium vs Umeclidinium 1.15 0.16-8.04 0.11-12.10 - - - -

Umeclidinium/Vilanterol vs Umeclidinium 0.83 0.12-5.52 0.08-8.23 1.02 0.14-7.33 -- 1 439

Tiotropium/Fluticasone/Salmeterol vs Umeclidinium 2.10 0.17-26.10 0.10-44.13 - - - -

Tiotropium/Budesonide/Formoterol vs Umeclidinium 1.27 0.10-15.30 0.06-25.72 - - - -

Budesonide/Formoterol vs Beclomethasone/Formoterol 1.11 0.36-3.48 0.28-4.46 1.38 0.43-4.40 -- 1 478

Fluticasone/Vilanterol vs Beclomethasone/Formoterol 1.88 0.44-8.02 0.32-10.91 - - - -

Fluticasone/Salmeterol vs Beclomethasone/Formoterol 1.68 0.49-5.77 0.37-7.53 - - - -

Mometasone/Formoterol vs Beclomethasone/Formoterol 0.78 0.16-3.68 0.12-5.12 - - - -



0.75 0.20-2.80 0.15-3.71 - - - -

Umeclidinium/Vilanterol vs Beclomethasone/Formoterol 0.54 0.07-4.26 0.05-6.55 - - - -



1.38 0.17-10.93 0.11-16.87 - - - -



0.83 0.11-6.37 0.07-9.77 - - - -

Fluticasone/Vilanterol vs Budesonide/Formoterol 1.69 0.68-4.18 0.56-5.11 - - - -

Fluticasone/Salmeterol vs Budesonide/Formoterol 1.50 0.91-2.48 0.80-2.82 - - - -

Mometasone/Formoterol vs Budesonide/Formoterol 0.70 0.24-2.04 0.19-2.58 - - - -

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Indacaterol/Glycopyrronium vs Budesonide/Formoterol 0.67 0.35-1.31 0.30-1.54 - - - -

Umeclidinium/Vilanterol vs Budesonide/Formoterol 0.49 0.09-2.72 0.06-3.91 - - - -



1.24 0.22-7.00 0.15-10.09 - - - -



0.75 0.14-4.05 0.10-5.79 - - - -

Fluticasone/Salmeterol vs Fluticasone/Vilanterol 0.89 0.41-1.96 0.34-2.34 2.04 0.18-

22.62

-- 1 528

Mometasone/Formoterol vs Fluticasone/Vilanterol 0.41 0.11-1.53 0.08-2.02 - - - -

Indacaterol/Glycopyrronium vs Fluticasone/Vilanterol 0.40 0.16-0.98 0.13-1.20 - - - -

Umeclidinium/Vilanterol vs Fluticasone/Vilanterol 0.29 0.05-1.73 0.03-2.52 - - - -



0.73 0.12-4.60 0.08-6.76 - - - -



0.44 0.07-2.67 0.05-3.89 - - - -

Mometasone/Formoterol vs Fluticasone/Salmeterol 0.46 0.16-1.35 0.13-1.70 - - - -

Indacaterol/Glycopyrronium vs Fluticasone/Salmeterol 0.45 0.27-0.75 0.24-0.85 0.11 0.01-2.09 -- 1 522

Umeclidinium/Vilanterol vs Fluticasone/Salmeterol 0.32 0.06-1.71 0.04-2.43 - - - -



0.82 0.15-4.41 0.11-6.29 - - - -



0.50 0.10-2.55 0.07-3.60 - - - -

Indacaterol/Glycopyrronium vs Mometasone/Formoterol 0.97 0.31-3.08 0.24-3.95 - - - -

Umeclidinium/Vilanterol vs Mometasone/Formoterol 0.70 0.10-4.98 0.07-7.51 - - - -


Mometasone/Formoterol

1.78 0.25-12.79 0.16-19.35 - - - -



1.07 0.15-7.44 0.10-11.18 - - - -

Umeclidinium/Vilanterol vs Indacaterol/Glycopyrronium 0.72 0.13-3.97 0.09-5.68 - - - -



1.84 0.33-10.21 0.23-14.66 - - - -



1.11 0.21-5.90 0.15-8.41 - - - -


Umeclidinium/Vilanterol

2.54 0.25-26.17 0.15-42.60 - - - -



1.53 0.15-15.30 0.09-24.76 - - - -



0.60 0.06-6.09 0.04-9.87 - - - -

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34.33 (31,0.311,0.00)

Arrhythmia: 26 studies (1 five-arm, 1 four-arm, 2 three-arm, 22 two-arm), 12 treatments, 27407 patients






Glycopyrronium vs Placebo 1.52 0.63-3.62 0.44-5.21 2.92 0.35-

24.37

0.00 2 1522


Budesonide/Formoterol vs Placebo 2.75 0.87-8.64 0.54-13.93 2.93 0.27-

32.10

1.50 2 1556

Fluticasone/Vilanterol vs Placebo 8.88 0.33-240.14 0.08-948.41 - - - -

Fluticasone/Salmeterolvs Placebo 0.80 0.17-3.86 0.09-7.43 - - - -


51.45

-- 1 706

Formoterol vs Budesonide 0.77 0.13-4.37 0.06-9.03 0.48 0.04-5.35 -- 1 559






Budesonide/Formoterol vs Budesonide 1.40 0.24-8.11 0.12-16.87 0.98 0.14-7.00 -- 1 556


Fluticasone/Salmeterolvs Budesonide 0.41 0.04-4.26 0.01-11.29 - - - -







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Fluticasone/Salmeterolvs Formoterol 0.53 0.09-3.15 0.04-6.58 - - - -








Fluticasone/Salmeterolvs Indacaterol 0.56 0.10-3.23 0.05-6.71 - - - -




Tiotropium vs Salmeterol 1.18 0.41-3.36 0.27-5.21 - - - -



Fluticasone/Salmeterolvs Salmeterol 0.81 0.21-3.19 0.12-5.64 1.01 0.15-6.83 1.07 3 1875





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 - - - -





Fluticasone/Salmeterolvs Glycopyrronium 0.53 0.09-3.00 0.05-6.18 - - - -


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Fluticasone/Salmeterolvs Tiotropium 0.69 0.14-3.46 0.07-6.79 - - - -



Fluticasone/Salmeterolvs Budesonide/Formoterol 0.29 0.04-2.04 0.02-4.59 - - - -


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/Salmeterol 2.03 0.37-11.01 0.18-22.28 3.08 0.12-

75.99

-- 1 522




3.06 (11,0.9899,0.36)

Abbreviations and symbols: OR, Odds Ratio, NMA, Network Meta-analysis, MA, Meta-analysis, CI, Confidence Interval; PrI, Predictive Interval; LABA, long acting

beta agonists, χ², Chi Square Test, d.f., degrees of freedom

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

are presented)

Network Meta-analysis Results Pairwise Meta-anlaysis Results


Ratio CI

Odds

Ratio CI # studies # patients

Exacerbations: 25 studies (2 four-arm, 6 three-arm, 17 two-arm), 20 treatments, 33211 patients

Fluticasone vs Placebo 0.28 0.13-0.62 0.21 0.09-0.48 2.00 541.00

Vilanterol vs Fluticasone 3.88 1.68-8.93 4.86 1.62-14.64 1.00 407.00

Fluticasone/Vilanterol vs Fluticasone 2.86 1.23-6.64 3.40 1.09-10.62 1.00 408.00

Fluticasone/Vilanterol vs Vilanterol 0.74 0.59-0.92 0.75 0.62-0.91 3.00 2031.00


Glycopyrronium 0.62 0.47-0.82 0.63 0.51-0.77 1.00 1469.00

Indacaterol/Glycopyrronium vs Tiotropium 0.73 0.57-0.94 0.74 0.60-0.91 1.00 1466.00

Indacterol/Tiotropium vs Placebo 0.67 0.46-0.98

Indacaterol/Glycopyrronium vs Placebo 0.60 0.43-0.84

Indacaterol vs Fluticasone 3.30 1.44-7.55

Salmeterol vs Fluticasone 3.40 1.49-7.72

Glycopyrronium vs Fluticasone 3.44 1.47-8.07

Tiotropium vs Fluticasone 2.93 1.30-6.57

Umeclidinium vs Fluticasone 4.71 1.71-12.96

Fluticasone/Salmeterol vs Fluticasone 3.14 1.37-7.20 1.19 0.31-4.59 1.00 179.00

Tiotropium/Salmeterol vs Fluticasone 3.20 1.23-8.29

Indacterol/Tiotropium vs Fluticasone 2.41 1.02-5.73

Umeclidinium/Vilanterol vs Fluticasone 4.37 1.73-11.05


Fluticasone 2.60 1.00-6.73

Indacaterol/Glycopyrronium vs Indacaterol 0.65 0.47-0.90

Indacaterol/Glycopyrronium vs Salmeterol 0.63 0.46-0.86

Indacaterol/Glycopyrronium vs Vilanterol 0.55 0.33-0.92


Umeclidinium 0.46 0.23-0.90


Fluticasone/Salmeterol 0.68 0.50-0.93 0.67 0.44-1.03 1.00 522.00

Umeclidinium/Vilanterol vs

Indacterol/Tiotropium 1.81 1.00-3.27

Common within-network heterogeneity

variance

0.01

Design-by-treatment interaction model

for inconsistency χ² (d.f., P-value,

heterogeneity variance)

13.51(12,0.333,0.00)

Mortality Overall: 23 studies (3 four-arm, 5 three-arm, 15 two-arm), 21 treatments, 33624 patients

Salmeterol/Fluticasone vs Placebo 0.50 0.29-0.88

Salmeterol vs Salmeterol/Fluticasone 2.25 1.20-4.20

Tiotropium vs Salmeterol/Fluticasone 1.84 1.07-3.15 1.84 1.07 1 1323

Vilanterol vs Salmeterol/Fluticasone 3.56 1.03-12.38

Common within-network heterogeneity 0.00

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variance




9.51 (12, 0.659,0.00)

Pneumonia: 19 studies (2 four-arm, 4 three-arm, 13 two-arm), 18 treatments, 28763 patients

Budesonide/Formoterol vs Placebo 8.39 1.16-60.69

Fluticasone/Salmeterol vs Placebo 2.45 1.48-4.07

Salmeterol vs Budesonide 2.15 1.00-4.61

Beclomethasone/Formoterol vs Budesonide 11.02

1.05-

116.02

Budesonide/Formoterol vs Budesonide 13.42

1.66-

108.72

Fluticasone/Salmeterol vs Budesonide 3.92 1.68-9.15

Budesonide/Formoterol vs Mometasone 25.06

1.24-

506.42

Budesonide/Formoterol vs Formoterol 2.72 1.38-5.37 2.72 1.38-5.37 2.00 1290.00

Fluticasone/Salmeterol vs Indacaterol 2.08 1.10-3.93

Fluticasone/Salmeterol vs Salmeterol 1.82 1.02-3.26


Fluticasone/Salmeterol vs Glycopyrronium 2.24 1.14-4.41

Budesonide/Formoterol vs Tiotropium 7.97 1.10-57.95

Fluticasone/Salmeterol vs Tiotropium 2.33 1.43-3.78 2.20 1.33-3.62 1.00 1323.00

Mometasone/Formoterol vs

Budesonide/Formoterol 0.12 0.02-0.88






variance

0.00




4.88 (7, 0.675, 0.00)

Abbreviations: CI, Confidence Interval; d.f., degrees of freedom

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Appendix 12. SUCRA Values

The SUCRA allows identifying which treatment is the most effective overall and can be interpreted as 1 =

treatment is certain to be the best and 0 = treatment is certain to be the worst.

Panel A: SUCRA curves for the 17 treatments included in the exacerbations network meta-analysis;

Panel B: SUCRA curves for the 28 treatments included in the mortality overall network meta-analysis;

Panel C: SUCRA curves for the 20 treatments included in the cardiovascular-related mortality network

meta-analysis; Panel D: SUCRA curves for the 21 treatments included in the pneumonia network meta-

analysis; Panel E: SUCRA curves for the 12 treatments included in the arrythmia network meta-analysis.

A

B

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C

D

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E

Abbreviations: BECL, beclomethasone; BUDE, budesonide; FLUT, fluticasone; MOME, mometasone; TRIAM, triamcinolone

acetonide; AZD3199, AZD3199 (ultra LABA); FORM, formoterol; INDAC, indacaterol ; SALM, salmeterol; VILA, vilanterol;

ACLI, aclidinium bromide; GLYC, glycopyrronium bromide; DAROT, darotropium bromide; TIOT, tiotropium; UMEC,

umeclidinium; FORM/BECLO, formoterol/beclomethasone; FORM/BUDE, formoterol/budesonide; VILA/FLUT,

vilanterol/fluticasone; SALM/FLUT, salmeterol/fluticasone/; FORM/MOME, formoterol/mometasone; TIOT/BUDE,

tiotropium/budesonide; TIOT/FLUT, tiotropium/fluticasone; TIOT/FORM, tiotropium/formoterol; TIOT/SALM,

tiotropium/salmeterol; IND/TIOT, indacaterol/tiotropium; INDA/GLYC, indacaterol/glycopyrronium; VILA/UMEC,

vilanterol/umeclidinium; GSK961081, GSK961081; FORM/IPRATR, formoterol + ipratropium bromide; TIOT/FLUT/SALM,

tiotropium/ fluticasone /salmeterol; TIOT/BUDE/FORM, tiotropium/budesonide/formoterol; BUDE/FORM/IPRATR,

budesonide/formoterol/ipratropium bromide; TIOT+Resp, Tiotropium Respimat (Soft Mist Inhaler).

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97

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: Moderate to severe exacerations for patients who experienced an exacerbation in the past year network

meta-analysis forest plot versus placebo; Panel B: Mortality network meta-analysis forest plot versus placebo;

Panel C: Cardiovascular-related mortality network meta-analysis forest plot versus placebo; Panel D: Pneumonia

network meta-analysis forest plot versus placebo; Panel E: Arrhythmia network meta-analysis forest plot versus

placebo.

A

B

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C

D

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99

E

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,


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

Study

Kew KM, Seniukovich A, 2014

[43 studies]

Kew KM, Dias S, Cates CJ, 2014

[71 studies]

Included Published Studies (n = 208)

Aalbers, 2002 NO NO

Aaron , 2007 NO NO

Abrahams , 2013 NO YES

Agusti, 2014 YES NO

Ambrosino, 2008 NO NO

Anzueto , 2009 YES YES

Auffarth, 1991 NO NO

Barnes, 2006 NO NO

Bateman, 2010 NO YES


Bateman, 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 NO NO


Calverley, 2008 NO YES

Campbell, 2007 NO NO

Casaburi, 2005 NO NO

Cazzola, 2007 NO NO

Cazzola, 2000 NO NO

Celli, 2003 NO NO

Celli , 2003 NO NO

Chan , 2007 NO YES

Chanez, 2010 NO NO

Chapman, 2011 NO NO

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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 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, 2012a/b NO YES

Jones, 2012b - -

Jones, 1997 NO NO

Jones, 2012 NO YES

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Jung, 2012 NO NO

Kardos, 2007 YES YES

Kaushik, 1999 NO NO

Kerwin, 2013 YES NO

Kerwin, 2012 NO NO

Kerwin, 2012 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, 2012 - -

Mahler , 2002 YES YES

Maltais , 2011 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


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

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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

Sridevl, 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 NO YES

Tashkin , 2012 NO YES

Tashkin , 2008 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

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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


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 NO NO



GlaxoSmithKline, 2006 NO YES

GlaxoSmithKline, 2005 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 NO YES

Kelleher, 2011 NO NO


GlaxoSmithKline, 2008 YES NO


Novartis, 2006 NO NO

Sekiya, 2012 NO NO

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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist

Section/topic # Checklist item Reported on page #

TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. 1

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

3

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known. 5

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

5

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

6

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,

language, publication status) used as criteria for eligibility, giving rationale. 6

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

6-7

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

7

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,

included in the meta-analysis). 7

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

7-8

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

6-10

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

8

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 8-10

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I

2) for each meta-analysis.

8-10

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Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

9

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

8-10

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

10

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

10-11

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 11; Appendix 9

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

10-16; Appendix 10-13

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 11-16

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 11

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 11-16

DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

16-19

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

11;16-19

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 16-19

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.

5; 21

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097

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For more information, visit: www.prisma-statement.org. Page 2 of 2

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Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease:

A systematic review and network meta-analysis

Journal: BMJ Open

Manuscript ID bmjopen-2015-009183.R1

Article Type: Research

Date Submitted by the Author: 16-Sep-2015

Complete List of Authors: Tricco, Andrea; Li Ka Shing Knowledge Institute of St Michael's Hospital Strifler, Lisa; Li Ka Shing Knowledge Institute of St Michael's Hospital Veroniki, Areti Angeliki; Li Ka Shing Knowledge Institute of St Michael's

Hospital Yazdi, Fatemeh; Ottawa Hospital Research Institute, Center for Practice Changing Research Khan, Paul; Li Ka Shing Knowledge Institute of St Michael's Hospital Scott, Alistair; Li Ka Shing Knowledge Institute of St Michael's Hospital Ng, Carmen; Li Ka Shing Knowledge Institute of St Michael's Hospital Antony, Jesmin; Li Ka Shing Knowledge Institute of St Michael's Hospital Mrklas, Kelly; Alberta Health Services, ; Li Ka Shing Knowledge Institute of St Michael's Hospital D'Souza, Jennifer; Li Ka Shing Knowledge Institute of St. Michael's Hospital, Cardoso, Roberta; Li Ka Shing Knowledge Institute of St. Michael's

Hospital, Straus, Sharon; Li Ka Shing Knowledge Institute of St. Michael's Hospital,

<b>Primary Subject Heading</b>:

Respiratory medicine

Secondary Subject Heading: Evidence based practice, Research methods, Pharmacology and therapeutics

Keywords: Pulmonary Disease, Chronic Obstructive , Emphysema < THORACIC MEDICINE, Pulmonary Emphysema, Network Meta-analysis, Systematic Review


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Comparative safety and effectiveness of long-acting inhaled agents for treating chronic 1

obstructive pulmonary disease: A systematic review and network meta-analysis 2

Andrea C Tricco1,2

; Lisa Strifler1; Areti-Angeliki Veroniki

1; Fatemeh Yazdi

3; Paul A. Khan

1; 3

Alistair Scott1; Carmen Ng

1; Jesmin Antony

1; Kelly Mrklas

1,4; Jennifer D’Souza

1; Roberta 4

Cardoso1; Sharon E Straus

*1,5 5

6

1Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, 209 7

Victoria Street, East Building. Toronto, Ontario, M5B 1T8, Canada 8

2Epidemiology Division, Dalla Lana School of Public Health, University of Toronto, 155 9

College Street, 6th floor, Toronto, Ontario, M5T 3M7, Canada 10

3Ottawa Hospital Research Institute, Center for Practice Changing Research Building, The 11

Ottawa Hospital- General Campus, 501 Smyth Road/PO Box 201B, Ottawa, Ontario, K1H 8L6, 12

Canada 13

4Alberta Health Services, Seventh Street Plaza, 10030 – 107 Street NW, Edmonton, Alberta, T5J 14

3E4, Canada 15

5Department of Geriatric Medicine, University of Toronto, 27 Kings College Circle. Toronto, 16

Ontario M5S 1A1, Canada 17

18

Word count: 294 (abstract), 4013 (main text), 5 figures, 3 tables, 15 appendices. 19

20

Corresponding Author: 21

Dr. Sharon E. Straus, MSc, MD 22

Director, Knowledge Translation program, 23

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Li Ka Shing Knowledge Institute, St. Michael’s Hospital 24

209 Victoria Street, East Building, Room 716, Toronto, Ontario, M5B 1T8, Canada 25

Email: [email protected] 26

Phone: 416-864-3068, fax: 416-864-5805 27

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ABSTRACT 28

Objective: To compare the safety and effectiveness of long-acting beta-antagonists (LABA), 29

long-acting anti-muscarinic agents (LAMA), and inhaled corticosteroids (ICS) for managing 30

chronic obstructive pulmonary disease (COPD). 31

Setting: Systematic review and network meta-analysis (NMA). 32

Participants: 208 randomized clinical trials (RCTs) including 134,692 adults with COPD. 33

Interventions: LABA, LAMA, and/or ICS, alone or in combination, versus each other or 34

placebo. 35

Primary and secondary outcomes: The proportion of patients with moderate-to-severe 36

exacerbations. The number of patients experiencing mortality, pneumonia, serious arrhythmia, 37

and cardiovascular-related mortality were secondary outcomes. 38

Results: NMA was conducted including 20 RCTs for moderate-to-severe exacerbations for 39

26,141 patients with an exacerbation in the past year. Thirty-two treatments were effective 40

versus placebo including: tiotropium, budesonide/formoterol, salmeterol, indacaterol, 41

fluticasone/salmeterol, indacaterol/glycopyrronium, tiotropium/fluticasone/salmeterol, and 42

tiotropium/budesonide/formoterol. Tiotropium/budesonide/formoterol was most effective (99.2% 43

probability of being the most effective according to the Surface Under the Cumulative RAnking 44

[SUCRA] curve). 45

NMA was conducted on mortality (88 RCTs, 97,526 patients); fluticasone/salmeterol was more 46

effective in reducing mortality than placebo, formoterol, and fluticasone alone, and was the most 47

effective (SUCRA=71%). 48

NMA was conducted on cardiovascular-related mortality (CVM, 37 RCTs, 55,156 patients) and 49

the following were safest: salmeterol versus each placebo, tiotropium, and tiotropium (Soft Mist 50

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Inhaler [SMR]); fluticasone versus tiotropium (SMR); and salmeterol/fluticasone versus 51

tiotropium and tiotropium (SMR). Triamcinolone acetonide was the most harmful 52

(SUCRA=81% ). 53

NMA was conducted on pneumonia occurrence (54 RCTs, 61,551 patients). Twenty-four 54

treatments were more harmful, including two that increased risk of pneumonia versus placebo; 55

fluticasone and fluticasone/salmeterol. The most harmful agent was fluticasone/salmeterol 56

(SUCRA=89% ). 57

NMA was conducted for arrhythmia; no statistically significant differences between agents were 58

identified. 59

Conclusions: Many inhaled agents are available for COPD, some are safer and more effective 60

than others. Our results can be used by patients and physicians to tailor administration of these 61

agents. 62

Protocol registration number: PROSPERO # CRD42013006725 63

Keywords: Pulmonary Disease, Chronic Obstructive; Emphysema; Pulmonary Emphysema; 64

Systematic Review; Network Meta-analysis. 65

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STRENGTHS AND LIMITATIONS OF THIS STUDY: 66

• We included >200 randomized trials and this is one of the most comprehensive 67

systematic reviews in this area 68

• We follow the methodologically rigorous guidelines put forth by the Cochrane 69

Collaboration 70

• We conducted a network meta-analysis in accordance with guidance put forth by the 71

International Society For Pharmacoeconomics and Outcomes Research 72

• Many of the included randomized trials were at a high risk of bias for many of the 73

Cochrane risk-of-bias criteria 74

• We were unable to explore other important effect modifiers, such as duration of treatment 75

administration, as this was inconsistently reported across the included randomized trials 76

77

BACKGROUND 78

Evidence from previous systematic reviews and network meta-analyses suggests that inhaled 79

therapy with inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting 80

muscarinic antagonists (LAMA) for patients with chronic obstructive pulmonary disease 81

(COPD) is promising.[1-9] However, to date, it is not clear which combinations of inhaled 82

therapies are the safest and most effective for these patients for all relevant outcomes. In order to 83

examine this issue further, we conducted a systematic review and network meta-analysis. This 84

work is part of a Drug Class Review conducted by the Ontario Drug Policy Research Network 85

(ODPRN) that was funded by the Ontario Ministry of Health and Long-Term Care Health 86

System Research Fund. Our research question was “what is the comparative safety and 87

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effectiveness of long-acting inhaled agents (ICS, LABA, LAMA), alone or in any combination, 88

for patients with COPD?” 89

90

METHODS 91

Protocol 92

Our systematic review protocol was drafted using the Preferred Reporting Items for Systematic 93

reviews and Meta-analyses for Protocols (PRISMA-P) guidance.[10] The protocol was revised 94

based on feedback from various stakeholders, including policy makers from the Ontario Public 95

Drug Programs, industry stakeholders, patients, researchers within the ODPRN, and health care 96

professionals. The final protocol was registered with the PROSPERO registry 97

(CRD42013006725) and posted on the ODPRN website.[11] Since our full methods have been 98

posted online, they are summarized briefly here. 99

Eligibility criteria 100

Parallel-group randomized clinical trials (RCTs) including adults with COPD administered long-101

acting inhaled agent in any combination compared with each other or placebo were eligible for 102

inclusion. Concomitant COPD medications were included if both groups received the same 103

interventions (e.g., rescue medication with a short-acting beta-agonist). A list of included agents 104

can be found in Supplementary File: Appendix 1. A list of the excluded medications can be 105

found in Supplementary File: Appendix 2. 106

The primary outcome of interest was the proportion of patients with moderate-to-severe 107

exacerbations (i.e., worsening of COPD symptoms that may require hospitalization, emergency 108

department visits, treatment with oral steroids and/or antibiotics, use of rescue medication, or 109

unscheduled visits to a walk-in clinic or to a healthcare provider). Secondary outcomes included 110

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the number of patients experiencing mortality, pneumonia, serious arrhythmia, and 111

cardiovascular-related mortality. Outcomes were selected based on feedback from patients with 112

COPD and other stakeholders through a survey (Supplementary File: Appendix 3). The results of 113

the survey appear in Supplementary File: Appendix 4; these have been disseminated online.[12] 114

RCTs were included regardless of duration of follow-up, date of dissemination, or publication 115

status. Due to feasibility constraints, we limited inclusion to English language articles; this has 116

not been shown to bias meta-analysis estimates in the past.[13] Due to the large number of 117

unpublished citations conference abstracts identified, we limited inclusion of unpublished data to 118

abstracts from 2004 onwards because this is more likely to capture unreported data given the 119

greater than the average time it takes for a RCT to be published.[14] Authors were contacted for 120

unpublished data obtained through study protocols and conference abstracts, as well as English 121

translations of non-English articles. 122

Information sources and literature search 123

An experienced librarian conducted comprehensive literature searches in MEDLINE, EMBASE, 124

and the Cochrane Central Register of Controlled Trials from inception until December 2013. The 125

MEDLINE search was peer-reviewed by another experienced librarian using the Peer Review of 126

Electronic Search Strategies (PRESS) checklist,[15] and revised as necessary (Supplementary 127

File: Appendix 5). This was supplemented by manual searching of the reference lists of included 128

studies and relevant reviews.[1-9, 16] 129

Study selection process 130

Only when >90% agreement was achieved through a training exercise, pairs of reviewers 131

screened citations for inclusion, independently. The same process was followed for screening 132

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potentially relevant full-text articles. Conflicts were resolved by discussion or the involvement of 133

a third reviewer (ACT or SES). 134

Data items and data abstraction process 135

After a calibration exercise, study characteristics (e.g., year of conduct, sample size, setting) 136

patient characteristics (e.g., number of patients, age mean age and standard deviation) and the 137

definitions of outcome definitions (e.g., exacerbations [i.e., number of patients with at least 1 138

exacerbation in the past year]) were abstracted independently by pairs of reviewers, 139

independently. To ensure data integrity for the abstracted data, all data were verified by a third 140

reviewer (LS, FY, or AS). Since the Global Initiative for Chronic Obstructive Lung Disease 141

(GOLD) criteria have changed over time, a clinician (SES) reviewed all of the included studies 142

to ascertain the average COPD severity of the patients included in each RCT. 143

Risk of bias and methodological quality appraisal process 144

After a calibration exercise, pairs of reviewers independently assessed each of the included RCTs 145

using the 7-item Cochrane Risk-of-Bias tool.[17] 146

Synthesis 147

A restricted maximum likelihood (REML) method [18] and the I2 statistic [19] were used to 148

estimate the magnitude and measure the between-study heterogeneity variance in meta-analysis, 149

respectively. A random-effects network meta-analysis was conducted because we anticipated 150

that the treatment effects were heterogeneous across the included RCTs. We assumed common 151

heterogeneity across treatment comparisons. As the included treatments are of the same nature, it 152

is clinically reasonable to share a common heterogeneity parameter. 153

The treatment nodes of the network were selected based on input from clinicians, 154

methodologists, and statisticians on the team. Due to the complexity of the analysis, we did not 155

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account for differences in doses and durations assuming that all impact the treatment effect 156

equally. Specifically, when a study compared different doses of an intervention against another 157

intervention, we included only the recommended dose in the analysis. As well, we conducted a 158

specific drug analysis versus a drug class analysis, as this was what the policy-makers associated 159

with the ODPRN requested. 160

Before conducting the analyses, we assessed the transitivity assumption by exploring whether 161

any systematic differences were prevalent in the distribution of potential treatment effect 162

modifiers across treatment comparisons in the network. For each outcome, we examined the 163

percentage of female participants (gender) in the RCTs and the risk of bias results. For the 164

moderate-to-severe exacerbations outcome, we also examined RCTs with eligibility criteria 165

focusing on patients who experienced an exacerbation in the past year and severity of COPD. 166

To evaluate the consistency assumption, we evaluated the network as a whole using the design-167

by-treatment interaction model.[20] If inconsistency was prevalent, the loop-specific method was 168

used to identify local inconsistency in parts of the network.[21-23] When important 169

inconsistency and/or heterogeneity were observed, we assessed for potential data abstraction 170

errors, and if none were identified, we conducted a sub-group network meta-analysis on the 171

potential treatment effect modifiers. We explored the effect of study duration in a random-effects 172

meta-regression analysis for mortality and exacerbation outcomes, assuming a common fixed 173

coefficient across treatment comparisons. To assess the robustness of our results, we conducted a 174

sensitivity analysis limiting all of the analyses to studies with a low risk of bias according to the 175

randomization and allocation concealment components. 176

Summary treatment effects (odds ratios [ORs]) from the network meta-analysis are presented, 177

along with their respective 95% confidence intervals (CI) and 95% predictive intervals (PrI). The 178

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PrI is more conservative than the CI and indicates the possible treatment effects, should an 179

additional study become available.[24, 25] It should be noted that a PrI is available only when 180

the difference between the number of studies in the network and the number of available direct 181

comparisons is greater than 2. A comparison-adjusted funnel plot was used to investigate the 182

association between effect size and its standard error (the latter is closely related to study size). If 183

a relationship exists, this can be due to publication or related biases or due to systematic 184

differences between small and large studies.[26] A treatment hierarchy was also obtained using 185

the SUrface under the Cumulative RAnking (SUCRA) curve analysis which allows the ranking 186

of interventions according to the probability of being the most effective for each outcome (e.g., 187

most effective at reducing the risk of exacerbations, most harmful at increasing the risk of 188

cardiovascular-related mortality).[27] 189

Model fit 190

Random-effects meta-analyses were undertaken in R 3.1.2 using the meta package,[28, 29] while 191

random-effects network meta-analyses were conducted in STATA 13.1 using the mvmeta 192

command.[30, 31] We implemented network meta-regression analyses on the study duration 193

variable in OpenBUGS 3.2.3,[32] using 100,000 simulations with a thinning rate of 10 after 194

discarding the first 30,000 iterations. Convergence was assessed by visual inspection of the 195

mixing of 2 chains with different initial values. We assumed a vague prior for the coefficient 196

parameter (�(0,10�)) and an informative prior for the between-study variance, as suggested by 197

Turner et al.[33] (�~�� (−2.13,1.58)). 198

199

RESULTS 200

Literature search 201

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The literature search yielded a total of 2,447 titles and abstracts (Figure 1). Of these, 980 articles 202

were potentially relevant and their full-text was reviewed. Subsequently, 203 RCTs providing 203

data on 208 RCTs (some trials reported the results from more than one study) plus 58 companion 204

reports fulfilled our eligibility criteria and were included. The list of the included studies can be 205

found in Supplementary File: Appendix 6 and Supplementary File: References. Twenty of the 206

included studies were unpublished. 207

Study and patient characteristics 208

The year of publication ranged from 1989 to 2014 (Table 1, Supplementary File: Appendix 7). 209

Most RCTs were multi-center trials conducted across numerous countries. The duration of 210

treatment with long-acting inhaled agents ranged from 9 hours to almost 4 years. Most of the 211

RCTs reported moderate-to-severe COPD exacerbations (54%) and mortality (46%). The 212

presence of serious arrhythmia was the least frequently reported outcome (15% of studies). 213

The total number of patients across the RCTs was 134,692, with an average of 648 patients per 214

trial (Table 2, Supplementary File: Appendix 8). The severity of COPD was most commonly 215

moderate-to-severe or moderate-to-very severe (61%) in nature. The percentage of females in the 216

included studies ranged from 0 to 58%. 217

Risk of bias 218

Across the included RCTs, the majority had an unclear random sequence generation (63%) and 219

unclear allocation concealment (84%) risk of bias (Figure 2, Supplementary File: Appendix 9). 220

In addition, the majority had an unclear risk of bias (55%) related to selective outcome reporting, 221

as the outcomes reported in the trial protocols differed from those reported in the final 222

publication. Finally, many of the RCTs had a high (52%) or unclear (39%) risk of bias due to the 223

‘other bias’ item, mainly owing to the potential for funding bias as many studies were funded by 224

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a pharmaceutical company and included study authors who were employed by the drug 225

manufacturer. Finally, visual inspection of the comparison adjusted funnel plots showed that 226

there was no evidence for small-study effects and publication bias across all analyses. 227

Moderate-to-severe exacerbations 228

A network meta-analysis was attempted with 112 RCTs including 77,749 patients and 26 inhaled 229

treatments for patients presenting with moderate-to-severe exacerbations (i.e., worsening of 230

COPD symptoms that may require hospitalization, emergency department visits, treatment with 231

oral steroids and/or antibiotics, use of rescue medication, unscheduled walk-in clinic/healthcare 232

provider visits). However, significant inconsistency was observed between direct and indirect 233

evidence (χ2=80.74, degrees of freedom=51, P-value=0.005, heterogeneity variance=0.01). As 234

such, a sub-group network meta-analysis was conducted including only those trials with patients 235

who had experienced an exacerbation in the past year (Figure 3: Panel A). For this analysis, 20 236

RCTs were included with 26,141 patients and 17 treatments; there was no evidence of statistical 237

inconsistency (χ2=3.37, degrees of freedom=4, P-value=0.50, heterogeneity variance=0.00). Of 238

the 136 treatment comparisons in the network meta-analysis model, 32 were statistically 239

significant (Table 3, Supplementary File: Appendices 10 and 11) and eight of these were more 240

effective than placebo in reducing the risk of moderate-to-severe exacerbations: tiotropium, 241

salmeterol, indacaterol, budesonide/formoterol, fluticasone/salmeterol, 242


tiotropium/budesonide/formoterol. The most effective were tiotropium/budesonide/formoterol 244

(99% probability of being the most effective in reducing exacerbations) and 245

indacaterol/glycopyrronium (86%) according to the SUCRA curves (Supplementary File: 246

Appendix 12). 247

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A sensitivity analysis was conducted with studies at a low risk of randomization and allocation 248

concealment biases. Based on 25 RCTs, 20 treatments, and 33,211 patients meeting these 249

criteria, 190 treatment comparisons were made in the network meta-analysis model. Twenty-four 250

of these were statistically significant, including three that reduced the risk of moderate-to-severe 251

exacerbations compared to placebo; fluticasone, indacaterol/tiotropium, and 252

indacaterol/glycopyrronium ( Figure 4). The most effective agent was fluticasone according to 253

the SUCRA curves (96%), which was followed by indacaterol/glycopyrronium (80%), and 254

mometasone/formoterol (80%). A statistically significant association was not observed in our 255

meta-regression analysis conducted using the study duration as a covariate (estimated 256

coefficient: 1.01 (95% credible interval (CrI): 0.41, 2.41), heterogeneity variance=0.02). 257

Mortality 258

Six studies were excluded from the analysis because they reported 0 events in all relevant 259

treatment arms.[34-39] As such, a network meta-analysis was conducted with 88 RCTs, 28 260

treatments, and 97,526 patients (Figure 3: Panel B). There was no evidence of statistical 261

inconsistency (χ2=31.44, degrees of freedom=50, P-value=0.98, heterogeneity variance=0.00). 262

Of the 378 treatment comparisons in the network meta-analysis model, only 3 were statistically 263

significant. Fluticasone/salmeterol combination therapy resulted in a reduced risk of mortality 264

compared with placebo, formoterol, and fluticasone alone (Table 3, Supplementary File: 265

Appendices 10 and 11). The most effective agent in having a reduced risk of mortality was 266

fluticasone/salmeterol as determined by the SUCRA curves (71%) (Supplementary File: 267

Appendix 12). 268

A sensitivity analysis was conducted with studies at a low risk of randomization generation and 269

allocation concealment biases. Based on 23 RCTs, 21 treatments, and 33,624 patients, 210 270

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treatment comparisons were made in the network meta-analysis model. Four of these were 271

statistically significant, as follows: fluticasone/salmeterol was superior to placebo, salmeterol 272

alone, tiotropium, and vilanterol (Figure 5). The most effective agent was the inhaled 273

combination of fluticasone/salmeterol (90%) according to the SUCRA curves. A statistically 274

significant association was not observed in our meta-regression analysis conducted using the 275

study duration as a covariate (estimated coefficient 1.00 (95% CrI: 0.88, 1.14), heterogeneity 276

variance=0.03). 277

Cardiovascular-related mortality 278

Nine studies were excluded from the analysis of cardiovascular-related mortality (including 279

cardiac arrest, aortic aneurysm, and myocardial infarction) because they reported 0 events in all 280

relevant treatment arms.[34-42] As such, a network meta-analysis was conducted including 37 281

RCTs, 20 treatments, and 55,156 patients (Figure 3: Panel C). There was no evidence of 282

statistical inconsistency (χ2=13.05, degrees of freedom=24, P-value=0.97, heterogeneity 283

variance=0.00). A total of 190 treatment comparisons were made in the network meta-analysis 284

model and the following six were statistically significant: salmeterol had a decreased risk of 285

cardiovascular-related mortality versus placebo, tiotropium (Handihaler), and tiotropium (Soft 286

Mist Inhaler). In addition, fluticasone was superior to tiotropium (Soft Mist Inhaler); and the 287

salmeterol/fluticasone combination was superior to both tiotropium (Handihaler) and tiotropium 288

(Soft Mist Inhaler) (Table 3, Supplementary File: Appendices 10 and 11). None of these 289

treatment comparisons remained statistically significant according to the PrI, except for 290

salmeterol versus tiotropium (Soft Mist Inhaler). According to the SUCRA curves 291

(Supplementary File: Appendix 12), the following were the most harmful: triamcinolone 292

acetonide (81% probability of being the most harmful because of a greater risk of cardiovascular-293

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related mortality), formoterol/budesonide (73%), and vilanterol/umeclidinium (73%). However, 294

these particular SUCRA results should be interpreted with caution, as some of these 295

interventions were not statistically different from the other agents according to the effect sizes 296

and 95% CIs. 297

A sensitivity analysis was conducted including only studies with a low risk of bias for 298

cardiovascular-related mortality with 11 RCTs, 12 treatments, 16,443 patients, and 66 treatment 299

comparisons; none of the results were statistically significant. 300

Pneumonia 301

One study was excluded from the analysis for reporting 0 events in all treatment arms.[39] As 302

such, 54 RCTs including 21 treatments, and 61,551 patients were included in a network meta-303

analysis for pneumonia (Figure 3: Panel D). There was no evidence of statistical inconsistency 304

(χ2=34.33, degrees of freedom=31, P-value=0.31, heterogeneity variance=0.00). A total of 210 305

treatment comparisons were made in the network meta-analysis model; 24 were statistically 306

significant (Table 3, Supplementary File: Appendices 11 and 12). Of these, two agents had a 307

greater risk of pneumonia versus placebo; fluticasone and fluticasone/salmeterol. The following 308

were the most harmful agents because they had a greater risk of pneumonia; 309

fluticasone/salmeterol (SUCRA=89%), fluticasone/vilanterol (SUCRA=88%), and fluticasone 310

(SUCRA=82%) (Supplementary File: Appendix 12). 311

A sensitivity analysis was conducted including only studies with a low risk of bias with 19 312

RCTs, 18 treatments, and 28,763 patients. There were 153 treatment comparisons in the network 313

meta-analysis model and 17 were statistically significant (Supplementary File: Appendix 13) 314

including two that were more harmful than placebo because they had a greater risk of 315

pneumonia; budesonide/formoterol and fluticasone/salmeterol. The most harmful agents were 316

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budesonide/formoterol (SUCRA=94%), beclomethasone/formoterol (SUCRA=89%), and 317

fluticasone/salmeterol (SUCRA=78%). 318

Serious arrhythmia 319

Five studies were excluded from the analysis because they reported 0 events in all treatment 320

arms.[39, 43-46] As such, a network meta-analysis was conducted including 26 RCTs, 12 321

treatments, and 27,407 patients (Figure 3: Panel E) for serious arrhythmia (including atrial 322

fibrillation, tachycardia). None of the 66 treatment comparisons were statistically significant 323

(Supplementary File: Appendices 11 and 12) and no evidence of statistical inconsistency was 324

observed (χ2=3.06, degrees of freedom=11, P-value=0.99, heterogeneity variance=0.36). The 325

same results were observed in a sensitivity analysis involving 6 studies at low risk of bias with 7 326

treatments, 13,060 patients, and 22 treatment comparisons. 327

328

DISCUSSION 329

For risk of a moderate-to-severe COPD exacerbation, we could not complete a network meta-330

analysis overall because the data were inconsistent. Here we were able to present results of our 331

network meta-analysis for moderate-to-severe COPD exacerbation amongst patients who had 332

experienced an exacerbation in the past year. We found that tiotropium/budesonide/formoterol 333

and indacaterol/glycopyrronium combinations were the most effective inhaled agents at 334

minimizing the risk of a moderate-to-severe COPD exacerbation. Furthermore, we performed 335

sensitivity analysis for moderate-to-severe exacerbations which included all studies rated as 336

scoring a low risk of bias on the randomization and allocation concealment components. For this 337

network meta-analysis, fluticasone, indacaterol/glycopyrronium, and mometasone/formoterol 338

were the most effective agents at reducing the risk of moderate-to-severe COPD exacerbations. 339

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Our results are similar to a previously published network meta-analysis funded by industry 340

(Merck, Dhome, and Nycomed) that included 35 RCTs with 26,786 patients and concluded that 341

combination therapy with an ICS and LABA is likely superior to single therapy regarding 342

exacerbations.[9] Inclusion criteria included patients with moderate to severe COPD and trials of 343

at least 24 weeks’ duration. A second network meta-analysis of inhaled drugs for COPD in trials 344

of at least 4 weeks’ duration concluded that ICS/LABA combination therapy reduced 345

exacerbations only in patients with low forced expiratory volume.[8] Differences in study 346

eligibility will lead to slightly different network meta-analysis results, reliability, and 347

applicability, due to variations in the network of trials. 348

We also analyzed all-cause mortality in a network meta-analysis and found that the most 349

effective agent was fluticasone/salmeterol because it had a decreased risk of mortality compared 350

with the other agents. These results were consistent when we limited the analysis to those studies 351

with a low risk of bias. We also conducted a network meta-analysis on cardiovascular-related 352

mortality and found that use of tiotropium Handihaler and/or tiotropium Soft Mist Inhalers 353

increased the risk compared to some of the other agents. However, in our sensitivity analysis 354

including only studies with a low risk of allocation concealment or randomization bias no 355

statistically significant results were observed, suggesting that these particular results should be 356

interpreted with caution. 357

Our mortality results are different, yet the cardiovascular-related mortality results are similar to a 358

previously published network meta-analysis including 42 trials (52,516 patients) of at least 24 359

weeks’ duration involving patients allocated to tiotropium Soft Mist Inhalers, tiotropium 360

HandiHalers, ICS+LABA, LABA, ICS or placebo.[47] Patients receiving the tiotropium Soft 361

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Mist Inhalers had the greatest risk of mortality overall, as well as cardiovascular-related 362

mortality. 363

A recent Cochrane review and network meta-analysis compared four classes of long acting 364

inhalers for COPD (ICS, LABA, ICS/LABA combination, and LAMA) for 2 efficacy outcomes: 365

mean trough forced expiratory volume in one second (FEV1) and mean total score on the St 366

George’s Respiratory Questionnaire (SGRQ) in trials of at least 24 weeks’ duration.[48] In their 367

review, 71 RCTs with 73,062 patients were included. As this recent Cochrane review and 368

network meta-analysis did not examine outcomes pertaining to either exacerbations or mortality, 369

there is no overlap in results with our review. 370

We found that the following were the most harmful agents for being associated with increasing 371

risk of pneumonia: fluticasone/salmeterol, fluticasone/vilanterol, and fluticasone according to the 372

SUCRA. These results are consistent with a recent Cochrane review on ICS, LABA and 373

ICS/LABA combination which looked at pneumonia in patients with COPD in trials of at least 374

12 weeks’ duration.[49] Those study authors found an increased risk of pneumonia with 375

fluticasone use versus placebo and for any fluticasone/LABA combination versus LABA alone. 376

However, our pneumonia sensitivity analysis including studies with a low risk of bias found that 377

the most harmful agents that increased the risk of pneumonia were budesonide/formoterol, 378

beclomethasone/formoterol, and fluticasone/salmeterol. Of note, we included 132 more studies 379

comprising 56,727 more patients than the previous Cochrane reviews (Supplementary File: 380

Appendix 14). 381

We found no statistically significant differences in risks of serious arrhythmia across any of the 382

compared agents in our rapid review. This finding is clinically important as clinicians have 383

raised concerns about increasing risk of arrhythmia with use of LABA.[50-52] We are unaware 384

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of any other network meta-analysis that examines this outcome for patients with COPD. We also 385

attempted a network meta-analysis for the dyspnea outcome, yet the results were unreliable so 386

are not presented here, despite numerous sub-group and sensitivity analyses. Such an analysis 387

should be attempted in the future, perhaps utilizing advanced individual patient data network 388

meta-analysis techniques that are currently emerging. 389

There are some limitations of our systematic review that are worth noting. First, we are aware of 390

21 new trials that have been published in 16 papers since our original literature search in 391

December of 2013 (Appendix 15). This is particularly apparent for the LABA/LAMA 392

combinations. The number of new trials that would be included by outcome are: 4 trials with 157 393

patients for moderate-to-severe exacerbations (comparisons include LAMA vs. LAMA, 394

ICS/LABA vs. LABA, and LABA/LAMA vs. LAMA vs. LABA vs. placebo); 16 trials with 104 395

patients for mortality (comparisons include LABA vs. LABA vs. placebo, ICS/LABA vs. 396

LABA, ICS/LABA vs. LAMA, ICS/LABA vs. ICS/LABA, and LABA/LAMA vs. LAMA vs. 397

LABA vs. placebo); 16 trials with 148 patients for pneumonia (comparisons include LABA vs. 398

LABA vs. placebo, ICS/LABA vs. LABA, ICS/LABA vs. LAMA, ICS/LABA vs. ICS/LABA, 399

and LABA/LAMA vs. LAMA vs. LABA vs. placebo); 13 trials with 125 patients for serious 400

arrhythmia (comparisons include LAMA vs. LAMA, ICS/LABA vs. LABA, ICS/LABA vs. 401

ICS/LABA, and LABA/LAMA vs. LAMA vs. LABA vs. placebo); and 7 trials with 11 patients 402

for cardiovascular-related mortality (comparisons include ICS/LABA vs. ICS/LABA, and 403

LABA/LAMA vs. LAMA vs. LABA vs. placebo). However, the current review is one of the 404

largest published network meta-analyses [53] and we have included 208 RCTs and 134,692 405

patients and we believe that our results for the other agents are valid. Second, many of the 406

included RCTs were at a high risk of bias for many of the Cochrane risk-of-bias criteria, 407

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especially for important items such as random sequence generation and allocation concealment, 408

which are imperative for the internal validity of a RCT. In order to address this limitation, we 409

conducted a sensitivity analysis for all outcomes, which focused on inclusion of studies with a 410

low risk of bias in the analysis. Third, we were unable to explore other important effect 411

modifiers, such as duration of treatment administration, as this was inconsistently reported across 412

the included RCTs. Fourth, given the inconsistency across the data, we could not complete a 413

network meta-analysis for risk of moderate-to-severe exacerbations overall. Fifth, we limited 414

inclusion to RCTs published in English, yet this has not been shown to bias meta-analysis results 415

in the past.[13] Finally, we were unable to calculate the PrI for all outcomes, due to the small 416

number of studies included in the exacerbations and sensitivity analyses. 417

In conclusion, tiotropium/budesonide/formoterol inhaled combination therapy reduces risk of 418

moderate-to-severe exacerbations in patients having already experienced a COPD-related 419

exacerbation in the past year. Inhaled fluticasone/salmeterol reduces risk of mortality, yet may 420

increase risk of pneumonia. Tiotropium may increase risk of cardiovascular-related mortality. 421

These agents likely do not increase risk of serious arrhythmia. Future research should update our 422

review to include studies examining the LABA/LAMA combination, as well as the dyspnea 423

outcome, as we were presently unable to conduct a network meta-analysis on this. 424

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SUPPLEMENTARY FILES 425

File name: Supplementary File.pdf 426


Title of the Data: Appendix 1-15 428

429

Description of Data: Protocol 430

File name: Protocol.pdf 431


Title of the Data: Study Protocol 433

434

ACKNOWLEDGEMENTS 435

We thank Becky Skidmore for conducting the literature search and Heather McDonald for peer 436

reviewing the search, Inthuja Selvaratnam for formatting the paper, and Alissa Epworth for 437

obtaining the full-text articles. We also thank Sandra Knowles for all of her support and useful 438

feedback on the draft manuscript. 439

440

AUTHORS’ CONTRIBUTIONS 441

ACT conceived and designed the study, helped obtain funding for the study, screened citations, 442

abstracted data, guided the analysis, interpreted the results, and drafted the manuscript. LS 443

coordinated the review, screened citations and full-text articles, abstracted data, cleaned the data, 444

wrote sections of the manuscript, and edited the manuscript. AAV analyzed and interpreted the 445

data, wrote sections of the manuscript, and edited the manuscript. FY screened citations and full-446

text articles, abstracted data, appraised quality, cleaned the data, and edited the manuscript. PAK 447

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abstracted data, appraised quality, cleaned the data, and edited the manuscript. AS screened 448

citations and full-text articles, abstracted data, helped clean the data, and edited the manuscript. 449

CN screened full-text articles, abstracted data, and edited the manuscript. JA screened citations 450

and full-text articles, abstracted data, and edited the manuscript. KM abstracted data, and edited 451

the manuscript. JD screened citations and full-text articles, and edited the manuscript. RC 452

abstracted data, helped clean the data, and edited the manuscript. SES conceived and designed 453

the study, helped obtain funding for the study, guided the analysis, interpreted the results, and 454

edited the manuscript. All authors read and approved the final paper. 455

456

FUNDING 457

This study was funded by the Ontario Ministry of Health and Long-Term Care Health System 458

Research Fund. ACT is funded by a Canadian Institutes of Health Research (CIHR)/Drug Safety 459

and Effectiveness Network New Investigator Award in Knowledge Synthesis. SES is funded by 460

a Tier 1 Canada Research Chair in Knowledge Translation. AAV is funded by the CIHR Banting 461

Postdoctoral Fellowship Program. 462

463

COMPETING INTERESTS 464

No, there are no competing interests. 465

466

DATA SHARING STATEMENT 467

The full data set is available, including data from the 20 included unpublished studies, on request 468

from the corresponding author (SES, [email protected]).469

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470

Table 1. Study characteristics

Characteristic No. of studies* (n=208) % of studies

Year of publication

1989–1994 3 1.4

1995–1999 15 7.2

2000–2004 35 16.8

2005–2009 68 32.7

2010–2014 87 41.8

Geographic region

Europe 72 34.6%

Multi-continent 44 21.2%

North America 36 17.3%

Multi-country (not specified) 24 11.5%

Asia 20 9.6%

Not reported 9 4.3%

Africa 1 0.5%

Australia 1 0.5%

South America 1 0.5%

Setting

Single centre 32 15.4

Multi-centre 152 73.1

Not reported 24 11.5

Duration of follow-up†

0 to ≤ 6 45 21.6

> 6 to ≤ 12 52 25

> 12 to ≤ 24 35 16.8

> 24 to ≤ 48 19 9.1

> 48 to ≤ 72 39 18.8

> 72 to ≤ 96 2 1

>96 to ≤ 120 6 2.9

> 120 weeks 9 4.3

Not reported 1 0.5

Outcomes examined: frequency§

Efficacy - Exacerbations 112 53.8

Efficacy - Mortality 95 45.7

Harm - Cardiovascular –related mortality 46 22.1

Harm - Pneumonia 54 26.0

Harm - Arrhythmia 32 15.4 *Includes unpublished data

†Duration is in weeks unless otherwise noted; §Multiple interventions and outcomes

reported per study.

Abbreviations: NR; not reported

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471

Table 2. Patient characteristics

Total number of patients 134692

Mean sample size 648

Mean % female 27.7%

Characteristic No. of studies* (n=) % of studies

Age Category

Adult & Elderly ( ≥18) 195 93.8

Adult (18-64) 4 1.9

Elderly ( ≥65) 0 0.0

NR 9 4.3

Severity of COPD

Mild to moderate 10 4.8

Mild to severe 9 4.3

Mild to very severe 8 3.8

Moderate 7 3.4

Moderate to severe 60 28.9

Moderate to very severe 67 32.2

Severe 5 2.4

Severe to very severe 6 2.9

Stable (severity NR) 5 2.4

NR 31 14.9

% Female

0-25% 90 43.3

26%-50% 104 50

51-100% 4 1.9

Not reported 10 4.8

Note: *Includes unpublished studies. Abbreviation: NR; not reported

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Table 3. Statistically Significant Network Meta-analysis Results

Treatment

Comparison

NMA

estimate OR

(95 % CI) CI

MA estimate

OR (95 %

CI) CI

# studies

(# patients) Heterogeneity

Variance

Exacerbation Past year – 20 studies, 17 treatments, 26141 patients

FLUT/SALM vs SALM 0.85 0.75-0.97 0.82 0.70-0.95 4 (2784) 0.00

TIOT vs INDAC 0.83 0.72-0.96 0.83 0.72-0.96 1 (3439) --

TIOT vs SALM 0.82 0.73-0.93 0.84 0.76-0.92 1 (7376) --

SALM vs Placebo 0.79 0.64-0.97 0.80 0.58-1.09 1 (634) --

INDAC vs Placebo 0.78 0.61-1.00 . . . .

BUDE/FORM vs FORM 0.76 0.64-0.91 0.76 0.62-0.93 4 (3080) 0.01

FLUT/F vs VILA 0.75 0.62-0.92 0.75 0.61-0.94 2 (1624) 0.00

INDAC/GLYC vs TIOT 0.74 0.60-0.91 0.74 0.60-0.91 1 (1466) --

INDAC/GLYC vs

FLUT/SALM 0.71 0.55-0.92 . . . .

FLUT/SALM vs Placebo 0.67 0.53-0.85 . . . .

TIOT vs Placebo 0.65 0.53-0.79 0.64 0.50-0.83 1 (1003) --

BUDE/FORM vs

Placebo 0.64 0.45-0.91 0.55 0.36-0.83 1 (519) --

INDAC/GLYC vs GLYC 0.63 0.51-0.78 0.63 0.51-0.77 1 (1469) --

INDAC/GLYC vs

INDAC 0.62 0.48-0.79 . . . .

INDAC/GLYC vs SALM 0.61 0.48-0.78 . . . .

TIOT/FLUT/SALM vs

Placebo 0.58 0.35-0.96 . . . .

INDAC/GLYC vs

FORM 0.57 0.36-0.90 . . . .

TIOT/BUDE/FORM vs

INDAC/GLYC 0.48 0.28-0.83 . . . .

INDAC/GLYC vs

Placebo 0.48 0.36-0.64 . . . .

TIOT/BUDE/FORM vs

TIOT/FLUT/SALM 0.40 0.21-0.80 . . . .

TIOT/BUDE/FORM vs

BUDE/FORM 0.36 0.19-0.69 . . . .

TIOT/BUDE/FORM vs

TIOT 0.36 0.22-0.59 0.36 0.22-0.59 1 (660) --

TIOT/BUDE/FORM vs

FLUT/SALM 0.35 0.21-0.58 . . . .

TIOT/BUDE/FORM vs

TIOT/SALM 0.33 0.17-0.65 . . . .

TIOT/BUDE/FORM vs

BECL/FORM 0.32 0.15-0.65 . . . .

TIOT/BUDE/FORM vs

BUDE 0.31 0.16-0.60 . . . .

TIOT/BUDE/FORM vs

GLYC 0.30 0.18-0.52 . . . .

TIOT/BUDE/FORM vs

INDAC 0.30 0.18-0.50 . . . .

TIOT/BUDE/FORM vs

SALM 0.30 0.18-0.49 . . . .

TIOT/BUDE/FORM vs

FLUT 0.29 0.14-0.60 . . . .

TIOT/BUDE/FORM vs

FORM 0.28 0.15-0.52 . . . .

TIOT/BUDE/FORM vs

Placebo 0.23 0.14-0.40 . . . .


Design-by-treatment interaction model for 3.37 (4,0.498,0.00)

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

Mortality Overall – 88 studies, 28 treatments, 97526 patients

FORM vs FLUT/SALM 1.64 1.01-2.67 . . . 0.00

FLUT/SALM vs Placebo 0.78 0.63-0.96 0.81 0.66-1.00 6 (4852) 0.00

FLUT/SALM vs FLUT 0.75 0.60-0.94 0.76 0.62-0.93 3 (3752) 0.00




Cardiovascular-related Mortality – 37 studies, 20 treatments, 55156 patients

TIOT+Resp vs SALM 2.32 1.38-3.88 . . . .

TIOT vs SALM 2.00 1.23-3.26 1.32 0.46-3.81 1 (7798) --

TIOT+Resp vs

FLUT/SALM 1.87 1.14-3.06 . . . .

TIOT+Resp vs FLUT 1.75 1.04-2.94 . . . .

TIOT vs FLUT/SALM 1.61 1.02-2.56 2.12 0.95-4.72 1 (1448) --

SALM vs Placebo 0.63 0.45-0.88 0.60 0.42-0.87 4 (5171) 0.00




Pneumonia – 54 studies, 21 treatments, 61551 patients

FLUT/VILA vs ACLI 3.15 1.07-9.24 . . . .

FLUT/VILA vs BUDE 2.83 1.10-7.25 . . . .

FLUT/SALM vs ACLI 2.81 1.30-6.07 . . . .

FLUT/VILA vs GLYC 2.59 1.09-6.18 . . . .

FLUT/SALM vs BUDE 2.52 1.44-4.43 . . . .

FLUT/SALM vs GLYC 2.31 1.47-3.64 . . . .

FLUT/VILA vs TIOT 2.25 1.02-4.96 . . . .

FLUT vs BUDE 2.21 1.25-3.92 . . . .

FLUT/SALM vs FORM 2.09 1.29-3.37 . . . .

FLUT/SALM vs TIOT 2.00 1.52-2.64 2.20 1.33-3.62 1 (1323) --

FLUT/SALM vs. INDAC 1.95 1.20-3.17 . . . .

FLUT/SALM vs. Placebo 1.90 1.53-2.34 1.75 1.44-2.13 4 (3872) <0.0001

FLUT/VILA vs. VILA 1.87 1.18-2.96 1.90 1.20-3.01 4 (2442) 0.00

FLUT/SALM vs. SALM 1.70 1.38-2.09 1.69 1.40-2.04 8 (7613) 0.00

FLUT vs. Placebo 1.66 1.32-2.08 1.60 1.32-1.95 5 (4258) 0.00

SALM vs. FLUT 0.67 0.54-0.84 0.68 0.56-0.83 2 (3174) 0.00

INDAC vs. FLUT 0.58 0.36-0.95 . . . .

TIOT vs. FLUT 0.57 0.43-0.75 . . . .

FORM vs. FLUT 0.55 0.33-0.90 . . . .

INDAC/GLYC vs. FLUT 0.51 0.31-0.85 . . . .

GLYC vs. FLUT 0.49 0.31-0.78 . . . .

INDAC/GLYC vs.

FLUT/SALM 0.45 0.27-0.75 0.11 0.01-2.09 1 (522) --

ACLI vs. FLUT 0.41 0.19-0.88 . . . .

INDAC/GLYC vs.

FLUT/VILA 0.40 0.16-0.98 . . . .



inconsistency χ² (def., P-value, heterogeneity) 34.33 (31,0.311,0.00)

Abbreviations: OR: Odds Ratio, NMA: Network Meta-analysis, MA: Meta-analysis, CI: Confidence Interval, def.: Degrees of

freedom, vs.: Versus

Treatment Abbreviations: BECL, beclomethasone; BUDE, budesonide; FLUT, fluticasone; FORM, formoterol; INDAC,

indacaterol ; SALM, salmeterol; VILA, vilanterol; ACLI, aclidinium bromide; GLYC, glycopyrronium bromide; TIOT, tiotropium;

TIOT+Resp, Tiotropium Respimat (Soft Mist Inhaler).

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FIGURES 472

Figure 1. Study Flow Diagram Details the flow of information through the different phases of 473

the review; maps out the number of records identified, included and excluded, and the reasons 474

for their exclusion. 475

476

Figure 2. Risk of Bias Appraisal Results 477

Abbreviations: High, High risk of bias; Low, Low risk of bias; Unclear, Unclear risk of bias. 478

Items: 479

1. Random sequence generation 480

2. Allocation concealment 481

3. Blinding of participants and personnel 482

4. Blinding of outcome assessment 483

5. Incomplete outcome data 484

6. Selective reporting 485

7. Other bias 486

Figure 3. Network Meta-analysis Plots. Panel A: Exacerbation, Panel B: Mortality, Panel C: 487

Cardiovascular-related Mortality, Panel D: Pneumonia, and Panel E: Serious Arrhythmia. Nodes are proportional to 488

the number of patients included in the corresponding treatments, and edges are weighted according to the number of 489

studies included in the respective comparisons. Abbreviations: BECL, beclomethasone; BUDE, budesonide; FLUT, 490

fluticasone; MOME, mometasone; TRIAM, triamcinolone acetonide; AZD3199, AZD3199 (ultra LABA); FORM, 491

formoterol; INDAC, indacaterol ; SALM, salmeterol; VILA, vilanterol; ACLI, aclidinium bromide; GLYC, 492

glycopyrronium bromide; DAROT, darotropium bromide; TIOT, tiotropium; UMEC, umeclidinium; 493

FORM/BECLO, formoterol/beclomethasone; FORM/BUDE, formoterol/budesonide; VILA/FLUT, 494

vilanterol/fluticasone; SALM/FLUT, salmeterol/fluticasone/; FORM/MOME, formoterol/mometasone; 495

TIOT/BUDE, tiotropium/budesonide; TIOT/FLUT, tiotropium/fluticasone; TIOT/FORM, tiotropium/formoterol; 496

TIOT/SALM, tiotropium/salmeterol; IND/TIOT, indacaterol/tiotropium; INDA/GLYC, indacaterol/glycopyrronium; 497

VILA/UMEC, vilanterol/umeclidinium; GSK961081, GSK961081; FORM/IPRATR, formoterol + ipratropium 498

bromide; TIOT/FLUT/SALM, tiotropium/ fluticasone /salmeterol; TIOT/BUDE/FORM, 499

tiotropium/budesonide/formoterol; BUDE/FORM/IPRATR, budesonide/formoterol/ipratropium bromide; 500

TIOT+Resp, Tiotropium Respimat (Soft Mist Inhaler). 501

502

Figure 4. Moderate to severe exacerbations for patients who experienced an exacerbation 503

in the past year network meta-analysis forest plot versus placebo 504 Forest Plot treatments compared to placebo. The black horizontal lines represent the 95% confidence intervals (CI) 505 of the summary treatment effects and red horizontal lines the 95% predictive intervals (PrI). The results are 506 presented on the odds ratio scale. Abbreviations: CI, confidence interval; PrI, predictive interval; NMA, network 507

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meta-analysis; REML, restrictive maximum likelihood. Treatment Abbreviations: BUDE, budesonide; FLUT, 508 fluticasone; FORM, formoterol; INDAC, indacaterol ; SALM, salmeterol; VILA, vilanterol; GLYC, 509 glycopyrronium bromide; TIOT, tiotropium; FORM/BECLO, formoterol/beclomethasone; FORM/BUDE, 510 formoterol/budesonide; VILA/FLUT, vilanterol/fluticasone; SALM/FLUT, salmeterol/fluticasone; TIOT/SALM, 511 tiotropium/salmeterol; INDA/GLYC, indacaterol/glycopyrronium; TIOT/FLUT/SALM, tiotropium/ fluticasone 512 /salmeterol; TIOT/BUDE/FORM, tiotropium/budesonide/formoterol. 513 514

Figure 5. Mortality network meta-analysis forest plot versus placebo 515 Forest Plot treatments compared to placebo. The black horizontal lines represent the 95% confidence intervals (CI) 516 of the summary treatment effects and red horizontal lines the 95% predictive intervals (PrI). The results are 517 presented on the odds ratio scale. Abbreviations: CI, confidence interval; PrI, predictive interval; NMA, network 518 meta-analysis; REML, restrictive maximum likelihood. Treatment Abbreviations: AZD3199, AZD3199 (ultra 519 LABA); FORM/TIOT, formoterol/ tiotropium; FORM/MOME, formoterol/mometasone; ACLI, aclidinium 520 bromide; GLYC, glycopyrronium bromide; BECL/FORM, beclomethasone/formoterol; TRIAM, triamcinolone 521 acetonide; SALM/FLUT, salmeterol/fluticasone; BUDE, budesonide; INDA, indacaterol; INDA/GLYC, 522 indacaterol/glycopyrronium; SALM, salmeterol; FLUT/TIOT, fluticasone/tiotropium; TIOT, tiotropium; 523 TIOT+Resp, Tiotropium Respimat (Soft Mist Inhaler); FLUT, fluticasone; FORM/BUDE, formoterol/budesonide; 524 INDA/TIOT, indacaterol/tiotropium; UMEC, umeclidinium; VILA/FLUT, vilanterol/fluticasone; FORM, 525 formoterol; VILA/UMEC, vilanterol/umeclidinium; MOME, mometasone; VILA, vilanterol; SALM/TIOT, 526 salmeterol/tiotropium; SALM/FLUT/TIOT, salmeterol/fluticasone/tiotropium; FORM/BUDE/TIOT, 527 formoterol/budesonide/ tiotropium 528

529

530

531

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47. Dong YH, Lin HH, Shau WY et al. Comparative safety of inhaled medications in patients with 649

chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-650

analysis of randomised controlled trials. Thorax. 2013; 68(1):48-56. 651

48. Kew KM, Dias S, Cates CJ. Long-acting inhaled therapy (beta-agonists, anticholinergics and 652

steroids) for COPD: a network meta-analysis. Cochrane Database of Systematic Reviews. 653

2014(3):CD010844. 654

49. Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive 655

pulmonary disease. Cochrane Database of Systematic Reviews. 2014(3):CD010115. 656

50. Insulander P, Juhlin-Dannfelt A, Freyschuss U et al. Electrophysiologic effects of salbutamol, a 657

beta2-selective agonist. J Cardiovasc Electrophysiol. 2004; 15(3):316-322. 658

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51. Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of beta-agonists in patients with 659

asthma and COPD: a meta-analysis. Chest. 2004; 125(6):2309-2321. 660

52. Cazzola M, Matera MG, Donner CF. Inhaled beta2-adrenoceptor agonists: cardiovascular safety 661

in patients with obstructive lung disease. Drugs. 2005; 65(12):1595-1610. 662

53. Nikolakopoulou A, Chaimani A, Veroniki AA et al. Characteristics of networks of interventions: 663

a description of a database of 186 published networks. PLoS One. 2014; 9(1):e86754. 664

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Figure 1. Study Flow Diagram Details the flow of information through the different phases of the review; maps out the number of records identified, included and excluded, and the reasons for their exclusion.

187x190mm (300 x 300 DPI)

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Figure 2. Risk of Bias Appraisal Results Abbreviations: High, High risk of bias; Low, Low risk of bias; Unclear, Unclear risk of bias.

Items:

1. Random sequence generation 2. Allocation concealment

3. Blinding of participants and personnel 4. Blinding of outcome assessment

5. Incomplete outcome data 6. Selective reporting

7. Other bias

242x107mm (300 x 300 DPI)

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Figure 3. Network Meta-analysis Plots. Panel A: Exacerbation, Panel B: Mortality, Panel C: Cardiovascular-related Mortality, Panel D: Pneumonia, and Panel E: Serious Arrhythmia. Nodes are proportional to the number of patients included in the corresponding treatments, and edges are weighted according to the number of studies included in the respective comparisons. 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).

247x173mm (300 x 300 DPI)

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Figure 4. Moderate to severe exacerbations for patients who experienced an exacerbation in the past year network meta-analysis forest plot versus placebo. Forest Plot treatments 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. Abbreviations: CI, confidence interval; PrI, predictive interval; NMA, network meta-analysis; REML,

restrictive maximum likelihood. Treatment Abbreviations: BUDE, budesonide; FLUT, fluticasone; FORM, formoterol; INDAC, indacaterol ; SALM, salmeterol; VILA, vilanterol; GLYC, glycopyrronium bromide; TIOT, tiotropium; FORM/BECLO, formoterol/beclomethasone; FORM/BUDE, formoterol/budesonide; VILA/FLUT, vilanterol/fluticasone; SALM/FLUT, salmeterol/fluticasone; TIOT/SALM, tiotropium/salmeterol; INDA/GLYC,

indacaterol/glycopyrronium; TIOT/FLUT/SALM, tiotropium/ fluticasone /salmeterol; TIOT/BUDE/FORM, tiotropium/budesonide/formoterol.

254x190mm (300 x 300 DPI)

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Figure 5. Mortality network meta-analysis forest plot versus placebo.Forest Plot treatments 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. Abbreviations: CI, confidence interval; PrI, predictive interval; NMA, network meta-analysis; REML, restrictive maximum likelihood. Treatment Abbreviations: AZD3199, AZD3199 (ultra LABA);

FORM/TIOT, formoterol/ tiotropium; FORM/MOME, formoterol/mometasone; ACLI, aclidinium bromide; GLYC, glycopyrronium bromide; BECL/FORM, beclomethasone/formoterol; TRIAM, triamcinolone acetonide;

SALM/FLUT, salmeterol/fluticasone; BUDE, budesonide; INDA, indacaterol; INDA/GLYC, indacaterol/glycopyrronium; SALM, salmeterol; FLUT/TIOT, fluticasone/tiotropium; TIOT, tiotropium;

TIOT+Resp, Tiotropium Respimat (Soft Mist Inhaler); FLUT, fluticasone; FORM/BUDE, formoterol/budesonide; INDA/TIOT, indacaterol/tiotropium; UMEC, umeclidinium; VILA/FLUT,

vilanterol/fluticasone; FORM, formoterol; VILA/UMEC, vilanterol/umeclidinium; MOME, mometasone; VILA, vilanterol; SALM/TIOT, salmeterol/tiotropium; SALM/FLUT/TIOT, salmeterol/fluticasone/tiotropium;

FORM/BUDE/TIOT, formoterol/budesonide/ tiotropium.

254x190mm (300 x 300 DPI)

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1

APPENDICES

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Appendix 1. Inhalers included in the systematic review


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

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3

Combo LABA plus Short-acting muscarinic anticholinergic (SAMA)

formoterol/ipratropium bromide

Combo LAMA plus LABA in one inhaler**

vilanterol/umeclidinium AnoroEllipta

indacaterol/glycopyrronium QVA149, Ultibro

tiotropium/formoterol

indacterol/tiotropium

tiotropium/salmeterol

Combo LAMA plus LABA in one inhaler (MABA)

GSK961081 (formerly TD5959)

Combo ICS plus LABA plus LAMA in one inhaler

tiotropium/fluticasone/salmeterol

tiotropium/budesonide/formoterol

Combo ICS plus LABA plus SAMA

budesonide/formoterol/ipratropium bromide

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

inhalers.

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4

Appendix 2. Full list of excluded medications


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.

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5

Appendix 3. All efficacy and safety outcomes considered

Efficacy outcomes:

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

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

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

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

5. Forced expiratory volume (FEV)

6. Quality of life

7. Mortality

Safety outcomes:

1. All harms

2. Serious harms

3. Withdrawals due to lack of efficacy

4. Treatment-related withdrawals

5. Cardiovascular-related mortality

6. Bone mineral density

7. Dyspnea

8. Ischemic heart disease

9. Heart failure

10. Arrhythmia

11. Pneumonia

12. Cataracts

13. Oral thrush

14. Palpitations

15. Headache

16. Constipation

17. Dry mouth

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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)

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7

Appendix 5. Final MEDLINE Search

1 exp Pulmonary Disease, Chronic Obstructive/

2 exp Emphysema/ or exp Pulmonary Emphysema/


air flow*)).tw.



6 emphysema*.tw.

7 or/1-6

8 Formoterol*.tw,rn.


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.


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

20 94749-08-3.rn.










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8

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














30 exp Adrenergic beta-Agonists/ or Bronchodilator Agents/



32 30 and 31

33 or/21-29,32

34 Administration, Inhalation/

35 exp Aerosols/


37 or/34-36

38 33 and 37

39 or/8-20,38 )

40 Beclomethasone/









45 4419-39-0.rn.

46 Budesonide/

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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.



51 Glucocorticoids/


53 Adrenal Cortex Hormones/


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.


62 (formoterol adj3 mometasone).tw,rn.


64 (formoterol adj3 budesonide).tw,rn.


66 (vilanterol adj3 fluticasone).tw,rn.

67 Breo Ellipta.tw.

68 or/60-67

69 tiotropium.tw,rn.


XX112XZP0J).tw.

71 aclidiniumbromide.tw,rn.



73 glycoyrroniumbromide.tw,rn.




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10




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/


air flow*)).tw.



105 emphysema*.tw.

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11

106 or/100-105

107 formoterol/ or formoterolfumarate/


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/


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

119 94749-08-3.rn.










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












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



131 129 and 130

132 or/120-128,131

133 inhalational drug administration/

134 aerosol/


136 or/133-135

137 132 and 136

138 or/107-119,137

139 beclometasone/









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/



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

151 glucocorticoid/


153 corticosteroid/


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13

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

156 or/151-155

157 156 and 136

158 or/139-150,157

159 fluticasone propionate plus salmeterol/


161 (fluticasone adj3 salmeterol).tw.

162 136112-01-1.rn.

163 formoterolfumarate plus mometasonefuroate/

164 (formoterol adj3 mometasone).tw.


166 budesonide plus formoterol/

167 (formoterol adj3 budesonide).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/


XX112XZP0J).tw.

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

177 aclidinium bromide/



179 320345-99-1.rn.

180 glycoyrronium bromide.tw.







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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

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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].

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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].

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Appendix 7. Characteristics of the randomized controlled trials

Author, year Country of conduct Setting Study

conduct

period

(weeks)

Treatme

nt

duration

(weeks)

# of

treatme

nt

groups

Overall

Sample

size

Aalbers, 2002[96] Australia, Belgium,

Denmark, Germany,

Hungary, The Netherlands,

Norway, Poland, UK


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

Abrahams,

2013[133]

10 countries multi-center 24 24 2 856

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

Ambrosino,

2008[164]

Italy multi-center 25 25 2 234

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

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

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

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

Bateman, 2010[7]

CR:[210]


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

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

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

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

the Netherlands, Slovakia


Beier, 2013[70] Czech Republic, Germany,

Hungary, Poland


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

Ukraine


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

Bourbeau,

1998[128]

Canada single center 26 26 2 79

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

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

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

Portugal, Sweden, Turkey,

UK, USA


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

Canada, Columbia,

Denmark, Finland, France,

Germany, Greece, Hungary,

Israel, Italy, Mexico,

Norway, Poland, Russia,

Slovakia, Spain,



Burge, 2000 [129]

CR:[204-208]

UK multi-center 156.53 156.53 2 751

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

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Calverley, 2003[34]

CR:[214-216, 261]


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

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

Calverley,

2007[138] CR: [234-

242]

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

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

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

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

Casaburi, 2005[103]

CR:[243]

USA multi-center 25 25 2 108

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

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

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

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

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

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

Chapman,

2002[147]

Canada, Denmark, The

Netherlands, Russia,

Sweden, UK


Chapman,

2011[115] CR: [249-

251]

USA, Argentina, Canada,

Germany, India, Italy,

Spain, Sweden, Turkey


Choudhury,

2007[173]

UK multi-center 52 52 2 260

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

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

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

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

D’Urzo, 2011[79] NR NR 30.29 26 2 822

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

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

Czech, Denmark, Ecuador,

Egypt, Estonia, France,

Germany, Hungary, Israel,

Italy, Korea, Latvia,

Lithuania, Netherlands,

Peru, Romania, Russia,

Slovakia, Spain,



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

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

Canada, India, Korea, South

Africa


Dal Negro,

2003[137]

Italy single center 52 52 3 18

Decramer,

2013[122]

Argentina, Australia,

Austria, Belgium, Brazil,

Canada, China, Columbia,


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Costa Rica, Czech,

Denmark, Estonia, Finland,

France, Germany, Hungary,

Iceland, India, Israel, Italy,

Latvia, Lithuania, Mexico,

the Netherlands, Peru,

Philippines, Poland,

Portugal, Romania, Russia,


Spain, Sweden, Switzerland,

Taiwan, Thailand, Turkey,

UK, Venzuela

Decramer,

2014[183]a

Germany, Italy, Mexico,

Peru, Poland, Romania,

Russia, Ukraine, USA


Decramer,

2014[183]b


Canada, Chile, Germany,

Mexico, Romania, South

Africa, South Korea, USA


Doherty, 2012 North, Central and South

America, Europe, Africa,

Asia (not specified)


Donohue, 2002[3]

CR:[257, 258]


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

Chile, Czech Republic,

Greece, Japan, Mexico,

Poland, Russia, South

Africa, Spain, Thailand


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

Dransfield,

2013[180]a


Dransfield,

2013[180]b


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

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

Feldman, 2010[76] USA, New Zealand,

Belgium


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

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

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

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

Philippines, Vietnam, India,

Russia, Poland, Ukraine


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

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

Hagedorn,

2013[109]

Germany multi-center 52 52 2 212

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

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

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

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

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Hattotuwa,

2002[157] CR:[260]

UK single center 12 12 2 37

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

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

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

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

Belgium, France, Germany,

Italy, The Netherlands, New

Zealand


Jones, 2011[176]a

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

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

American countries


Jones, 2012[85] 9 European countries (not

specified), South Africa


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

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

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

Kerwin, 2011[177]a


Kerwin, 2011[177]b


Kerwin, 2012[68]

CR:[244]

USA, Canada multi-center 12 12 3 560

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

Chile, France, Germany,

Hungary, Israel, Italy,

Korea, Mexico,

Netherlands, New Zealand,

Peru, Poland, Russia


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

Japan, Korea, Philippines,

Poland, Russian Federation,

USA


Kinoshita, 2012[75]

CR: [253]

Hong Kong, India, Japan,

Korea, Singapore, Taiwan


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

Hungary, India, Slovakia,

Spain, Turkey


Kornmann,

2011[123]

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

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

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

Poland, Russia


Lapperre, 2009[49]

CR:[252]

The Netherlands multi-center 120 (24

weeks

for one

group)

120 (24

weeks

for one

group)

4 75

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

Llewellyn-Jones,

1996[44]

UK NR 14 8 2 16

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

South Korea, Latvia,

Lithuania, The Netherlands,

New Zealand, Russia,


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Slovenia, South Africa, UK

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

Magnussen,

2008[106]

Belgium, Canada, Germany,

Denmark, France, Italy, the

Netherlands, South Africa


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

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

Mahler, 2012[175]a


Colombia, Denmark,

Germany, Greece,

Guatemala, Mexico, Peru,

Philippines, South Africa,

Spain, Turkey, USA


Mahler, 2012[175]b Argentina, Canada,

Colombia, Czech Republic,

Hungary, India,


Slovakia, Spain, USA


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

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

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

Martinez, 2013[94] Czech Republic, Germany,

Japan, Poland, Romania,

Russian Federation,

Ukraine, USA


Mathioudakis,

2013[100]

Greece single center 208 208 5 564

McNicholas,

2004[113]

UK, Ireland, The

Netherlands


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

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

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

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

Niewoehner,

2005[126] CR:[211,

212]


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

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

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

Paggiaro, 1998[120] 13 European countries (not

specified), New Zealand,

South Africa


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

Pauwels, 1999[117]

CR:[245, 246]

Belgium, Denmark, Finland,

Italy, the Netherlands,

Norway, Spain, Sweden,

UK


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

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

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

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

France, Germany,

Netherlands, South Africa,

Sweden


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

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

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

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

specified)


Rossi, 2002[38] Austria, Belgium, Czech

Republic, France, Germany,

Greece, Hungary, Italy,


Spain, USA


Rubin, 2008[99] Brazil single center 0.14 0.003

(30

minutes)

2 40

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

Rutten-van,

1999[18]

The Netherlands multi-center 12 12 2 97

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

Schermer,

2007[118]


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

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

Senderovitz,

1999[144]

Denmark multi-center 24 24 2 26

Shaker, 2009[151]

CR:[256]

Denmark single center 208 104 -208 2 254

Sharafkhaneh,

2012[42]

USA, Central and South

America, South Africa


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

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

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

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

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

Croatia, Czech Republic,

Denmark, Ireland, Estonia,

France, Germany, Holland,

Hungary, Latvia, Poland,

Spain, Slovak Republic,

Slovenia, Ukraine, UK


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

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

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

Szafranski, 2003[73]

CR:[259]

Argentina, Brazil, Denmark,

Finland, UK, Italy, Mexico,

Poland, Portugal, South

Africa, Spain


Tashkin, 2008 [2]

CR: [217-224, 227-


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232]

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

Netherlands, Poland, South

Africa


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

Tashkin, 2012[69] South America, Asia,

Africa, Europe, North

America (not specified)


The Lung Health

Study Research

Group, 2000 [51]

CR: [209]

NR multi-center 208 mean

160

2 1116

Tonnel, 2008 France multi-center 36 36 2 554

Troosters, 2014[182] Belgium, Canada, Czech

Republic, Germany, Great

Britain, Greece, the

Netherlands, Portugal,

Ukraine, USA


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

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

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

Van de Maele,

2010[33]

Belgium multi-center 2 2 5 255

van Den Boom,

2001[149] CR: [247,

248]


van den Broek,

2008[89]

Netherlands single center 104 0.006 2 77

van der Valk,

2002[43]


van Noord,

2000[116]


Verhoeven,

2002[59] CR: [254,

255]

The Netherlands NR 24 24 2 23

Verkindre,

2006[155]

France multi-center 14 12 2 100

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

Vogelmeier,

2008[97]


Vogelmeier,

2010[135]

Germany, France, the

Netherland, Spain, Turkey,

USA


Vogelmeier,

2011[169] CR: [213]


Vogelmeier,

2013[80]

Belgium, Czech, Estonia,

Germany, Hungary, Korea,

Lithuania, Norway, Spain,

South Africa

multi-center 26

efficacy,

30 safety

26 2 523

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

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

Wedzicha, 2008[22]

CR:[233]

Austria, Belgium, Czech

Republic, Denmark,


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Estonia, Germany, Greece,

Italy, Latvia, Lithuania, the

Netherlands, Norway,

Romania, Russia, Slovakia,

Slovenia, Spain, Sweden,

Ukraine, UK

Wedzicha,

2013[162]

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

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

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

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

Wesseling,

1991[110]


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

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

Denmark, Germany and

other countries not specified

multi-center mean

119.6

median

119.28

3 17135

Woolhouse,

2001[145]

UK NR 2 2 2 23

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

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

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

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

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

Unpublished Studies (n= 20)

Calverley,

2003†[186] USA NR 52 52 2 631

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

da Fonseca Reis,

2010†[200] NR NR 12 12 2 18

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

GlaxoSmithKline,

2005

(SCO100470)†[193]

Australia, Bulgaria, Croatia,

Czech Republic, France,

Germany, Greece, Italy,

Latvia, Lithuania,


Poland, Romania, Russian

Federation, Slovakia,

Slovenia, Sweden, Thailand,

UK multi-center

24 24 2 1050

GlaxoSmithKline,

2005

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

12 12 2 125

GlaxoSmithKline,

2005 (SLMF

4010)†[187] France multi-center

24 24 2 34

GlaxoSmithKline,

2005

(SMS40298)†[197] Canada multi-center

16 16 2 347

GlaxoSmithKline,

2005 USA multi-center 4 8 2 316

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(SMS40315)†[196]

GlaxoSmithKline,

2005 ,SFCT01

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

54 52 3 387

GlaxoSmithKline,

2006

(SCO100540)†[194] China multi-center

24 24 2 445

GlaxoSmithKline,

2007

(SCO104925)†[185]

Russian Federation, USA,

Chile, Estonia multi-center

12 12 4 161

GlaxoSmithKline,

2008

(SCO40041)†[184] USA multi-center

156 156 2 186

Kelleher,

2011†[201] NR NR 1 1 3 38

Maltais, 2010†[202]

Canada, Germany, USA,

France NR 4 4 4 360

Novartis, 2006

(CQAB149B2205)†

[191]

Belgium, Canada, Denmark,

France, Germany, Italy, the

Netherlands, Norway, Peru,

Russia, Sweden,

Switzerland, USA multi-center

2 2 6 635

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

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

Sricharoenchai,

2008†[190] Thailand NR NR 0.012 2 15

To, 2011†[188] Japan NR 52 52 2 186

Note: †Unpublished data (n=20 studies)

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

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Appendix 8. Patient characteristics

Author, year Age category % Female COPD Definition Diagnosis of

COPD (GOLD

criteria)

COPD Severity COPD

duration

range

(mos)

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

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

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

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

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

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

emphysema

NA moderate to very severe† NR

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

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

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

Bateman,

2010[7]CR:[210]

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

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

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

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

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

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

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

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

diagnosed

patients

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

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

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

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

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

(salbutamol 400 mg)

No moderate to severe† NR

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forced expiratory volume

in 1 s (FEV1) ,<80% and

≥30% predicted,

FEV1/forced vital

capacity (FVC),<70%)

Burge, 2000[129]

CR: [204-208]

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

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

Calverley, 2003[34]

CR:[214-216, 261]


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

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

Calverley,

2007[138] CR:

[234-242]


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

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

according to the

GOLD guidelines

severe† >24

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

Casaburi, 2005[103]

CR:[243]


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

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

less than 50% of

predicted, and a

post-bronchodilator

FEV1/ FVC<70%

following

salbutamol 400 mg

according with the

GOLD criteria of

severity

severe to very severe NR

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

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

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

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

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

Chapman,

2011[115] CR:

[249-251]

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

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

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

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

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

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

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

guidelines

moderate to severe† NR

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

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

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

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

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

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

airflow limitations

Yes severe† NR

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

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

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

diagnoses


Donohue, 2002[3]

CR:[257, 258]

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

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

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

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

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

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

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

for at least three months

a year during at least the

NR mild to moderate† at least the

preceding 2

years

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preceding 2 years, and

moderate to severe

bronchial

hyperresponsiveness as

judged by a bronchial

histamine challenge

(provocative

concentration producing

a 20% fall in FEV1

≤2.0mg/ histamine ml)

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

240

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

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

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

symptoms/events of

>3days in duration

requiring a change in

treatment

NR mild to very severe† NR

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

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

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

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

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

dyspnea

NR moderate to very severe† 12-636

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

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

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

Hattotuwa,

2002[157] CR:[260]

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

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

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

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

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

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

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

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

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

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

and IV

severe to very severe† NR

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

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

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

Kerwin, 2012[68]

CR:[244]

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

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

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

Kinoshita, 2012[75]

CR: [253]

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

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

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

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

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

Lapperre, 2009[49]

CR:[252]

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

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

Llewellyn-Jones,

1996

Adult & elderly (≥18) 50 chronic bronchitis and

emphysema

NR moderate to severe† >24

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

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

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

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

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

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

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

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

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

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

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

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

emphysematic" and

"predominantly

bronchitic patients."

II and III NR NR

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

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

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

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

in the appendix but

linked only to the

introduction section

that describes

COPD as a

progressive,

inflammatory

condition leading to

airflow limitation,

pulmonary

hyperinflation,

resulting in

dyspnea, decreased

exercise tolerance

and impaired QoL.

NR NR

Nanshan/Zhong,

2012


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

Niewoehner,

2005[126] CR:[211,

212]




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

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

characterised by

decreased maximum

NR mild to severe† NR

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expiratory flow and slow

forced emptying of the

lungs, which is slowly

progressive, irreversible,

and does not change

markedly over several

months."

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

Pauwels, 1999[117]

CR:[245, 246]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Shaker, 2009[151]

CR:[256]

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

"preventable and

treatable disease state

characterised by airflow

limitation that is not

fully reversible. The

airflow limitation is

NR moderate to severe† ≥24

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usually progressive and

is associated with an

abnormal inflammatory

response of the lungs to

noxious particles or

gases, primarily caused

by cigarette smoking."

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

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

exacerbation for at least

4 weeks)


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

COPD as per

GOLD

moderate to severe, stable NR

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

COPD


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

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

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

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

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

Szafranski,

2003[73] CR:[259]

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

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

Tashkin, 2008[2]

CR: [217-224, 227-

232]

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

(44%); IV (8.5%)


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

exacerbations

NR moderate to verey severe† >24

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

The Lung Health

Study Research

Group, 2000[51]

CR: [209]

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

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

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

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

diagnosis according

to GOLD

guidelines

NR NR

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

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

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

van Den Boom,

2001[149] CR:

[247, 248]

Adult & elderly (≥18) 58.1 Obstructive airway

disease

NA moderate to severe† NR

van den Broek,

2008

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

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

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

according to ATS.

COPD is "defined as a

disease state

characterized by the

presence of airflow

obstruction, due to

chronic bronchitis or

emphysema, and is

generally progressive but

may be partially

reversible."

NR mild to moderate† NR

Verhoeven,

2002[59] CR: [254,

255]

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

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

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

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

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

COPD according to 2006

GOLD guidelines

moderate to severe moderate to severe† NR

Vogelmeier,

2011[169] CR:[213]

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

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

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

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

Wedzicha, 2008[22]

CR:[233]

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

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

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

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

years

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

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

without marked airflow

obstruction (FEV ~70%

predicted)

NR NR NR

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

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

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

defined by daily sputum

production for at least 3

months of 2 consecutive

years

NA NR NR

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

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

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

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

Society and GOLD

guidelines


Unpublished Studies (n=20)

Calverley,

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

Cheng, 2012* NR NR COPD NR NR NR

da Fonseca Reis,

2010* NR NR COPD III Severe NR

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

GlaxoSmithKline,

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

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GlaxoSmithKline,


NR

GlaxoSmithKline,

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

NR

GlaxoSmithKline,

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

NR

GlaxoSmithKline,

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

NR

GlaxoSmithKline,

2005 ,SFCT01

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

NR

GlaxoSmithKline,


NR

GlaxoSmithKline,

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

NR

GlaxoSmithKline,


NR

Kelleher, 2011* NR NR COPD NR NR† NR

Maltais, 2010* NR 45.5 COPD NR NR NR

Novartis, 2006

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

NR

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

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

Sricharoenchai,

2008* NR NR COPD NR NR

NR

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

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

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

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

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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


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

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Chapman, 2011 Unclear Unclear Low Low Low Low High

Cheng, 2012 Unclear Unclear Low Low Unclear Unclear Unclear

Choudhury, 2007 Low Low Low Low Low Low Low

Cooper, 2013 Unclear Unclear Low Low Low High High

Cote, 2009 High Unclear Low Low Low Unclear Unclear

Covelli, 2005 Unclear Unclear Low Low Low Unclear Unclear

Criner, 2008 Unclear Unclear Low Low Unclear Low High

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

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

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

Dahl, 2001 Unclear Unclear Low Low Unclear Unclear Unclear

Dahl, 2010 Low Unclear Low Low High Low High

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

Dal Negro, 2003 Unclear Unclear Low Low Low High Unclear

Dawber, 2005 Unclear Unclear Low Low Unclear Unclear Unclear

Decramer, 2013 Low Low Low Low High Low High

Decramer, 2014a Low Low Low Low Low Low High

Decramer, 2014b Low Low Low Low Low Low High

Doherty, 2012 Unclear Unclear Low Low Low Low High

Donohue, 2002 Unclear Unclear Low Low High Unclear High

Donohue, 2013 Low Low Low Low Low Low High

Dransfield, 2011 Unclear Unclear Low Low Low High High

Dransfield, 2013a Low Low Low Low Low Low High

Dransfield, 2013b Low Low Low Low Low Low High

Dusser, 2006 Unclear Unclear Low Low Low Unclear High

Engel, 1989 Unclear Unclear Low Low High Unclear Unclear

Feldman, 2010 Unclear Unclear Low Low Low Low High

Feldman, 2012 Low Low Low Low Low Low High

Ferguson, 2008 Unclear Unclear Low Low High Low High

Freeman, 2007 Unclear Unclear Low Low Low Low High

Fukuchi, 2013 Unclear Unclear Low Low Low Low Unclear

Gelb, 2013 Unclear Unclear Low Low Low Low High

GlaxoSmithKline, 2005

(SMS40298)



(SMS40315)


GlaxoSmithKline,

2005(SCO40034)



(SCO100470)

Unclear Unclear Low Low Low Low High


(SCO30002)

Unclear Unclear Low Low Low Low High


(SLMF4010)

Unclear Unclear Low Low Low Unclear High


(SCO100540)


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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


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

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Maltais, 2011 Unclear Unclear Low Low Low Low High

Mansori, 2010 Unclear Unclear Low Low Unclear Unclear Low

Martinez, 2013 Low Low Low Low Low Low High

Mathioudakis, 2013 Unclear Unclear Low Low Low Unclear Unclear

McNicholas, 2004 Unclear Unclear Low Low Low Unclear High

Mirici, 2001 Low High Low Low Low Unclear Unclear

Moita, 2008 Unclear Unclear Low Low Low Unclear Unclear

Mroz, 2013 Unclear Unclear Unclear Low Unclear Unclear Unclear

Nanshan Z/ or Zhong

N,2012

Low Unclear Low Low Low Low Low

Nicolini, 2012 Low Unclear Low Low Low Unclear Low

Niewoehner, 2005 Low Unclear Low Low Low Low High

Novartis, 2006 Unclear Unclear Low Low Low Unclear Unclear

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

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

Ohar, 2013 Unclear Unclear Low Low Low Low High

Ozol, 2005 Low Unclear Low Low High Unclear Unclear

Paggiaro, 1998 Low Unclear Low Low Low Unclear Unclear

Pasqua, 2010 Unclear Unclear Low Low Unclear Unclear Low

Pauwels, 1999 Unclear Unclear Low Low Low Unclear High

Perng, 2009 Low Unclear Low Low Unclear Unclear Low

Powrie, 2007 Unclear Unclear Low Low High Low High

Pukhta, 2010 Unclear Unclear Low Low Low Unclear Unclear

Rabe, 2008 Unclear Unclear Low Low Low Low High

Reid, 2008 Low Unclear Low Low High Unclear Low

Renkema, 1996 Low Unclear Low Low Low Unclear Low

Rennard, 2009 Unclear Unclear Low Low Low Low High

Rennard, 2001 Unclear Unclear Low Low High Unclear High

Rossi, 2002 Unclear Unclear Low Low Low Unclear High

Rubin, 2008 Unclear Unclear Low Low Low Unclear Unclear

Rutgers, 1998 Unclear Unclear Low Low Low Unclear Unclear

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

Santus, 2012 Unclear Unclear Unclear Unclear Unclear Unclear Low

Schermer, 2007 Low Unclear Low Low Low Unclear High

Scherr, 2012 Unclear Unclear Low Low Low High Low

Sechaud, 2012 Unclear Unclear Low Low Low Unclear High

Sekiya, 2012 Unclear Unclear High Low High Unclear Unclear

Senderovitz, 1999 Unclear Unclear Low Low Low Unclear Unclear

Shaker, 2009 Low Unclear Low Low High Low Unclear

Sharafkhaneh, 2012 Low Low Low Low Unclear Low High

Sin, 2008 Low Low Low Low Low Low Low

Sposato, 2008 Unclear Unclear Low Low Unclear Unclear Unclear

Sricharoenchai, 2008 Unclear Unclear Low Low Unclear Unclear Unclear

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Sridevi, 2012 Unclear Unclear Unclear Unclear High High Unclear

Stahl, 2001 Unclear Unclear Low Low Unclear Unclear Unclear

Stockley, 2006 Low Low Low Low Low Low Unclear

Struijs, 1997 Unclear Unclear Low Low Low Unclear Unclear

Sugiura H, 2002 Unclear Unclear Low Low Low Low Low

Suzuki, 2010 Unclear Unclear Low Low Low Low Unclear

Szafranski, 2003 Unclear Unclear Low Low Low Unclear Unclear

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

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

Tashkin, 2009 Low Unclear Low Low Low Unclear High

Tashkin, 2012 Low Low Low Low High Low High

The Lung Health Study

Research Group, 2000


To, 2011 Unclear Unclear Low Unclear Low Unclear Unclear

Tonnel, 2008 Low Unclear Low Low High Unclear High

Troosters, 2014 Low Unclear Low Low Low Low Unclear

Tzani, 2011 Low Unclear Low Low Low Low High

Ulubay, 2005 Unclear Unclear Low Low Unclear Unclear Unclear

Um, 2007 Low Unclear High Low High Unclear Low

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

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

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

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

van Noord, 2000 Unclear Unclear Low Low Low Unclear High

Verhoeven, 2002 Unclear Unclear Low Low Low Low Unclear

Verkindre, 2006 Unclear Unclear Low Low Low Unclear High

Vestbo, 1999 Low Low Low Low Low Unclear Unclear





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

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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

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Appendix 10. Network Meta-analysis Results Outcome

Network Meta-analysis Results Pairwise Meta-analysis


Ratio

CI PrI Odds

Ratio

CI Heteroge

neity

Variance

# studies # patients

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

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

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

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

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

Salmeterol vs Placebo 0.79 0.64-0.97 - 0.80 0.58-1.09 -- 1 634

Vilanterol vs Placebo 0.75 0.24-2.36 - 0.00 0.00-0.00

Glycopyrronium vs Placebo 0.77 0.57-1.03 - 0.00 0.00-0.00

Tiotropium vs Placebo 0.65 0.53-0.79 - 0.64 0.50-0.83 -- 1 1003

Beclomethasone/Formoterol vs Placebo 0.73 0.45-1.19 - 0.00 0.00-0.00

Budesonide/Formoterol vs Placebo 0.64 0.45-0.91 - 0.55 0.36-0.83 -- 1 519

Fluticasone/Vilanterol vs Placebo 0.57 0.18-1.75 - - - - -

Fluticasone/Salmeterol vs Placebo 0.67 0.53-0.85 - - - - -

Tiotropium/Salmeterol vs Placebo 0.71 0.43-1.18 - - - - -

Indacaterol/Glycopyrronium vs Placebo 0.48 0.36-0.64 - - - - -

Tiotropium/Fluticasone/Salmeterol vs Placebo 0.58 0.35-0.96 - - - - -

Tiotropium/Budesonide/Formoterol vs Placebo 0.23 0.14-0.40 - - - - -

Fluticasone vs Budesonide 1.07 0.57-2.01 - - - - -

Formoterol vs Budesonide 1.12 0.78-1.61 - 1.26 0.85-1.87 -- 1 512

Indacaterol vs Budesonide 1.04 0.66-1.65 - - - - -

Salmeterol vs Budesonide 1.05 0.68-1.64 - - - - -

Vilanterol vs Budesonide 1.00 0.30-3.36 - - - - -

Glycopyrronium vs Budesonide 1.02 0.63-1.67 - - - - -

Tiotropium vs Budesonide 0.87 0.56-1.34 - - - - -

Beclomethasone/Formoterol vs Budesonide 0.98 0.60-1.61 - - - - -

Budesonide/Formoterol vs Budesonide 0.86 0.59-1.24 - 0.73 0.48-1.12 -- 1 511

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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 - - - - -

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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 - - - - -

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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 - - - - -



0.65 0.37-1.15 - - - - -



0.78 0.39-1.58 - - - - -



0.32 0.15-0.65 - - - - -

Fluticasone/Vilanterol vs Budesonide/Formoterol 0.88 0.27-2.88 - - - - -

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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 - - - - -



0.90 0.49-1.66 - - - - -



0.36 0.19-0.69 - - - - -

Fluticasone/Salmeterol vs Fluticasone/Vilanterol 1.19 0.39-3.59 - 1.19 0.39-3.59 -- 1 528

Tiotropium/Salmeterol vs Fluticasone/Vilanterol 1.25 0.37-4.20 - - - - -

Indacaterol/Glycopyrronium vs Fluticasone/Vilanterol 0.85 0.27-2.64 - - - - -



1.02 0.30-3.41 - - - - -



0.41 0.12-1.39 - - - - -

Tiotropium/Salmeterol vs Fluticasone/Salmeterol 1.05 0.64-1.72 - - - - -

Indacaterol/Glycopyrronium vs Fluticasone/Salmeterol 0.71 0.55-0.92 - - - - -



0.86 0.52-1.40 - - - - -



0.35 0.21-0.58 - - - - -

Indacaterol/Glycopyrronium vs Tiotropium/Salmeterol 0.68 0.41-1.13 - - - - -



0.81 0.51-1.31 - 0.81 0.51-1.30 -- 1 293



0.33 0.17-0.65 - - - - -



1.20 0.72-2.00 - - - - -



0.48 0.28-0.83 - - - - -



0.40 0.21-0.80 - - - - -




3.37 (4,0.498,0.00)

Overall Mortality: 88 studies (1 five-arm, 12 four-arm, 14 three-arm, 61 two-arm), 28 treatments, 97526 patients



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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 - - - -



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/Tiotropium vs Placebo 0.66 0.08-5.18 0.08-5.68 0.33 0.01-8.27 -- 1 416




11.24

0.00 2 1044



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/Tiotropium vs Placebo 1.55 0.42-5.68 0.39-6.05 - - - -


Tiotropium Respimat vs Placebo 0.97 0.74-1.28 0.71-1.33 0.97 0.32-2.93 0.4011 2 4773

Triamcinoloneacetonide vs Placebo 0.78 0.39-1.57 0.37-1.64 0.78 0.39-1.55 -- 1 1116

Umeclidinium vs Placebo 1.13 0.27-4.68 0.26-5.01 4.73 0.24-

91.84

-- 1 698



92.96

-- 1 693

Aclidinium vs AZD3199 (Ultra LABA) 1.61 0.06-40.90 0.06-47.20 - - - -

Beclomethasone/Formoterol vs AZD3199 (Ultra LABA) 1.67 0.05-55.31 0.04-64.56 - - - -


Formoterol/Budesonide vs AZD3199 (Ultra LABA) 2.32 0.10-54.07 0.09-62.18 - - - -

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Formoterol/Budesonide/Tiotropium vs AZD3199 (Ultra

LABA)

6.39 0.07-561.41 0.06-683.41 - - - -



Salmeterol/Fluticasone/Tiotropium vs AZD3199 (Ultra

LABA)

3.46 0.12-101.64 0.10-118.04 - - - -

Fluticasone/Tiotropium vs AZD3199 (Ultra LABA) 1.99 0.04-104.80 0.03-124.79 - - - -



Formoterol/Tiotropium vs AZD3199 (Ultra LABA) 1.45 0.03-60.78 0.03-71.67 - - - -




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/Tiotropium vs AZD3199 (Ultra LABA) 3.39 0.12-99.48 0.10-115.53 - - - -



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 - - - -




Formoterol/Budesonide/Tiotropium vs Aclidinium 3.96 0.14-109.67 0.12-127.05 - - - -



Salmeterol/Fluticasone/Tiotropium vs Aclidinium 2.15 0.45-10.16 0.42-10.93 - - - -

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Fluticasone/Tiotropium vs Aclidinium 1.23 0.09-16.44 0.08-18.46 - - - -



Formoterol/Tiotropium vs Aclidinium 0.90 0.10-8.33 0.09-9.21 - - - -





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/Tiotropium vs Aclidinium 2.10 0.44-9.95 0.41-10.70 - - - -



Triamcinoloneacetonide vs Aclidinium 1.06 0.35-3.19 0.33-3.37 - - - -




Budesonide vs Beclomethasone/Formoterol 1.05 0.21-5.39 0.19-5.82 - - - -

Formoterol/Budesonide vs Beclomethasone/Formoterol 1.39 0.30-6.43 0.28-6.91 1.97 0.36-

10.84

-- 1 470



3.82 0.11-138.30 0.09-162.06 - - - -

Fluticasone vs Beclomethasone/Formoterol 1.36 0.27-6.88 0.25-7.42 - - - -

Salmeterol/Fluticasone vs Beclomethasone/Formoterol 1.02 0.20-5.17 0.19-5.58 - - - -



2.07 0.26-16.35 0.24-17.96 - - - -

Fluticasone/Tiotropium vs Beclomethasone/Formoterol 1.19 0.06-22.19 0.06-25.28 - - - -

Vilanterol/Fluticasone vs Beclomethasone/Formoterol 1.60 0.23-11.00 0.21-12.01 - - - -

Formoterol vs Beclomethasone/Formoterol 1.68 0.34-8.20 0.32-8.83 0.20 0.01-4.13 -- 1 465

Formoterol/Tiotropium vs Beclomethasone/Formoterol 0.87 0.06-11.74 0.06-13.19 - - - -

Glycopyrronium vs Beclomethasone/Formoterol 0.98 0.18-5.30 0.17-5.73 - - - -

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Indacaterol vs Beclomethasone/Formoterol 1.07 0.20-5.69 0.19-6.15 - - - -



1.12 0.20-6.08 0.19-6.58 - - - -

Indacaterol/Tiotropium vs Beclomethasone/Formoterol 1.41 0.15-13.15 0.14-14.55 - - - -

Mometasone vs Beclomethasone/Formoterol 1.82 0.30-10.87 0.28-11.80 - - - -

Formoterol/Mometasone vs Beclomethasone/Formoterol 0.90 0.12-6.89 0.11-7.56 - - - -

Salmeterol vs Beclomethasone/Formoterol 1.17 0.23-5.89 0.22-6.36 - - - -

Salmeterol/Tiotropium vs Beclomethasone/Formoterol 2.03 0.26-16.00 0.23-17.58 - - - -

Tiotropium vs Beclomethasone/Formoterol 1.26 0.25-6.33 0.23-6.83 - - - -

Tiotropium Respimat vs Beclomethasone/Formoterol 1.27 0.25-6.48 0.23-6.99 - - - -

Triamcinoloneacetonide vs Beclomethasone/Formoterol 1.02 0.18-5.90 0.16-6.39 - - - -

Umeclidinium vs Beclomethasone/Formoterol 1.48 0.17-12.64 0.16-13.93 - - - -

Vilanterol vs Beclomethasone/Formoterol 1.95 0.30-12.69 0.27-13.84 - - - -

Vilanterol/Umeclidinium vs Beclomethasone/Formoterol 1.69 0.23-12.48 0.21-13.67 - - - -

Formoterol/Budesonide vs Budesonide 1.32 0.74-2.35 0.71-2.45 1.19 0.57-2.49 0.00 4 1781

Formoterol/Budesonide/Tiotropium vs Budesonide 3.62 0.14-93.06 0.12-107.46 - - - -



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 - - - -



Formoterol/Tiotropium vs Budesonide 0.82 0.10-6.78 0.09-7.46 - - - -






Formoterol/Mometasone vs Budesonide 0.86 0.22-3.35 0.20-3.58 - - - -


Salmeterol/Tiotropium vs Budesonide 1.92 0.48-7.69 0.45-8.21 - - - -

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Triamcinoloneacetonide vs Budesonide 0.97 0.42-2.26 0.40-2.37 - - - -






2.75 0.11-71.01 0.09-82.01 - - - -





1.49 0.37-6.02 0.35-6.44 - - - -

Fluticasone/Tiotropium vs Formoterol/Budesonide 0.86 0.07-10.42 0.06-11.66 - - - -


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 - - - -





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/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 - - - -




Fluticasone vs Formoterol/Budesonide/Tiotropium 0.36 0.01-8.89 0.01-10.26 - - - -

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Salmeterol/Fluticasone vs


0.27 0.01-6.68 0.01-7.71 - - - -



0.54 0.02-17.20 0.01-20.04 - - - -



0.31 0.01-17.58 0.00-21.00 - - - -



0.42 0.01-12.34 0.01-14.33 - - - -

Formoterol vs Formoterol/Budesonide/Tiotropium 0.44 0.02-11.23 0.01-12.97 - - - -



0.23 0.01-10.28 0.00-12.16 - - - -

Glycopyrronium vs Formoterol/Budesonide/Tiotropium 0.26 0.01-6.60 0.01-7.63 - - - -

Indacaterol vs Formoterol/Budesonide/Tiotropium 0.28 0.01-7.15 0.01-8.26 - - - -



0.29 0.01-7.54 0.01-8.71 - - - -



0.37 0.01-12.96 0.01-15.17 - - - -

Mometasone vs Formoterol/Budesonide/Tiotropium 0.48 0.02-13.21 0.01-15.31 - - - -



0.24 0.01-7.57 0.01-8.82 - - - -

Salmeterol vs Formoterol/Budesonide/Tiotropium 0.31 0.01-7.62 0.01-8.79 - - - -



0.53 0.02-16.83 0.01-19.61 - - - -

Tiotropium vs Formoterol/Budesonide/Tiotropium 0.33 0.01-8.16 0.01-9.41 0.33 0.01-8.14 -- 1 660



0.33 0.01-8.30 0.01-9.57 - - - -



0.27 0.01-7.16 0.01-8.29 - - - -

Umeclidinium vs Formoterol/Budesonide/Tiotropium 0.39 0.01-12.95 0.01-15.12 - - - -

Vilanterol vs Formoterol/Budesonide/Tiotropium 0.51 0.02-14.56 0.02-16.88 - - - -



0.44 0.01-13.54 0.01-15.75 - - - -


Salmeterol/Fluticasone/Tiotropium vs Fluticasone 1.52 0.41-5.68 0.38-6.06 - - - -

Fluticasone/Tiotropium vs Fluticasone 0.88 0.08-10.14 0.07-11.32 - - - -

Vilanterol/Fluticasone vs Fluticasone 1.18 0.40-3.44 0.38-3.63 1.36 0.09-

19.56

1.163 2 820


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Formoterol/Tiotropium vs Fluticasone 0.64 0.08-5.01 0.07-5.51 - - - -






Formoterol/Mometasone vs Fluticasone 0.66 0.18-2.49 0.17-2.66 - - - -


Salmeterol/Tiotropium vs Fluticasone 1.49 0.40-5.56 0.37-5.93 - - - -



Triamcinoloneacetonide vs Fluticasone 0.75 0.36-1.56 0.35-1.63 - - - -



16.33

0.00 2 818



Salmeterol/Fluticasone

2.02 0.54-7.54 0.51-8.04 - - - -

Fluticasone/Tiotropium vs Salmeterol/Fluticasone 1.16 0.10-13.41 0.09-14.97 1.03 0.06-

17.24

-- 1 65


73.14

-- 1 528


Formoterol/Tiotropium vs Salmeterol/Fluticasone 0.85 0.11-6.62 0.10-7.27 0.99 0.06-

15.90

-- 1 605



Indacaterol/Glycopyrronium vs Salmeterol/Fluticasone 1.09 0.61-1.95 0.59-2.03 - - - -


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/Tiotropium vs Salmeterol/Fluticasone 1.98 0.53-7.38 0.50-7.87 - - - -

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Tiotropium vs Salmeterol/Fluticasone 1.23 0.96-1.58 0.92-1.65 1.80 1.05-3.07 0.00 2 1515


Triamcinoloneacetonide vs Salmeterol/Fluticasone 1.00 0.48-2.07 0.46-2.17 - - - -






0.58 0.04-9.14 0.03-10.34 - - - -



0.78 0.15-4.14 0.13-4.48 - - - -

Formoterol vs Salmeterol/Fluticasone/Tiotropium 0.81 0.21-3.21 0.19-3.43 - - - -



0.42 0.04-4.77 0.03-5.32 - - - -

Glycopyrronium vs Salmeterol/Fluticasone/Tiotropium 0.47 0.12-1.90 0.11-2.03 - - - -

Indacaterol vs Salmeterol/Fluticasone/Tiotropium 0.52 0.13-2.03 0.12-2.17 - - - -



0.54 0.13-2.18 0.12-2.33 - - - -



0.68 0.09-5.11 0.08-5.60 - - - -

Mometasone vs Salmeterol/Fluticasone/Tiotropium 0.88 0.18-4.18 0.17-4.50 - - - -



0.44 0.07-2.76 0.06-3.01 - - - -

Salmeterol vs Salmeterol/Fluticasone/Tiotropium 0.57 0.15-2.10 0.14-2.23 - - - -



0.98 0.31-3.13 0.29-3.32 0.98 0.31-3.11 -- 1 293

Tiotropium vs Salmeterol/Fluticasone/Tiotropium 0.61 0.17-2.22 0.16-2.36 0.61 0.17-2.21 -- 1 301



0.62 0.17-2.28 0.16-2.43 - - - -



0.49 0.11-2.17 0.11-2.33 - - - -

Umeclidinium vs Salmeterol/Fluticasone/Tiotropium 0.72 0.10-4.89 0.10-5.34 - - - -

Vilanterol vs Salmeterol/Fluticasone/Tiotropium 0.94 0.19-4.74 0.17-5.12 - - - -



0.82 0.14-4.74 0.13-5.14 - - - -

Vilanterol/Fluticasone vs Fluticasone/Tiotropium 1.35 0.09-19.30 0.08-21.74 - - - -

Formoterol vs Fluticasone/Tiotropium 1.41 0.12-16.90 0.11-18.89 - - - -

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Formoterol/Tiotropium vs Fluticasone/Tiotropium 0.73 0.03-17.70 0.03-20.39 - - - -

Glycopyrronium vs Fluticasone/Tiotropium 0.83 0.07-9.98 0.06-11.16 - - - -

Indacaterol vs Fluticasone/Tiotropium 0.90 0.08-10.78 0.07-12.05 - - - -

Indacaterol/Glycopyrronium vs Fluticasone/Tiotropium 0.94 0.08-11.42 0.07-12.78 - - - -

Indacaterol/Tiotropium vs Fluticasone/Tiotropium 1.18 0.07-21.32 0.06-24.25 - - - -

Mometasone vs Fluticasone/Tiotropium 1.52 0.11-20.37 0.10-22.87 - - - -

Formoterol/Mometasone vs Fluticasone/Tiotropium 0.76 0.05-12.12 0.04-13.71 - - - -

Salmeterol vs Fluticasone/Tiotropium 0.98 0.09-11.35 0.08-12.67 - - - -

Salmeterol/Tiotropium vs Fluticasone/Tiotropium 1.70 0.11-27.00 0.09-30.54 - - - -

Tiotropium vs Fluticasone/Tiotropium 1.06 0.09-12.20 0.08-13.62 0.94 0.06-

15.68

-- 1 66

Tiotropiumropium Respimat vs Fluticasone/Tiotropium 1.07 0.09-12.45 0.08-13.91 - - - -

Triamcinoloneacetonide vs Fluticasone/Tiotropium 0.86 0.07-10.92 0.06-12.24 - - - -

Umeclidinium vs Fluticasone/Tiotropium 1.24 0.07-20.96 0.07-23.77 - - - -

Vilanterol vs Fluticasone/Tiotropium 1.64 0.12-22.60 0.11-25.42 - - - -

Vilanterol/Umeclidinium vs Fluticasone/Tiotropium 1.42 0.09-21.46 0.08-24.23 - - - -


Formoterol/Tiotropium vs Vilanterol/Fluticasone 0.54 0.05-5.45 0.05-6.05 - - - -





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/Tiotropium vs Vilanterol/Fluticasone 1.26 0.24-6.74 0.22-7.29 - - - -



Triamcinoloneacetonide vs Vilanterol/Fluticasone 0.64 0.18-2.27 0.17-2.42 - - - -


Vilanterol vs Vilanterol/Fluticasone 1.21 0.59-2.49 0.57-2.60 1.30 0.62-2.74 0.00 4 2442

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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 - - - -


Indacaterol vs Formoterol 0.64 0.34-1.20 0.33-1.25 0.33 0.03-3.18 -- 1 871



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/Tiotropium vs Formoterol 1.21 0.31-4.77 0.29-5.10 - - - -



Triamcinoloneacetonide vs Formoterol 0.61 0.27-1.39 0.25-1.46 - - - -




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 - - - -

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Indacaterol vs Glycopyrronium 1.09 0.57-2.10 0.54-2.19 1.99 0.18-

22.04

-- 1 431


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/Tiotropium vs Glycopyrronium 2.06 0.52-8.23 0.48-8.80 - - - -



Triamcinoloneacetonide vs Glycopyrronium 1.04 0.44-2.47 0.42-2.60 - - - -



Vilanterol/Umeclidinium vs Glycopyrronium 1.72 0.47-6.24 0.44-6.65 - - - -


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/Tiotropium vs Indacaterol 1.89 0.48-7.42 0.45-7.92 - - - -



Triamcinoloneacetonide vs Indacaterol 0.95 0.41-2.20 0.39-2.31 - - - -




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/Tiotropium vs Indacaterol/Glycopyrronium 1.81 0.45-7.33 0.42-7.84 - - - -

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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/Tiotropium vs Indacaterol/Tiotropium 1.44 0.19-10.81 0.17-11.85 - - - -


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 - - - -




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/Tiotropium vs Mometasone 1.12 0.23-5.32 0.22-5.72 - - - -


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 - - - -



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 - - - -

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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 - - - -




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 - - - -



74.07

-- 1 417

Vilanterol/Umeclidinium vs Tiotropium 1.34 0.41-4.41 0.38-4.68 0.94 0.14-6.45 0.00 2 852

Triamcinoloneacetonide vs Tiotropium Respimat 0.80 0.38-1.70 0.36-1.78 - - - -

Umeclidinium vs Tiotropium Respimat 1.16 0.28-4.90 0.26-5.25 - -

Vilanterol vs Tiotropium Respimat 1.53 0.56-4.15 0.54-4.37 - -

Vilanterol/Umeclidinium vs Tiotropium Respimat 1.33 0.39-4.45 0.37-4.73 - -

Umeclidinium vs Triamcinoloneacetonide 1.45 0.30-7.05 0.28-7.60 - -

Vilanterol vs Triamcinoloneacetonide 1.90 0.58-6.28 0.54-6.66 - -

Vilanterol/Umeclidinium vs Triamcinoloneacetonide 1.65 0.41-6.58 0.39-7.03 - -

Vilanterol vs Umeclidinium 1.32 0.36-4.83 0.34-5.15 0.99 0.20-4.95 -- 1 1270

Vilanterol/Umeclidiniumlidinium vs Umeclidinium 1.14 0.31-4.20 0.29-4.47 1.27 0.30-5.32 0.00 2 839

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Vilanterolnterol/Umeclidinium vs Vilanterol 0.87 0.29-2.59 0.27-2.74 1.01 0.25-4.06 0.00 2 1255




31.44 (50,0.982,0.00)

Cardiovascular Related Mortality: 37 studies (6 four-arm, 6 three-arm, 25 two-arm), 20 treatments, 55156 patients


Aclidinium vs Placebo 3.06 0.12-75.35 0.02-556.25 3.06 0.12-

75.35

-- 1 542


Formoterol/Budesonide vs Placebo 2.38 0.30-18.87 0.08-68.73 5.38 0.26-

112.46

-- 1 581



Vilanterol/Fluticasone vs Placebo 0.91 0.15-5.73 0.05-18.00 0.33 0.01-8.23 -- 1 822


Glycopyrronium vs Placebo 0.23 0.02-2.83 0.00-13.38 0.16 0.01-3.97 -- 1 817


Indacaterol/Glycopyrronium vs Placebo 0.26 0.01-6.63 0.00-49.40 - - - -




Tiotropium Respimat vs Placebo 1.46 0.93-2.29 0.70-3.03 1.86 0.92-3.76 -- 1 3917

Triamcinolone Acetonide vs Placebo 3.01 0.61-14.98 0.22-40.76 3.01 0.61-

14.98

-- 1 1116



50.25

-- 1 693


Aclidinium vs AZD3199 (Ultra LABA) 7.50 0.08-668.55 0.01-

10996.94

- - - -


Formoterol/Budesonide vs AZD3199 (Ultra LABA) 5.84 0.15-222.91 0.02-

2161.81

- - - -


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Indacaterol/Tiotropium vs AZD3199 (Ultra LABA) 4.90 0.11-219.81 0.01-

2356.05

- - - -




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

- - - -














Triamcinolone Acetonide vs Aclidinium 0.99 0.03-35.50 0.00-331.99 - - - -


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Formoterol/Budesonide vs Budesonide 2.22 0.24-20.44 0.06-81.70 4.93 0.24-

103.12

-- 1 556




Formoterol vs Budesonide 0.76 0.11-5.55 0.03-19.11 2.92 0.12-

71.87

-- 1 559








Triamcinolone Acetonide vs Budesonide 2.81 0.34-23.20 0.09-86.58 - - - -







Formoterol vs Formoterol/Budesonide 0.34 0.05-2.28 0.02-7.39 0.49 0.04-5.47 -- 1 565






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 - - - -

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Vilanterol/Fluticasone vs Fluticasone 1.10 0.17-6.94 0.05-21.94 - - - -









Triamcinolone Acetonide vs Fluticasone 3.62 0.71-18.57 0.25-51.47 - - - -




74.80

-- 1 818


73.14

-- 1 528




Indacaterol/Glycopyrronium vs Salmeterol/Fluticasone 0.34 0.01-8.38 0.00-61.86 0.34 0.01-8.38 -- 1 522



Tiotropium vs Salmeterol/Fluticasone 1.61 1.02-2.56 0.76-3.42 2.12 0.95-4.72 -- 1 1448


Triamcinolone Acetonide vs Salmeterol/Fluticasone 3.87 0.75-19.84 0.27-55.04 - - - -




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Triamcinolone Acetonide vs Vilanterol/Fluticasone 3.30 0.29-37.79 0.06-172.95 - - - -


Vilanterol/Umeclidinium vs Vilanterol/Fluticasone 2.40 0.22-25.69 0.05-112.87 - - - -

Vilanterol vs Vilanterol/Fluticasone 1.76 0.22-14.00 0.06-51.11 3.03 0.12-

74.80

-- 1 818


Indacaterol vs Formoterol 0.93 0.14-6.09 0.04-19.69 2.99 0.12-

73.51

-- 1 871






Triamcinolone Acetonide vs Formoterol 3.68 0.36-37.84 0.08-162.01 - - - -




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

- - - -


Tiotropium vs Glycopyrronium 5.36 0.44-65.17 0.09-309.53 - - - -


Triamcinolone Acetonide vs Glycopyrronium 12.84 0.66-248.48 0.10-

1577.10

- - - -

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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

- - - -


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 - - - -


Tiotropium vs Indacaterol 1.66 0.57-4.81 0.29-9.34 2.99 0.12-

73.38

-- 1 1593


Triamcinolone Acetonide vs Indacaterol 3.97 0.60-26.27 0.18-85.38 - - - -





Indacaterolacaterol/Glycopyrronium

7.55 0.16-357.46 0.01-

3965.59

- - - -


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

- - - -



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 - - - -




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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 - - - -




Tiotropium Respimat vs Tiotropium 1.16 0.89-1.50 0.76-1.76 1.12 0.85-1.47 -- 1 11405

Triamcinolone Acetonide vs Tiotropium 2.40 0.46-12.61 0.16-35.53 - - - -

Umeclidinium vs Tiotropium 0.89 0.07-10.81 0.02-51.35 - - - -

Vilanterol/Umeclidinium vs Tiotropium 1.74 0.31-9.70 0.11-28.34 2.96 0.12-

73.01

-- 1 852


74.07

-- 1 417

Triamcinolone Acetonide vs Tiotropium Respimat 2.07 0.39-10.95 0.14-30.97 - - - -

Umeclidinium vs Tiotropium Respimat 0.77 0.06-9.41 0.01-44.96 - - - -

Vilanterol/Umeclidinium vs Tiotropium Respimat 1.50 0.27-8.48 0.09-24.94 - - - -

Vilanterol vs Tiotropium Respimat 1.10 0.25-4.93 0.10-12.54 - - - -

Umeclidinium vs Triamcinolone Acetonide 0.37 0.02-7.23 0.00-46.05 - - - -

Vilanterol/Umeclidinium vs Triamcinolone Acetonide 0.73 0.07-7.59 0.02-32.81 - - - -

Vilanterol vs Triamcinolone Acetonide 0.53 0.06-4.67 0.02-18.08 - - - -

Vilanterol/Umeclidinium vs Umeclidinium 1.96 0.18-20.93 0.04-91.76 3.04 0.12-

74.93

-- 1 1270

Vilanterol vs Umeclidinium 1.44 0.11-18.58 0.02-91.79 - - - -

Vilanterol vs Vilanterol/Umeclidinium 0.73 0.14-3.79 0.05-10.54 0.62 0.08-5.08 0.00 2 1255




11.79 (27,0.995,0.00)

Pneumonia: 54 studies (1 five-arm, 1 four-arm, 2 three-arm, 23 two-arm), 21 treatments, 61551 patients






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Budesonide/Formoterol vs Placebo 1.26 0.80-2.00 0.70-2.26 1.45 0.50-4.18 0.55 3 2066

Fluticasone/Vilanterol vs Placebo 2.13 0.98-4.64 0.82-5.54 1.87 0.50-6.97 0.00 2 822

Fluticasone/Salmeterol vs Placebo 1.90 1.53-2.34 1.39-2.59 1.75 1.44-2.13 <0.0001 4 3872

Mometasone/Formoterol vs Placebo 0.88 0.31-2.51 0.24-3.16 1.66 0.39-7.11 0.00 2 894


26.65

2.81 2 1044

Umeclidinium/Vilanterol vs Placebo 0.61 0.12-3.21 0.08-4.55 - - - -

Tiotropium/Fluticasone/Salmeterol vs Placebo 1.56 0.29-8.27 0.21-11.75 - - - -

Tiotropium/Budesonide/Formoterol vs Placebo 0.94 0.19-4.78 0.13-6.73 - - - -











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/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 - - - -

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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 - - - -





Vilanterol vs Fluticasone 0.69 0.32-1.47 0.27-1.75 1.18 0.39-3.54 0.00 2 818

Aclidinium vs Fluticasone 0.41 0.19-0.88 0.16-1.06 - - - -




Beclomethasone/Formoterol vs Fluticasone 0.68 0.20-2.36 0.15-3.08 - - - -

Budesonide/Formoterol vs Fluticasone 0.76 0.45-1.27 0.40-1.44 - - - -

Fluticasone/Vilanterol vs Fluticasone 1.28 0.59-2.78 0.49-3.32 1.01 0.32-3.24 0.00 2 820

Fluticasone/Salmeterol vs Fluticasone 1.14 0.91-1.43 0.83-1.57 1.08 0.90-1.29 0.00 3 3441

Mometasone/Formoterol vs Fluticasone 0.53 0.18-1.55 0.14-1.96 - - - -


Umeclidinium/Vilanterol vs Fluticasone 0.37 0.07-1.95 0.05-2.77 - - - -

Tiotropium/Fluticasone/Salmeterol vs Fluticasone 0.94 0.18-5.04 0.12-7.18 - - - -

Tiotropium/Budesonide/Formoterol vs Fluticasone 0.57 0.11-2.91 0.08-4.11 - - - -

Formoterol vs Mometasone 0.74 0.30-1.82 0.25-2.22 1.91 0.20-

18.09

1.55 2 915

Indacaterol vs Mometasone 0.79 0.30-2.12 0.24-2.64 - - - -



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 - - - -



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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 - - - -








Beclomethasone/Formoterol vs Formoterol 1.24 0.38-4.07 0.29-5.26 5.13 0.59-

44.24

-- 1 474



Fluticasone/Salmeterol vs Formoterol 2.09 1.29-3.37 1.14-3.83 - - - -

Mometasone/Formoterol vs Formoterol 0.96 0.34-2.71 0.27-3.39 0.66 0.18-2.36 0.11 2 898


Umeclidinium/Vilanterol vs Formoterol 0.68 0.12-3.75 0.08-5.38 - - - -

Tiotropium/Fluticasone/Salmeterol vs Formoterol 1.72 0.30-9.65 0.21-13.90 - - - -

Tiotropium/Budesonide/Formoterol vs Formoterol 1.03 0.19-5.59 0.13-7.98 - - - -






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Beclomethasone/Formoterol vs Indacaterol 1.17 0.32-4.29 0.24-5.68 - - - -



Fluticasone/Salmeterol vs Indacaterol 1.95 1.20-3.17 1.06-3.60 - - - -

Mometasone/Formoterol vs Indacaterol 0.90 0.29-2.83 0.23-3.62 - - - -


Umeclidinium/Vilanterol vs Indacaterol 0.63 0.12-3.43 0.08-4.90 - - - -

Tiotropium/Fluticasone/Salmeterol vs Indacaterol 1.61 0.29-8.83 0.20-12.65 - - - -

Tiotropium/Budesonide/Formoterol vs Indacaterol 0.97 0.18-5.11 0.13-7.25 - - - -






Beclomethasone/Formoterol vs Salmeterol 1.01 0.29-3.51 0.22-4.58 - - - -



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 - - - -


Umeclidinium/Vilanterol vs Salmeterol 0.55 0.11-2.89 0.07-4.10 - - - -

Tiotropium/Fluticasone/Salmeterol vs Salmeterol 1.40 0.26-7.45 0.18-10.60 - - - -

Tiotropium/Budesonide/Formoterol vs Salmeterol 0.84 0.17-4.30 0.12-6.08 - - - -

Aclidinium vs Vilanterol 0.59 0.20-1.72 0.16-2.17 - - - -

Glycopyrronium vs Vilanterol 0.72 0.31-1.70 0.25-2.06 - - - -

Tiotropium vs Vilanterol 0.83 0.38-1.81 0.32-2.16 2.03 0.18-

22.56

-- 1 408

Umeclidinium vs Vilanterol 0.65 0.09-4.97 0.06-7.61 - - - -

Beclomethasone/Formoterol vs Vilanterol 0.99 0.23-4.19 0.17-5.70 - - - -

Budesonide/Formoterol vs Vilanterol 1.11 0.45-2.70 0.37-3.29 - - - -

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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 - - - -






Fluticasone/Vilanterol vs Aclidinium 3.15 1.07-9.24 0.85-11.68 - - - -

Fluticasone/Salmeterol vs Aclidinium 2.81 1.30-6.07 1.09-7.24 - - - -

Mometasone/Formoterol vs Aclidinium 1.30 0.36-4.70 0.27-6.19 - - - -


Umeclidinium/Vilanterol vs Aclidinium 0.91 0.15-5.57 0.10-8.15 - - - -

Tiotropium/Fluticasone/Salmeterol vs Aclidinium 2.31 0.37-14.33 0.25-21.03 - - - -

Tiotropium/Budesonide/Formoterol vs Aclidinium 1.39 0.23-8.31 0.16-12.11 - - - -

Tiotropium vs Glycopyrronium 1.15 0.80-1.67 0.71-1.87 1.06 0.71-1.58 <0.0001 4 3385


Beclomethasone/Formoterol vs Glycopyrronium 1.38 0.38-5.02 0.29-6.63 - - - -



Fluticasone/Salmeterol vs Glycopyrronium 2.31 1.47-3.64 1.30-4.11 - - - -

Mometasone/Formoterol vs Glycopyrronium 1.07 0.35-3.31 0.27-4.22 - - - -


Umeclidinium/Vilanterol vs Glycopyrronium 0.75 0.14-4.04 0.10-5.76 - - - -

Tiotropium/Fluticasone/Salmeterol vs Glycopyrronium 1.90 0.35-10.39 0.24-14.87 - - - -

Tiotropium/Budesonide/Formoterol vs Glycopyrronium 1.15 0.22-6.01 0.15-8.52 - - - -


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Beclomethasone/Formoterol vs Tiotropium 1.20 0.35-4.14 0.26-5.41 - - - -



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 - - - -


Umeclidinium/Vilanterol vs Tiotropium 0.65 0.13-3.36 0.09-4.75 0.61 0.12-3.20 0.00 2 842

Tiotropium/Fluticasone/Salmeterol vs Tiotropium 1.65 0.31-8.65 0.22-12.27 1.65 0.32-8.61 0.00 2 797

Tiotropium/Budesonide/Formoterol vs Tiotropium 0.99 0.20-4.99 0.14-7.02 0.99 0.20-4.96 -- 1 660

Beclomethasone/Formoterol vs Umeclidinium 1.52 0.16-14.71 0.10-23.63 - - - -

Budesonide/Formoterol vs Umeclidinium 1.70 0.24-12.11 0.16-18.28 - - - -

Fluticasone/Vilanterol vs Umeclidinium 2.87 0.37-22.07 0.24-33.84 - - - -

Fluticasone/Salmeterol vs Umeclidinium 2.56 0.38-17.36 0.25-25.96 - - - -

Mometasone/Formoterol vs Umeclidinium 1.18 0.13-10.44 0.08-16.46 - - - -

Indacaterol/Glycopyrronium vs Umeclidinium 1.15 0.16-8.04 0.11-12.10 - - - -

Umeclidinium/Vilanterol vs Umeclidinium 0.83 0.12-5.52 0.08-8.23 1.02 0.14-7.33 -- 1 439

Tiotropium/Fluticasone/Salmeterol vs Umeclidinium 2.10 0.17-26.10 0.10-44.13 - - - -

Tiotropium/Budesonide/Formoterol vs Umeclidinium 1.27 0.10-15.30 0.06-25.72 - - - -

Budesonide/Formoterol vs Beclomethasone/Formoterol 1.11 0.36-3.48 0.28-4.46 1.38 0.43-4.40 -- 1 478

Fluticasone/Vilanterol vs Beclomethasone/Formoterol 1.88 0.44-8.02 0.32-10.91 - - - -

Fluticasone/Salmeterol vs Beclomethasone/Formoterol 1.68 0.49-5.77 0.37-7.53 - - - -

Mometasone/Formoterol vs Beclomethasone/Formoterol 0.78 0.16-3.68 0.12-5.12 - - - -



0.75 0.20-2.80 0.15-3.71 - - - -

Umeclidinium/Vilanterol vs Beclomethasone/Formoterol 0.54 0.07-4.26 0.05-6.55 - - - -



1.38 0.17-10.93 0.11-16.87 - - - -



0.83 0.11-6.37 0.07-9.77 - - - -


Fluticasone/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 - - - -

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Umeclidinium/Vilanterol vs Budesonide/Formoterol 0.49 0.09-2.72 0.06-3.91 - - - -



1.24 0.22-7.00 0.15-10.09 - - - -



0.75 0.14-4.05 0.10-5.79 - - - -

Fluticasone/Salmeterol vs Fluticasone/Vilanterol 0.89 0.41-1.96 0.34-2.34 2.04 0.18-

22.62

-- 1 528

Mometasone/Formoterol vs Fluticasone/Vilanterol 0.41 0.11-1.53 0.08-2.02 - - - -


Umeclidinium/Vilanterol vs Fluticasone/Vilanterol 0.29 0.05-1.73 0.03-2.52 - - - -



0.73 0.12-4.60 0.08-6.76 - - - -



0.44 0.07-2.67 0.05-3.89 - - - -

Mometasone/Formoterol vs Fluticasone/Salmeterol 0.46 0.16-1.35 0.13-1.70 - - - -

Indacaterol/Glycopyrronium vs Fluticasone/Salmeterol 0.45 0.27-0.75 0.24-0.85 0.11 0.01-2.09 -- 1 522

Umeclidinium/Vilanterol vs Fluticasone/Salmeterol 0.32 0.06-1.71 0.04-2.43 - - - -



0.82 0.15-4.41 0.11-6.29 - - - -



0.50 0.10-2.55 0.07-3.60 - - - -

Indacaterol/Glycopyrronium vs Mometasone/Formoterol 0.97 0.31-3.08 0.24-3.95 - - - -

Umeclidinium/Vilanterol vs Mometasone/Formoterol 0.70 0.10-4.98 0.07-7.51 - - - -



1.78 0.25-12.79 0.16-19.35 - - - -



1.07 0.15-7.44 0.10-11.18 - - - -

Umeclidinium/Vilanterol vs Indacaterol/Glycopyrronium 0.72 0.13-3.97 0.09-5.68 - - - -



1.84 0.33-10.21 0.23-14.66 - - - -



1.11 0.21-5.90 0.15-8.41 - - - -



2.54 0.25-26.17 0.15-42.60 - - - -



1.53 0.15-15.30 0.09-24.76 - - - -



0.60 0.06-6.09 0.04-9.87 - - - -

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34.33 (31,0.311,0.00)

Arrhythmia: 26 studies (1 five-arm, 1 four-arm, 2 three-arm, 22 two-arm), 12 treatments, 27407 patients






Glycopyrronium vs Placebo 1.52 0.63-3.62 0.44-5.21 2.92 0.35-

24.37

0.00 2 1522


Budesonide/Formoterol vs Placebo 2.75 0.87-8.64 0.54-13.93 2.93 0.27-

32.10

1.50 2 1556

Fluticasone/Vilanterol vs Placebo 8.88 0.33-240.14 0.08-948.41 - - - -

Fluticasone/Salmeterolvs Placebo 0.80 0.17-3.86 0.09-7.43 - - - -


51.45

-- 1 706

Formoterol vs Budesonide 0.77 0.13-4.37 0.06-9.03 0.48 0.04-5.35 -- 1 559






Budesonide/Formoterol vs Budesonide 1.40 0.24-8.11 0.12-16.87 0.98 0.14-7.00 -- 1 556


Fluticasone/Salmeterolvs Budesonide 0.41 0.04-4.26 0.01-11.29 - - - -







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Fluticasone/Salmeterolvs Formoterol 0.53 0.09-3.15 0.04-6.58 - - - -








Fluticasone/Salmeterolvs Indacaterol 0.56 0.10-3.23 0.05-6.71 - - - -




Tiotropium vs Salmeterol 1.18 0.41-3.36 0.27-5.21 - - - -



Fluticasone/Salmeterolvs Salmeterol 0.81 0.21-3.19 0.12-5.64 1.01 0.15-6.83 1.07 3 1875





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 - - - -





Fluticasone/Salmeterolvs Glycopyrronium 0.53 0.09-3.00 0.05-6.18 - - - -


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Fluticasone/Salmeterolvs Tiotropium 0.69 0.14-3.46 0.07-6.79 - - - -



Fluticasone/Salmeterolvs Budesonide/Formoterol 0.29 0.04-2.04 0.02-4.59 - - - -


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/Salmeterol 2.03 0.37-11.01 0.18-22.28 3.08 0.12-

75.99

-- 1 522




3.06 (11,0.9899,0.36)

Abbreviations and symbols: OR, Odds Ratio, NMA, Network Meta-analysis, MA, Meta-analysis, CI, Confidence Interval; PrI, Predictive Interval; LABA, long acting

beta agonists, χ², Chi Square Test, d.f., degrees of freedom

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Appendix 11. Sensitivity Network Meta-analysis results (only statistically significant results

are presented)

Network Meta-analysis Results Pairwise Meta-anlaysis Results


Ratio CI

Odds

Ratio CI # studies # patients

Exacerbations: 25 studies (2 four-arm, 6 three-arm, 17 two-arm), 20 treatments, 33211 patients

Fluticasone vs Placebo 0.28 0.13-0.62 0.21 0.09-0.48 2.00 541.00

Vilanterol vs Fluticasone 3.88 1.68-8.93 4.86 1.62-14.64 1.00 407.00

Fluticasone/Vilanterol vs Fluticasone 2.86 1.23-6.64 3.40 1.09-10.62 1.00 408.00



Glycopyrronium 0.62 0.47-0.82 0.63 0.51-0.77 1.00 1469.00

Indacaterol/Glycopyrronium vs Tiotropium 0.73 0.57-0.94 0.74 0.60-0.91 1.00 1466.00

Indacterol/Tiotropium vs Placebo 0.67 0.46-0.98

Indacaterol/Glycopyrronium vs Placebo 0.60 0.43-0.84

Indacaterol vs Fluticasone 3.30 1.44-7.55

Salmeterol vs Fluticasone 3.40 1.49-7.72

Glycopyrronium vs Fluticasone 3.44 1.47-8.07

Tiotropium vs Fluticasone 2.93 1.30-6.57

Umeclidinium vs Fluticasone 4.71 1.71-12.96

Fluticasone/Salmeterol vs Fluticasone 3.14 1.37-7.20 1.19 0.31-4.59 1.00 179.00

Tiotropium/Salmeterol vs Fluticasone 3.20 1.23-8.29

Indacterol/Tiotropium vs Fluticasone 2.41 1.02-5.73

Umeclidinium/Vilanterol vs Fluticasone 4.37 1.73-11.05


Fluticasone 2.60 1.00-6.73

Indacaterol/Glycopyrronium vs Indacaterol 0.65 0.47-0.90

Indacaterol/Glycopyrronium vs Salmeterol 0.63 0.46-0.86

Indacaterol/Glycopyrronium vs Vilanterol 0.55 0.33-0.92


Umeclidinium 0.46 0.23-0.90



Umeclidinium/Vilanterol vs

Indacterol/Tiotropium 1.81 1.00-3.27


variance

0.01




13.51(12,0.333,0.00)

Mortality Overall: 23 studies (3 four-arm, 5 three-arm, 15 two-arm), 21 treatments, 33624 patients

Salmeterol/Fluticasone vs Placebo 0.50 0.29-0.88

Salmeterol vs Salmeterol/Fluticasone 2.25 1.20-4.20

Tiotropium vs Salmeterol/Fluticasone 1.84 1.07-3.15 1.84 1.07 1 1323

Vilanterol vs Salmeterol/Fluticasone 3.56 1.03-12.38

Common within-network heterogeneity 0.00

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variance




9.51 (12, 0.659,0.00)

Pneumonia: 19 studies (2 four-arm, 4 three-arm, 13 two-arm), 18 treatments, 28763 patients

Budesonide/Formoterol vs Placebo 8.39 1.16-60.69

Fluticasone/Salmeterol vs Placebo 2.45 1.48-4.07

Salmeterol vs Budesonide 2.15 1.00-4.61

Beclomethasone/Formoterol vs Budesonide 11.02

1.05-

116.02

Budesonide/Formoterol vs Budesonide 13.42

1.66-

108.72

Fluticasone/Salmeterol vs Budesonide 3.92 1.68-9.15

Budesonide/Formoterol vs Mometasone 25.06

1.24-

506.42

Budesonide/Formoterol vs Formoterol 2.72 1.38-5.37 2.72 1.38-5.37 2.00 1290.00

Fluticasone/Salmeterol vs Indacaterol 2.08 1.10-3.93

Fluticasone/Salmeterol vs Salmeterol 1.82 1.02-3.26


Fluticasone/Salmeterol vs Glycopyrronium 2.24 1.14-4.41

Budesonide/Formoterol vs Tiotropium 7.97 1.10-57.95

Fluticasone/Salmeterol vs Tiotropium 2.33 1.43-3.78 2.20 1.33-3.62 1.00 1323.00

Mometasone/Formoterol vs







variance

0.00




4.88 (7, 0.675, 0.00)

Abbreviations: CI, Confidence Interval; d.f., degrees of freedom

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Appendix 12. SUCRA Values

The SUCRA allows identifying which treatment is the most effective overall and can be interpreted as 1 =

treatment is certain to be the best and 0 = treatment is certain to be the worst.

Panel A: SUCRA curves for the 17 treatments included in the exacerbations network meta-analysis;

Panel B: SUCRA curves for the 28 treatments included in the mortality overall network meta-analysis;

Panel C: SUCRA curves for the 20 treatments included in the cardiovascular-related mortality network

meta-analysis; Panel D: SUCRA curves for the 21 treatments included in the pneumonia network meta-

analysis; Panel E: SUCRA curves for the 12 treatments included in the arrythmia network meta-analysis.

A

B

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C

D

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E

Abbreviations: BECL, beclomethasone; BUDE, budesonide; FLUT, fluticasone; MOME, mometasone; TRIAM, triamcinolone

acetonide; AZD3199, AZD3199 (ultra LABA); FORM, formoterol; INDAC, indacaterol ; SALM, salmeterol; VILA, vilanterol;

ACLI, aclidinium bromide; GLYC, glycopyrronium bromide; DAROT, darotropium bromide; TIOT, tiotropium; UMEC,

umeclidinium; FORM/BECLO, formoterol/beclomethasone; FORM/BUDE, formoterol/budesonide; VILA/FLUT,

vilanterol/fluticasone; SALM/FLUT, salmeterol/fluticasone/; FORM/MOME, formoterol/mometasone; TIOT/BUDE,

tiotropium/budesonide; TIOT/FLUT, tiotropium/fluticasone; TIOT/FORM, tiotropium/formoterol; TIOT/SALM,

tiotropium/salmeterol; IND/TIOT, indacaterol/tiotropium; INDA/GLYC, indacaterol/glycopyrronium; VILA/UMEC,

vilanterol/umeclidinium; GSK961081, GSK961081; FORM/IPRATR, formoterol + ipratropium bromide; TIOT/FLUT/SALM,

tiotropium/ fluticasone /salmeterol; TIOT/BUDE/FORM, tiotropium/budesonide/formoterol; BUDE/FORM/IPRATR,


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Appendix 13. Forest Plots Forest Plots show all treatments are compared to placebo. The black horizontal lines represent the 95% confidence

intervals (CI) of the summary treatment effects and red horizontal lines the 95% predictive intervals (PrI). The

results are presented on the odds ratio scale.

Panel A: Cardiovascular-related mortality network meta-analysis forest plot versus placebo; Panel B: Pneumonia

network meta-analysis forest plot versus placebo; Panel C: Arrhythmia network meta-analysis forest plot versus

placebo.

A

B

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C

Abbreviations: CI, confidence interval; PrI, predictive interval; NMA, network meta-analysis; REML, restrictive

maximum likelihood.

Treatment Abbreviations: BECL, beclomethasone; BUDE, budesonide; FLUT, fluticasone; MOME, mometasone;

TRIAM, triamcinolone acetonide; AZD3199, AZD3199 (ultra LABA); FORM, formoterol; INDAC, indacaterol ;

SALM, salmeterol; VILA, vilanterol; ACLI, aclidinium bromide; GLYC, glycopyrronium bromide; DAROT,

darotropium bromide; TIOT, tiotropium; UMEC, umeclidinium; FORM/BECLO, formoterol/beclomethasone;

FORM/BUDE, formoterol/budesonide; VILA/FLUT, vilanterol/fluticasone; SALM/FLUT, salmeterol/fluticasone/;

FORM/MOME, formoterol/mometasone; TIOT/BUDE, tiotropium/budesonide; TIOT/FLUT,

tiotropium/fluticasone; TIOT/FORM, tiotropium/formoterol; TIOT/SALM, tiotropium/salmeterol; IND/TIOT,

indacaterol/tiotropium; INDA/GLYC, indacaterol/glycopyrronium; VILA/UMEC, vilanterol/umeclidinium;

GSK961081, GSK961081; FORM/IPRATR, formoterol + ipratropium bromide; TIOT/FLUT/SALM, tiotropium/

fluticasone /salmeterol; TIOT/BUDE/FORM, tiotropium/budesonide/formoterol; BUDE/FORM/IPRATR,


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Appendix 14. Included studies in our review versus previous Cochrane reviews

Study

Kew KM, Seniukovich A, 2014

[43 studies]

Kew KM, Dias S, Cates CJ, 2014

[71 studies]

Included Published Studies (n = 208)

Aalbers, 2002 NO NO

Aaron, 2007 NO NO

Abrahams, 2013 NO YES

Agusti, 2014 YES NO

Ambrosino, 2008 NO NO

Anzueto , 2009 YES YES

Auffarth, 1991 NO NO

Barnes, 2006 NO NO



Bateman, 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, 2003[34] YES YES


Calverley, 2003[53] NO NO

Calverley, 2003[119] YES 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

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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

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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



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



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

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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

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Vogelmeier, 2013 NO NO

Vogelmeier, 2011 NO YES

Vogelmeier , 2008 NO YES

Vogelmeier , 2010 NO NO

Wadbo, 2002 NO NO

Watkins, 2013 NO NO



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

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Appendix 15. Characteristics of new studies published since our search date

Year Citation Trial Name/NCT Interventions Outcomes*

2014

Celli B, Crater G, Kilbride S, Mehta R, Tabberer M, Kalberg C et

al. Once-daily umeclidinium/vilanterol 125/25 mcg in COPD: a

randomized, controlled study. Chest. 2014; 145(5):981-991.

NCT01313637

umeclidinium/vilanterol vs.

umeclidinium vs. vilanterol vs.

placebo

Mortality, Pneumonia, CVM

2014

Chapman KR, Beeh K-M, Beier J, Bateman ED, D’Urzo A,

Nutbrown R et al. A blinded evaluation of the efficacy and safety

of glycopyrronium, a once-daily long-acting muscarinic

antagonist, versus tiotropium, in patients with COPD: the GLOW5

study. BMC pulmonary medicine. 2014; 14(1):4.

GLOW5 glycopyrronium+placebo vs.

tiotropium (HandiHaler)+placebo

Mod/severe exacerbation,

Serious arrhythmia

2014

Donohue JF, Niewoehner D, Brooks J, O’Dell D, Church A.

Safety and tolerability of once-daily umeclidinium/vilanterol

125/25 mcg and umeclidinium 125 mcg in patients with chronic

obstructive pulmonary disease: results from a 52-week,

randomized, double-blind, placebo-controlled study. Respiratory

research. 2014; 15(1):78.

NCT01316887 umeclidinium/vilanterol vs.

umeclidinium vs. placebo

Mod/severe exacerbation, Mortality,

Pneumonia, Serious arrhythmia, CVM

2014

Dransfield MT, Feldman G, Korenblat P, LaForce CF, Locantore

N, Pistolesi M et al. Efficacy and safety of once-daily fluticasone

furoate/vilanterol (100/25 mcg) versus twice-daily fluticasone

propionate/salmeterol (250/50 mcg) in COPD patients. Respiratory

medicine. 2014; 108(8):1171-1179.

(NCT01323634,

NCT01323621,

NCT01706328)

fluticasone/vilanterol vs.

fluticasone/salmeterol Pneumonia, Serious arrhythmia

2014

D’Urzo AD, Rennard SI, Kerwin EM, Mergel V, Leselbaum A,

Caracta C. Efficacy and safety of fixed-dose combinations of

aclidinium bromide/formoterol fumarate: the 24-week,

randomized, placebo-controlled AUGMENT COPD study. Respir

Res. 2014; 15(1):123.

AUGMENT COPD

(NCT01437397)

aclidinium/formoterol (400/12

μg) vs. aclidinium vs. formoterol

vs. placebo

Mortality, Pneumonia,

Serious arrhythmia, CVM

2014

Ferguson GT, Feldman GJ, Hofbauer P, Hamilton A, Allen L,

Korducki L et al. Efficacy and safety of olodaterol once daily

delivered via Respimat® in patients with GOLD 2–4 COPD:

results from two replicate 48-week studies. International journal of

chronic obstructive pulmonary disease. 2014; 9:629.

Olodaterol Phase III

clinical program in COPD; NCT00782210,

NCT00782509

olodaterol (5 μg Respimat) vs.

placebo


CVM (for NCT00782210 only)

2014

Koch A, Pizzichini E, Hamilton A, Hart L, Korducki L, De Salvo

MC et al. Lung function efficacy and symptomatic benefit of

olodaterol once daily delivered via Respimat® versus placebo and

formoterol twice daily in patients with GOLD 2–4 COPD: results

from two replicate 48-week studies. International journal of

chronic obstructive pulmonary disease. 2014; 9:697..

Olodaterol Phase III

clinical program in COPD; NCT00793624,

NCT00796653

olodaterol (5 μg Respimat) vs.

formoterol vs. placebo Mortality, Pneumonia

2014

Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A.

Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and

tiotropium 18 mcg in chronic obstructive pulmonary disease:

NCT01777334 umeclidinium/vilanterol vs.

tiotropium



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results of a 24-week, randomized, controlled trial. Respiratory

medicine. 2014; 108(12):1752-1760.

2014

Pepin J-L, Cockcroft JR, Midwinter D, Sharma S, Rubin DB,

Andreas S. Long-acting bronchodilators and arterial stiffness in

patients with COPD: a comparison of fluticasone furoate/vilanterol

with tiotropium. CHEST Journal. 2014; 146(6):1521-1530.

NCT01395888 fluticasone/vilanterol vs.

tiotropium (HandiHaler) Mortality, Pneumonia

2014

Rossi A, van der Molen T, del Olmo R, Papi A, Wehbe L, Quinn

M et al. INSTEAD: a randomised switch trial of indacaterol versus

salmeterol/fluticasone in moderate COPD. European Respiratory

Journal. 2014; 44(6):1548-1556.

INSTEAD; NCT01555138 indacaterol vs.

salmeterol/fluticasone


Pneumonia, Serious arrhythmia

2014

Singh D, Jones PW, Bateman ED, Korn S, Serra C, Molins E et al.

Efficacy and safety of aclidinium bromide/formoterol fumarate

fixed-dose combinations compared with individual components

and placebo in patients with COPD (ACLIFORM-COPD): a

multicentre, randomised study. BMC pulmonary medicine. 2014;

14(1):178.

ACLIFORM-COPD; NCT01462942

aclidinium/formoterol (400/12

μg) vs. aclidinium vs. formoterol

vs. placebo


Pneumonia, Serious arrhythmia, CVM

2014

Singh D, Nicolini G, Bindi E, Corradi M, Guastalla D,

Kampschulte J et al. Extrafine Beclomethasone/formoterol

compared to Fluticasone/salmeterol Combination Therapy in

COPD. BMC pulmonary medicine. 2014; 14(1):43.

FUTURE;

NCT01245569

extrafine

beclomethasone/formoterol vs.

fluticasone/salmeterol



2014

Trivedi R, Richard N, Mehta R, Church A. Umeclidinium in

patients with COPD: a randomised, placebo-controlled study.

European Respiratory Journal. 2014; 43(1):72-81.

NCT01387230 umeclidinium (125 μg) vs.

placebo Serious arrhythmia

2014

Wedzicha J, Singh D, Vestbo J, Paggiaro P, Jones P, Bonnet-

Gonod F et al. Extrafine beclomethasone/formoterol in severe

COPD patients with history of exacerbations. Respiratory

medicine. 2014; 108(8):1153-1162.

FORWARD

extrafine

beclomethasone/formoterol vs.

formoterol


Serious arrhythmia

2014

ZuWallack R, Allen L, Hernandez G, Ting N, Abrahams R.

Efficacy and safety of combining olodaterol Respimat® and

tiotropium HandiHaler® in patients with COPD: results of two

randomized, double-blind, active-controlled studies. International

journal of chronic obstructive pulmonary disease. 2014; 9:1133.

ANHELTO 1 and

ANHELTO 2 ; NCT01694771,

NCT01696058

tiotropium (HandiHaler)+

olodaterol (Respimat) vs.

tiotropium (HandiHaler)+

placebo (Respimat)

Mortality

2013

Rennard SI, Scanlon PD, Ferguson GT, Rekeda L, Maurer BT, Gil

EG et al. ACCORD COPD II: a randomized clinical trial to

evaluate the 12-week efficacy and safety of twice-daily aclidinium

bromide in chronic obstructive pulmonary disease patients.

Clinical drug investigation. 2013; 33(12):893-904.

ACCORD COPD II; NCT01045161

placebo vs. aclidinium (400 μg) Mortality, Serious arrhythmia

Notes: *Outcomes from our NMA that were assessed as outcomes in the trial

Abbreviations: CVM, Cardiovascular related mortality; Mod/severe, Moderate/severe

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TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. 1

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

3

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known. 5

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

5

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

6

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,

language, publication status) used as criteria for eligibility, giving rationale. 6

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

6-7

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

7

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,

included in the meta-analysis). 7

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

7-8

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

6-10

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

8

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 8-10

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I

2) for each meta-analysis.

8-10

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Page 1 of 2


Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

9

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

8-10

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

10

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

10-11

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 11; Appendix 9

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

10-16; Appendix 10-13

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 11-16

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 11

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 11-16

DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

16-19

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

11;16-19

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 16-19

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.

5; 21

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097

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For more information, visit: www.prisma-statement.org. Page 2 of 2

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1BMJ Open 2019;9:e009183corr1. doi:10.1136/bmjopen-2015-009183corr1

Open access

Correction: Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease: a systematic review and network meta-analysis

Tricco AC, Strifler L, Veroniki A, et al. Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease: a systematic review and network meta-analysis. BMJ Open 2015;5:e009183. DOI: 10.1136/bmjopen-2015-009183.

The previous version of this manuscript contains a data extraction error in Table 3 in the line comparing ‘BUDE/FORM vs placebo’. Revising this data extraction error in the sample size resulted in a slight change in the second digits of the MA and NMA estimates; however, the overall conclusions for this comparison remain the same. The line in Table 3 should appear as: BUDE/FORM vs Placebo NMA OR 0.61 (0.43 to 0.87) MA OR 0.52 (0.35 to 0.79) 1 (510) Instead of: BUDE/FORM vs Placebo NMA OR 0.64 (0.45 to 0.91) MA OR 0.55 (0.36 to 0.83) 1 (519) In addition, the NMA odds ratio and confidence intervals are also plotted in Figure 4 of the paper. A revised version of Figure 4 is attached.

Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited,

Correction


2 BMJ Open 2019;9:e009183corr1. doi:10.1136/bmjopen-2015-009183corr1

Open access

appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ Open 2019;9:e009183corr1. doi:10.1136/bmjopen-2015-009183corr1

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