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
indacaterol/glycopyrronium, tiotropium/fluticasone/salmeterol, and 234
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
File format: Adobe Acrobat Document (.pdf) 406
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
Between –study heterogeneity 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
Between –study heterogeneity 0.00
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity) 11.79 (27,0.995,0.00)
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 . . . .
Between –study heterogeneity 0.01
Design-by-treatment interaction model for
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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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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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
Generic name(s)* Trade name(s)*
We will exclude the following formulations:
Long-acting beta2-agonists (LABA) in nebulizer and transdermal form
formoterol (when in nebulizer form)
arformoterol
tulobuterol
Inhaled corticosteroids (ICS) in nebulizer form
beclomethasone (when in nebulizer form)
budesonide (when in nebulizer form)
We will exclude ALL of the following agents:
Short-acting beta2-agonists (SABA) (inhaled, nebulizer, oral, injection)
fenoterol
levosalbutamol or levalbuterol Xopenex
salbutamol or albuterol Ventolin
terbutaline Bricanyl
Short-acting muscarinic anticholinergics (SAMA) (inhaler, nebulizer)
ipratropium bromide Combivent, Atrovent
oxitropium bromide
Combo SABA plus anticholinergic in one inhaler (inhaler, nebulizer)
fenoterol/ipratropium
salbutamol/ipratropium
Methylxanthines (oral, injection)
aminophylline
theophylline
Systemic corticosteroids (oral)
prednisone
methyl-prednisolone
Phosphodiesterase-4 (PDE4) inhibitors (oral)
roflumilast
Note: *This is not an exhausitve list.
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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.
22 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (beta-2-agonist* or beta-2agonist* or beta-2-adrenergic* or adrenergic
beta-2-receptor* or beta-2-receptor agonist* or beta-2-adrenoceptor agonist*)).tw.
23 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (beta2-agonist* or beta2agonist* or beta2-adrenergic* or adrenergic beta2-
receptor* or beta2-receptor agonist* or beta2- adrenoceptor agonist*)).tw.
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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.
25 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (B2-agonist* or B2-adrenergic* or adrenergic B2-receptor* or B2-receptor
agonist* or B2-adrenoceptor agonist*)).tw.
26 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (B-2-agonist* or B-2-adrenergic* or adrenergic B-2-receptor* or B-2-
receptor agonist* or B-2-adrenoceptor agonist*)).tw.
27 (LABA or LABAs or Ultra-LABA* or UltraLABA*).tw.
28 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and bronchodilator*).tw.
29 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (betamimetic* or beta-mimetic*)).tw.
30 exp Adrenergic beta-Agonists/ or Bronchodilator Agents/
31 (longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting).tw.
32 30 and 31
33 or/21-29,32
34 Administration, Inhalation/
35 exp Aerosols/
36 (inhal* or aerosol*).tw.
37 or/34-36
38 33 and 37
39 or/8-20,38 )
40 Beclomethasone/
41 (Aerobec or AeroBec Forte or Aldecin or Apo-Beclomethasone or Ascocortonyl or
AsmabecClickhaler).tw.
42 (Beclamet or Beclazone or BecloAsma or Beclo AZU or Beclocort or Becloforte or
Beclomet or Beclometason* or Beclomethasone or Beclorhinol or Becloturmant or Beclovent or
Becodisk* or Beconase or Becotide or BemedrexEasyhaler or Bronchocort).tw.
43 (Ecobec or Filair or Junik or Nasobec Aqueous or Prolair or Propaderm or Qvar or
Respocort or Sanasthmax or Sanasthmyl or Vancenase or Vanceril or Ventolair or Viarin).tw.
44 (BMJ 5800 or EINECS 224-585-9 or UNII-KGZ1SLC28Z).tw.
45 4419-39-0.rn.
46 Budesonide/
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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.
75 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (anticholinergic* or anti-cholinergic* or cholinolytic* or cholinergic-
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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/
102 ((chronic adj2 obstructi*) and (pulmonary or airway* or air way* or lung$1 or airflow* or
air flow*)).tw.
103 (COPD or COAD).tw.
104 (chronic adj2 bronchitis).tw.
105 emphysema*.tw.
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106 or/100-105
107 formoterol/ or formoterolfumarate/
108 (BD 40A or HSDB 7287 or Oxis or UNII-5ZZ84GCW8B).tw.
109 (eformoterol or Foradil or formoterol).tw.
110 (73573-87-2 or 183814-30-4).rn.
111 indacaterol/
112 (Arcapta or Onbrez or indacaterol or QAB 149 or QAB149 or UNII-8OR09251MQ).tw.
113 312753-06-3.rn.
114 salmeterol/
115 (Aeromax or Astmerole or "GR 33343 X" or "GR 33343X" or HSDB 7315 or Salmeterol
or SN408D or UNII-2I4BC502BT).tw.
116 89365-50-4.rn.
117 salmeterolxinafoate/
118 (Arial or Asmerole or Beglan or Betamican or Dilamax or Inaspir or Salmetedur or
Salmeterolxinafoate or Serevent or Ultrabeta or UNII-6EW8Q962A5).tw.
119 94749-08-3.rn.
120 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (beta-agonist* or betaagonist* or beta-adrenergic* or adrenergic beta-
receptor* or beta-receptor agonist* or beta-adrenoceptor agonist*)).tw.
121 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (beta-2-agonist* or beta-2agonist* or beta-2-adrenergic* or adrenergic
beta-2-receptor* or beta-2-receptor agonist* or beta-2-adrenoceptor agonist*)).tw.
122 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (beta2-agonist* or beta2agonist* or beta2-adrenergic* or adrenergic beta2-
receptor* or beta2-receptor agonist* or beta2- adrenoceptor agonist*)).tw.
123 ((longacting or long-acting) and ("beta(2)-agonist*" or "beta(2)-agonist*" or "beta(2)-
adrenergic*" or "adrenergic beta(2)-receptor*" or "beta(2)-receptor agonist*" or "beta(2)-
adrenoceptor agonist*")).tw.
124 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (B2-agonist* or B2-adrenergic* or adrenergic B2-receptor* or B2-receptor
agonist* or B2-adrenoceptor agonist*)).tw.
125 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (B-2-agonist* or B-2-adrenergic* or adrenergic B-2-receptor* or B-2-
receptor agonist* or B-2-adrenoceptor agonist*)).tw.
126 (LABA or LABAs or Ultra-LABA* or UltraLABA*).tw.
127 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and bronchodilator*).tw.
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128 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (betamimetic* or beta-mimetic*)).tw.
129 exp beta adrenergic receptor stimulating agent/ or brochodilating agent/
130 (longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting).tw.
131 129 and 130
132 or/120-128,131
133 inhalational drug administration/
134 aerosol/
135 (inhal* or aerosol*).tw.
136 or/133-135
137 132 and 136
138 or/107-119,137
139 beclometasone/
140 (Aerobec or AeroBec Forte or Aldecin or Apo-Beclomethasone or Ascocortonyl or
AsmabecClickhaler).tw.
141 (Beclamet or Beclazone or BecloAsma or Beclo AZU or Beclocort or Becloforte or
Beclomet or Beclometason* or Beclomethasone or Beclorhinol or Becloturmant or Beclovent or
Becodisk* or Beconase or Becotide or BemedrexEasyhaler or Bronchocort).tw.
142 (Ecobec or Filair or Junik or Nasobec Aqueous or Prolair or Propaderm or Qvar or
Respocort or Sanasthmax or Sanasthmyl or Vancenase or Vanceril or Ventolair or Viarin).tw.
143 (BMJ 5800 or EINECS 224-585-9 or UNII-KGZ1SLC28Z).tw.
144 4419-39-0.rn.
145 budesonide/
146 (Budesonide or Micronyl or Preferid or Pulmicort or Respules or Rhinocort or "S 1320"
or Spirocort or Uceris or UNII-Q3OKS62Q6X).tw.
147 51333-22-3.rn.
148 fluticasone/ or fluticasone propionate/
149 (Cutivate or Flixonase or Flixotide or Flonase or Flovent or Fluticason* or HSDB 7740 or
UNII-CUT2W21N7U).tw.
150 (90566-53-3 or 80474-14-2).rn.
151 glucocorticoid/
152 glucocorticoid*.tw.
153 corticosteroid/
154 (corticoid* or corticosteroid* or cortico-steroid*).tw.
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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/
160 (Adoair or Advair or Foxair or "Quikhale SF" or Seretide or Viani).tw.
161 (fluticasone adj3 salmeterol).tw.
162 136112-01-1.rn.
163 formoterolfumarate plus mometasonefuroate/
164 (formoterol adj3 mometasone).tw.
165 (Zenhale or Dulera).tw.
166 budesonide plus formoterol/
167 (formoterol adj3 budesonide).tw.
168 (Rilast or Symbicord or Symbicort or Vannair).tw.
169 150693-37-1.rn.
170 fluticasone furoate plus vilanterol/
171 (vilanterol adj3 fluticasone).tw.
172 Breo Ellipta.tw.
173 or/159-172
174 tiotropium bromide/
175 (BA 679 BR or BA 679BR or Spiriva or tiotropium or UNII-0EB439235F or UNII-
XX112XZP0J).tw.
176 (186691-13-4 or 136310-93-5).rn.
177 aclidinium bromide/
178 (LAS 34273 or LAS W-330 or BretarisGenuair or EkliraGenuair or TudorzaPressair or
UNII-UQW7UF9N91).tw.
179 320345-99-1.rn.
180 glycoyrronium bromide.tw.
181 (erythro-glycopyrronium bromide or UNII-9SFK0PX55W).tw.
182 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (anticholinergic* or anti-cholinergic* or cholinolytic* or cholinergic-
blocking or antimuscarinic* or anti-muscarinic* or ((cholinergic or acetylcholine or muscarinic)
adj3 antagonist*))).tw.
183 (LAMA or LAMAs or Ultra-LAMA* or UltraLAMA*).tw.
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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].
REFERENCES
1. Feldman G, Walker RR, Brooks J, Mehta R, Crater G. 28-Day safety and tolerability of umeclidinium in combination with vilanterol in COPD: a randomized placebo-controlled trial. Pulm Pharmacol Ther. 2012; 25(6):465-471.
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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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208. Calverley PM, Spencer S, Willits L, Burge PS, Jones PW. Withdrawal from treatment as an outcome in the ISOLDE study of COPD. CHEST Journal. 2003; 124(4):1350-1356.
209. Scanlon PD, Connett JE, Wise RA, Tashkin DP, Madhok T, Skeans M et al. Loss of bone density with inhaled triamcinolone in Lung Health Study II. Am J Respir Crit Care Med. 2004; 170(12):1302-1309.
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213. Vogelmeier C, Fabbri LM, Rabe KF, Beeh KM, Schmidt H, Metzdorf N et al. Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naive patients. Respir Med. 2013; 107(1):75-83.
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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.
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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.
241. Sacchetta A. Long term therapy and outcome of chronic obstructive pulmonary disease with or without co-morbidity: the TORCH study. Italian Journal of Medicine. 2008; 2(3):11-15.
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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247. van Grunsven PM, van Schayck CP, van Deuveren M, van Herwaarden CL, Akkermans RP, van Weel C. Compliance during long-term treatment with fluticasone propionate in subjects with early signs of asthma or chronic obstructive pulmonary disease (COPD): results of the Detection, Intervention, and Monitoring Program of COPD and Asthma (DIMCA) Study. Journal of Asthma. 2000; 37(3):225-234.
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249. Donohue JF, Fogarty C, Lotvall J, Mahler DA, Worth H, Yorgancioglu A et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. American journal of respiratory and critical care medicine. 2010; 182(2):155-162.
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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
multi-center 5 4 3 163
Beier, 2013 Czech Republic, Germany,
Hungary, Poland
multi-center 6 6 3 414
Bogdan, 2011 Japan, Romania, Russia,
Ukraine
multi-center 12 12 3 613
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
multi-center 12 12 2 653
Buhl, 2011 USA, Austria, Belgium,
Canada, Columbia,
Denmark, Finland, France,
Germany, Greece, Hungary,
Israel, Italy, Mexico,
Norway, Poland, Russia,
Slovakia, Spain,
Switzerland, Turkey, UK
multi-center 12 12 2 1598
Burge, 2000 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
multi-center 26 24 2 408
Chapman, 2011 USA, Argentina, Canada,
Germany, India, Italy,
Spain, Sweden, Turkey
multi-center 52 52 3 414
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,
Switzerland, Turkey, UK
multi-center 52 52 4 1732
Dahl, 2013 Denmark multi-center 4 4 2 193
Dahl, 2013 Europe (not specified),
Canada, India, Korea, South
Africa
multi-center 52 52 2 338
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,
multi-center 52 52 2 3439
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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
multi-centre 25 24 4 869
Doherty, 2012 North, Central and South
America, Europe, Africa,
Asia (not specified)
multi-center 52 26 5 1196
Donohue, 2002 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
multi-center 24 24 4 1532
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
multi-center 12 12 2 416
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
multi-center 12 12 2 1293
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
multi-center 16 16 3 283
Jones, 2011 NR - 16 European countries multi-center 52 52 2 843
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Jones, 2011 NR - 7 mostly North
American countries
multi-center 52 52 2 804
Jones, 2012 9 European countries (not
specified), South Africa
multi-center 24 24 3 819
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
multi-center 52 52 3 1066
Kerwin, 2013 Chile, Estonia, Germany,
Japan, Korea, Philippines,
Poland, Russian Federation,
USA
multi-center 24 24 5 1030
Kinoshita, 2012 Hong Kong, India, Japan,
Korea, Singapore, Taiwan
multi-center 12 12 3 347
Korn, 2011 USA, Czech, Germany,
Hungary, India, Slovakia,
Spain, Turkey
multi-center 12 12 2 1123
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
multi-center 4 4 5 329
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
multi-center 12 12 2 197
L'tvall, 2012 Norway, Sweden multi-center 4 4 2 60
Magnussen, 2008 Belgium, Canada, Germany,
Denmark, France, Italy, the
Netherlands, South Africa
multi-center 12 12 2 472
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,
multi-center 12 12 2 1131
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Spain, Turkey, USA
Mahler, 2012 Argentina, Canada,
Colombia, Czech Republic,
Hungary, India,
Netherlands, Philippines,
Slovakia, Spain, USA
multi-center 12 12 2 1142
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
multi-center 24 24 6 1224
Mathioudakis, 2013 Greece single center 208 208 5 564
McNicholas, 2004 UK, Ireland, The
Netherlands
multi-center 4 4 3 95
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
multi-center 24 24 2 281
Pasqua, 2010 Italy NR 4 4 2 22
Pauwels, 1999 Belgium, Denmark, Finland,
Italy, the Netherlands,
Norway, Spain, Sweden,
UK
multi-center 156 144 2 1277
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
multi-center 6 6 2 605
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)
multi-center 56 52 4 1964
Rossi, 2002 Austria, Belgium, Czech
Republic, France, Germany,
Greece, Hungary, Italy,
Slovakia, South Africa,
Spain, USA
multi-center 52 52 3 854
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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
multi-center 54 52 3 1219
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
multi-center 52 52 2 634
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
multi-center 52 52 4 812
Tashkin, 2008 37 countries multi-center 208 208 2 5992
Tashkin, 2008 USA, Czech Republic, The
Netherlands, Poland, South
Africa
multi-center 28 26 6 1704
Tashkin, 2009 USA multi-center 12 12 2 255
Tashkin, 2012 South America, Asia,
Africa, Europe, North
America (not specified)
multi-center 52 26 5 1055
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
multi-center 24 24 2 457
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
multi-center 4 4 3 281
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
multi-center 104 104 2 1323
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,
Netherlands, Philippines,
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
O'Donnell, 2006 Adult & elderly (≥18) 30.12 COPD NR moderate to very severe† NR
Ozol, 2005 Adult & elderly (≥18) 18.18 COPD NR mild to moderate NR
Paggiaro, 1998 Adult & elderly (≥18) 22.78 COPD: "as a disorder
characterised by
decreased maximum
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
NR moderate to very severe† NR
Stahl, 2001 Adult & elderly (≥18) 46.99 COPD NR moderate to severe NR
Stockley, 2006 Adult & elderly (≥18) 24.04 COPD NR moderate to very severe† NR
Struijs, 1997 Adult & elderly (≥18) 39.39 COPD NR NR NR
Sugiura, 2002 Adult & elderly (≥18) 11.11 COPD NR NR NR
Suzuki, 2010 Adult & elderly (≥18) 10 COPD I; II-III moderate to severe NR
Szafranski, 2003 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%)
moderate to very severe† NR
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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50
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
NR moderate to very severe† NR
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,
2006 (SCO100540)* Adult & elderly (≥18) 10.79 COPD NR moderate to very severe†
NR
GlaxoSmithKline,
2007 (SCO104925)* Adult & elderly (≥18) 23.6 bronchitis and COPD NR moderate to severe†
NR
GlaxoSmithKline,
2008 (SCO40041)* Adult & elderly (≥18) 38.71 COPD NR moderate to very severe†
NR
Kelleher, 2011* NR NR COPD NR NR† NR
Maltais, 2010* NR 45.5 COPD NR NR NR
Novartis, 2006 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
Calverley, 2010 Low Low Low Low Low Low High
Campbell, 2007 Unclear Unclear Low Low Low Unclear High
Casaburi, 2005 Unclear Unclear Low Low Low Unclear High
Cazzola, 2000 Low Unclear Low Unclear High Unclear Unclear
Cazzola, 2007 Unclear Unclear Low Low Unclear Unclear Unclear
Celli, 2003 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 Unclear Unclear
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
GlaxoSmithKline, 2006 Unclear Unclear Low Low Low Unclear Unclear
Glaxo 2007 (SCO104925) Unclear Unclear Low Low Unclear Unclear High
Glaxo 2008 (SCO40041) Unclear Unclear Low Low Unclear Unclear High
Gupta, 2002 Low Unclear Low Low Low Unclear Unclear
Hagedorn , 2013 Unclear Unclear Low Low Low Low High
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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
Jones, 2011 Unclear Unclear Low Low Low Low High
Jones, 2012 Unclear Unclear Low Low Low Low High
Jung, 2012 Low Unclear Low Low Low Unclear High
Kardos, 2007 Low Unclear Low Low Low Unclear Unclear
Kaushik, 1999 Unclear Unclear Low Low Unclear Unclear Unclear
Kelleher, 2011 Unclear Unclear Low Low High Unclear Unclear
Kerwin, 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, 2010 Unclear Unclear Low Low Low Low High
Vogelmeier, 2011 Low Low Low Low Low Low High
Vogelmeier, 2013 Low Low Low Low Low Low High
Wadbo, 2002 Unclear Unclear Low Low High Unclear Unclear
Watkins, 2013 Unclear Unclear Low Low Low Low High
Wedzicha, 2008 Low Low Low Low Low Low Unclear
Wedzicha, 2013 Low Low Low Low Low Low High
Weir, 1999 Unclear Unclear Low Low High Unclear Unclear
Welte, 2008 Unclear Unclear Low Low Low Unclear High
Welte, 2009 Low Unclear Low Low Low Low High
Wesseling, 1991 Unclear Unclear Low Low Low Unclear Unclear
Wielders, 2013 Unclear Unclear Low Low Low Low High
Wise, 2013 Unclear Unclear Low Low Low Low Low
Woolhouse, 2001 Unclear Unclear Low Low Low Unclear Unclear
Wouters, 2005 Low Unclear Low Low High Unclear High
Yao, 2014 Low Low Low Low Low Low High
Yildiz, 2004 Unclear Unclear Low Low Low Unclear Unclear
Zheng, 2007 Unclear Unclear Low Low Low Unclear Unclear
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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
Beclomethasone/Formoterol
0.78 0.39-1.58 - - - - -
Tiotropium/Budesonide/Formoterol vs
Beclomethasone/Formoterol
0.32 0.15-0.65 - - - - -
Fluticasone/Vilanterol vs Budesonide/Formoterol 0.88 0.27-2.88 - - - - -
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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 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Budesonide/Formoterol
0.90 0.49-1.66 - - - - -
Tiotropium/Budesonide/Formoterol vs
Budesonide/Formoterol
0.36 0.19-0.69 - - - - -
Fluticasone/Salmeterol vs Fluticasone/Vilanterol 1.19 0.39-3.59 - 1.19 0.39-3.59 -- 1 528
Tiotropium/Salmeterol vs Fluticasone/Vilanterol 1.25 0.37-4.20 - - - - -
Indacaterol/Glycopyrronium vs Fluticasone/Vilanterol 0.85 0.27-2.64 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Fluticasone/Vilanterol
1.02 0.30-3.41 - - - - -
Tiotropium/Budesonide/Formoterol vs
Fluticasone/Vilanterol
0.41 0.12-1.39 - - - - -
Tiotropium/Salmeterol vs Fluticasone/Salmeterol 1.05 0.64-1.72 - - - - -
Indacaterol/Glycopyrronium vs Fluticasone/Salmeterol 0.71 0.55-0.92 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Fluticasone/Salmeterol
0.86 0.52-1.40 - - - - -
Tiotropium/Budesonide/Formoterol vs
Fluticasone/Salmeterol
0.35 0.21-0.58 - - - - -
Indacaterol/Glycopyrronium vs Tiotropium/Salmeterol 0.68 0.41-1.13 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Tiotropium/Salmeterol
0.81 0.51-1.31 - 0.81 0.51-1.30 -- 1 293
Tiotropium/Budesonide/Formoterol vs
Tiotropium/Salmeterol
0.33 0.17-0.65 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Indacaterol/Glycopyrronium
1.20 0.72-2.00 - - - - -
Tiotropium/Budesonide/Formoterol vs
Indacaterol/Glycopyrronium
0.48 0.28-0.83 - - - - -
Tiotropium/Budesonide/Formoterol vs
Tiotropium/Fluticasone/Salmeterol
0.40 0.21-0.80 - - - - -
Common within-network heterogeneity variance 0.00
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity variance)
3.37 (4,0.498,0.00)
Overall Mortality: 88 studies (1 five-arm, 12 four-arm, 14 three-arm, 61 two-arm), 28 treatments, 97526 patients
AZD3199 (Ultra LABA) vs Placebo 0.46 0.02-10.32 0.02-11.85 0.32 0.01-7.95 -- 1 128
Aclidinium vs Placebo 0.74 0.31-1.72 0.30-1.81 0.74 0.32-1.72 0.00 4 2565
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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
Beclomethasone/Formoterol
3.82 0.11-138.30 0.09-162.06 - - - -
Fluticasone vs Beclomethasone/Formoterol 1.36 0.27-6.88 0.25-7.42 - - - -
Salmeterol/Fluticasone vs Beclomethasone/Formoterol 1.02 0.20-5.17 0.19-5.58 - - - -
Salmeterol/Fluticasone/Tiotropium vs
Beclomethasone/Formoterol
2.07 0.26-16.35 0.24-17.96 - - - -
Fluticasone/Tiotropium vs Beclomethasone/Formoterol 1.19 0.06-22.19 0.06-25.28 - - - -
Vilanterol/Fluticasone vs Beclomethasone/Formoterol 1.60 0.23-11.00 0.21-12.01 - - - -
Formoterol vs Beclomethasone/Formoterol 1.68 0.34-8.20 0.32-8.83 0.20 0.01-4.13 -- 1 465
Formoterol/Tiotropium vs Beclomethasone/Formoterol 0.87 0.06-11.74 0.06-13.19 - - - -
Glycopyrronium vs Beclomethasone/Formoterol 0.98 0.18-5.30 0.17-5.73 - - - -
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Indacaterol vs Beclomethasone/Formoterol 1.07 0.20-5.69 0.19-6.15 - - - -
Indacaterol/Glycopyrronium vs
Beclomethasone/Formoterol
1.12 0.20-6.08 0.19-6.58 - - - -
Indacaterol/Tiotropium vs Beclomethasone/Formoterol 1.41 0.15-13.15 0.14-14.55 - - - -
Mometasone vs Beclomethasone/Formoterol 1.82 0.30-10.87 0.28-11.80 - - - -
Formoterol/Mometasone vs Beclomethasone/Formoterol 0.90 0.12-6.89 0.11-7.56 - - - -
Salmeterol vs Beclomethasone/Formoterol 1.17 0.23-5.89 0.22-6.36 - - - -
Salmeterol/Tiotropium vs Beclomethasone/Formoterol 2.03 0.26-16.00 0.23-17.58 - - - -
Tiotropium vs Beclomethasone/Formoterol 1.26 0.25-6.33 0.23-6.83 - - - -
Tiotropium Respimat vs Beclomethasone/Formoterol 1.27 0.25-6.48 0.23-6.99 - - - -
Triamcinoloneacetonide vs Beclomethasone/Formoterol 1.02 0.18-5.90 0.16-6.39 - - - -
Umeclidinium vs Beclomethasone/Formoterol 1.48 0.17-12.64 0.16-13.93 - - - -
Vilanterol vs Beclomethasone/Formoterol 1.95 0.30-12.69 0.27-13.84 - - - -
Vilanterol/Umeclidinium vs Beclomethasone/Formoterol 1.69 0.23-12.48 0.21-13.67 - - - -
Formoterol/Budesonide vs Budesonide 1.32 0.74-2.35 0.71-2.45 1.19 0.57-2.49 0.00 4 1781
Formoterol/Budesonide/Tiotropium vs Budesonide 3.62 0.14-93.06 0.12-107.46 - - - -
Fluticasone vs Budesonide 1.29 0.77-2.17 0.74-2.26 - - - -
Salmeterol/Fluticasone vs Budesonide 0.97 0.58-1.63 0.56-1.70 - - - -
Salmeterol/Fluticasone/Tiotropium vs Budesonide 1.96 0.49-7.85 0.46-8.39 - - - -
Fluticasone/Tiotropium vs Budesonide 1.13 0.09-13.64 0.08-15.25 - - - -
Vilanterol/Fluticasone vs Budesonide 1.52 0.48-4.87 0.45-5.16 - - - -
Formoterol vs Budesonide 1.59 0.92-2.75 0.89-2.86 1.62 0.79-3.34 0.00 3 1470
Formoterol/Tiotropium vs Budesonide 0.82 0.10-6.78 0.09-7.46 - - - -
Glycopyrronium vs Budesonide 0.93 0.46-1.87 0.44-1.95 - - - -
Indacaterol vs Budesonide 1.02 0.53-1.97 0.51-2.05 - - - -
Indacaterol/Glycopyrronium vs Budesonide 1.06 0.51-2.19 0.49-2.28 - - - -
Indacaterol/Tiotropium vs Budesonide 1.34 0.26-6.79 0.24-7.33 - - - -
Mometasone vs Budesonide 1.72 0.66-4.48 0.63-4.71 - - - -
Formoterol/Mometasone vs Budesonide 0.86 0.22-3.35 0.20-3.58 - - - -
Salmeterol vs Budesonide 1.11 0.67-1.85 0.64-1.93 - - - -
Salmeterol/Tiotropium vs Budesonide 1.92 0.48-7.69 0.45-8.21 - - - -
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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/Tiotropium vs
Formoterol/Budesonide
2.75 0.11-71.01 0.09-82.01 - - - -
Fluticasone vs Formoterol/Budesonide 0.98 0.57-1.69 0.55-1.76 - - - -
Salmeterol/Fluticasone vs Formoterol/Budesonide 0.74 0.43-1.27 0.41-1.32 - - - -
Salmeterol/Fluticasone/Tiotropium vs
Formoterol/Budesonide
1.49 0.37-6.02 0.35-6.44 - - - -
Fluticasone/Tiotropium vs Formoterol/Budesonide 0.86 0.07-10.42 0.06-11.66 - - - -
Vilanterol/Fluticasone vs Formoterol/Budesonide 1.16 0.36-3.74 0.34-3.97 - - - -
Formoterol vs Formoterol/Budesonide 1.21 0.77-1.90 0.74-1.98 1.14 0.69-1.91 0.0587 7 5046
Formoterol/Tiotropium vs Formoterol/Budesonide 0.63 0.08-5.17 0.07-5.69 - - - -
Glycopyrronium vs Formoterol/Budesonide 0.71 0.35-1.45 0.33-1.51 - - - -
Indacaterol vs Formoterol/Budesonide 0.77 0.39-1.52 0.38-1.59 - - - -
Indacaterol/Glycopyrronium vs Formoterol/Budesonide 0.81 0.38-1.69 0.37-1.77 - - - -
Indacaterol/Tiotropium vs Formoterol/Budesonide 1.01 0.20-5.20 0.18-5.62 - - - -
Mometasone vs Formoterol/Budesonide 1.31 0.51-3.35 0.49-3.52 - - - -
Formoterol/Mometasone vs Formoterol/Budesonide 0.65 0.17-2.51 0.16-2.67 - - - -
Salmeterol vs Formoterol/Budesonide 0.84 0.49-1.44 0.47-1.50 - - - -
Salmeterol/Tiotropium vs Formoterol/Budesonide 1.46 0.36-5.90 0.34-6.30 - - - -
Tiotropium vs Formoterol/Budesonide 0.91 0.54-1.54 0.52-1.60 - - - -
Tiotropium Respimat vs Formoterol/Budesonide 0.92 0.52-1.62 0.50-1.69 - - - -
Triamcinoloneacetonide vs Formoterol/Budesonide 0.74 0.31-1.75 0.30-1.83 - - - -
Umeclidinium vs Formoterol/Budesonide 1.07 0.24-4.82 0.22-5.18 - - - -
Vilanterol vs Formoterol/Budesonide 1.41 0.47-4.18 0.45-4.42 - - - -
Vilanterol/Umeclidinium vs Formoterol/Budesonide 1.22 0.33-4.44 0.31-4.73 - - - -
Fluticasone vs Formoterol/Budesonide/Tiotropium 0.36 0.01-8.89 0.01-10.26 - - - -
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Salmeterol/Fluticasone vs
Formoterol/Budesonide/Tiotropium
0.27 0.01-6.68 0.01-7.71 - - - -
Salmeterol/Fluticasone/Tiotropium vs
Formoterol/Budesonide/Tiotropium
0.54 0.02-17.20 0.01-20.04 - - - -
Fluticasone/Tiotropium vs
Formoterol/Budesonide/Tiotropium
0.31 0.01-17.58 0.00-21.00 - - - -
Vilanterol/Fluticasone vs
Formoterol/Budesonide/Tiotropium
0.42 0.01-12.34 0.01-14.33 - - - -
Formoterol vs Formoterol/Budesonide/Tiotropium 0.44 0.02-11.23 0.01-12.97 - - - -
Formoterol/Tiotropium vs
Formoterol/Budesonide/Tiotropium
0.23 0.01-10.28 0.00-12.16 - - - -
Glycopyrronium vs Formoterol/Budesonide/Tiotropium 0.26 0.01-6.60 0.01-7.63 - - - -
Indacaterol vs Formoterol/Budesonide/Tiotropium 0.28 0.01-7.15 0.01-8.26 - - - -
Indacaterol/Glycopyrronium vs
Formoterol/Budesonide/Tiotropium
0.29 0.01-7.54 0.01-8.71 - - - -
Indacaterol/Tiotropium vs
Formoterol/Budesonide/Tiotropium
0.37 0.01-12.96 0.01-15.17 - - - -
Mometasone vs Formoterol/Budesonide/Tiotropium 0.48 0.02-13.21 0.01-15.31 - - - -
Formoterol/Mometasone vs
Formoterol/Budesonide/Tiotropium
0.24 0.01-7.57 0.01-8.82 - - - -
Salmeterol vs Formoterol/Budesonide/Tiotropium 0.31 0.01-7.62 0.01-8.79 - - - -
Salmeterol/Tiotropium vs
Formoterol/Budesonide/Tiotropium
0.53 0.02-16.83 0.01-19.61 - - - -
Tiotropium vs Formoterol/Budesonide/Tiotropium 0.33 0.01-8.16 0.01-9.41 0.33 0.01-8.14 -- 1 660
Tiotropiumropium Respimat vs
Formoterol/Budesonide/Tiotropium
0.33 0.01-8.30 0.01-9.57 - - - -
Triamcinoloneacetonide vs
Formoterol/Budesonide/Tiotropium
0.27 0.01-7.16 0.01-8.29 - - - -
Umeclidinium vs Formoterol/Budesonide/Tiotropium 0.39 0.01-12.95 0.01-15.12 - - - -
Vilanterol vs Formoterol/Budesonide/Tiotropium 0.51 0.02-14.56 0.02-16.88 - - - -
Vilanterol/Umeclidinium vs
Formoterol/Budesonide/Tiotropium
0.44 0.01-13.54 0.01-15.75 - - - -
Salmeterol/Fluticasone vs Fluticasone 0.75 0.60-0.94 0.58-0.98 0.76 0.62-0.93 0.00 3 3752
Salmeterol/Fluticasone/Tiotropium vs Fluticasone 1.52 0.41-5.68 0.38-6.06 - - - -
Fluticasone/Tiotropium vs Fluticasone 0.88 0.08-10.14 0.07-11.32 - - - -
Vilanterol/Fluticasone vs Fluticasone 1.18 0.40-3.44 0.38-3.63 1.36 0.09-
19.56
1.163 2 820
Formoterol vs Fluticasone 1.23 0.76-2.01 0.73-2.09 - - - -
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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/Tiotropium vs
Salmeterol/Fluticasone
2.02 0.54-7.54 0.51-8.04 - - - -
Fluticasone/Tiotropium vs Salmeterol/Fluticasone 1.16 0.10-13.41 0.09-14.97 1.03 0.06-
17.24
-- 1 65
Vilanterol/Fluticasone vs Salmeterol/Fluticasone 1.57 0.54-4.58 0.51-4.84 2.97 0.12-
73.14
-- 1 528
Formoterol vs Salmeterol/Fluticasone 1.64 1.01-2.67 0.97-2.78 - - - -
Formoterol/Tiotropium vs Salmeterol/Fluticasone 0.85 0.11-6.62 0.10-7.27 0.99 0.06-
15.90
-- 1 605
Glycopyrronium vs Salmeterol/Fluticasone 0.96 0.56-1.66 0.54-1.72 - - - -
Indacaterol vs Salmeterol/Fluticasone 1.05 0.64-1.71 0.62-1.78 - - - -
Indacaterol/Glycopyrronium vs Salmeterol/Fluticasone 1.09 0.61-1.95 0.59-2.03 - - - -
Indacaterol/Tiotropium vs Salmeterol/Fluticasone 1.38 0.29-6.60 0.27-7.10 - - - -
Mometasone vs Salmeterol/Fluticasone 1.77 0.73-4.31 0.70-4.52 - - - -
Formoterol/Mometasone vs Salmeterol/Fluticasone 0.88 0.23-3.32 0.22-3.54 - - - -
Salmeterol vs Salmeterol/Fluticasone 1.14 0.93-1.41 0.88-1.48 1.08 0.89-1.31 0.00 8 8202
Salmeterol/Tiotropium vs Salmeterol/Fluticasone 1.98 0.53-7.38 0.50-7.87 - - - -
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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 - - - -
Fluticasone/Tiotropium vs
Salmeterol/Fluticasone/Tiotropium
0.58 0.04-9.14 0.03-10.34 - - - -
Vilanterol/Fluticasone vs
Salmeterol/Fluticasone/Tiotropium
0.78 0.15-4.14 0.13-4.48 - - - -
Formoterol vs Salmeterol/Fluticasone/Tiotropium 0.81 0.21-3.21 0.19-3.43 - - - -
Formoterol/Tiotropium vs
Salmeterol/Fluticasone/Tiotropium
0.42 0.04-4.77 0.03-5.32 - - - -
Glycopyrronium vs Salmeterol/Fluticasone/Tiotropium 0.47 0.12-1.90 0.11-2.03 - - - -
Indacaterol vs Salmeterol/Fluticasone/Tiotropium 0.52 0.13-2.03 0.12-2.17 - - - -
Indacaterol/Glycopyrronium vs
Salmeterol/Fluticasone/Tiotropium
0.54 0.13-2.18 0.12-2.33 - - - -
Indacaterol/Tiotropium vs
Salmeterol/Fluticasone/Tiotropium
0.68 0.09-5.11 0.08-5.60 - - - -
Mometasone vs Salmeterol/Fluticasone/Tiotropium 0.88 0.18-4.18 0.17-4.50 - - - -
Formoterol/Mometasone vs
Salmeterol/Fluticasone/Tiotropium
0.44 0.07-2.76 0.06-3.01 - - - -
Salmeterol vs Salmeterol/Fluticasone/Tiotropium 0.57 0.15-2.10 0.14-2.23 - - - -
Salmeterol/Tiotropium vs
Salmeterol/Fluticasone/Tiotropium
0.98 0.31-3.13 0.29-3.32 0.98 0.31-3.11 -- 1 293
Tiotropium vs Salmeterol/Fluticasone/Tiotropium 0.61 0.17-2.22 0.16-2.36 0.61 0.17-2.21 -- 1 301
Tiotropiumropium Respimat vs
Salmeterol/Fluticasone/Tiotropium
0.62 0.17-2.28 0.16-2.43 - - - -
Triamcinoloneacetonide vs
Salmeterol/Fluticasone/Tiotropium
0.49 0.11-2.17 0.11-2.33 - - - -
Umeclidinium vs Salmeterol/Fluticasone/Tiotropium 0.72 0.10-4.89 0.10-5.34 - - - -
Vilanterol vs Salmeterol/Fluticasone/Tiotropium 0.94 0.19-4.74 0.17-5.12 - - - -
Vilanterol/Umeclidinium vs
Salmeterol/Fluticasone/Tiotropium
0.82 0.14-4.74 0.13-5.14 - - - -
Vilanterol/Fluticasone vs Fluticasone/Tiotropium 1.35 0.09-19.30 0.08-21.74 - - - -
Formoterol vs Fluticasone/Tiotropium 1.41 0.12-16.90 0.11-18.89 - - - -
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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
Common within-network heterogeneity variance 0.00
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity variance)
31.44 (50,0.982,0.00)
Cardiovascular Related Mortality: 37 studies (6 four-arm, 6 three-arm, 25 two-arm), 20 treatments, 55156 patients
AZD3199 (Ultra LABA) vs Placebo 0.41 0.02-9.44 0.00-67.10 0.32 0.01-7.95 -- 1 128
Aclidinium vs Placebo 3.06 0.12-75.35 0.02-556.25 3.06 0.12-
75.35
-- 1 542
Budesonide vs Placebo 1.07 0.27-4.23 0.12-9.95 1.35 0.30-6.08 -- 1 1852
Formoterol/Budesonide vs Placebo 2.38 0.30-18.87 0.08-68.73 5.38 0.26-
112.46
-- 1 581
Fluticasone vs Placebo 0.83 0.61-1.14 0.50-1.38 0.85 0.61-1.17 0.00 4 4962
Salmeterol/Fluticasone vs Placebo 0.78 0.57-1.07 0.47-1.30 0.85 0.60-1.20 0.00 2 3839
Vilanterol/Fluticasone vs Placebo 0.91 0.15-5.73 0.05-18.00 0.33 0.01-8.23 -- 1 822
Formoterol vs Placebo 0.82 0.15-4.45 0.05-12.77 0.69 0.11-4.39 0.00 3 1580
Glycopyrronium vs Placebo 0.23 0.02-2.83 0.00-13.38 0.16 0.01-3.97 -- 1 817
Indacaterol vs Placebo 0.76 0.28-2.06 0.15-3.84 0.48 0.13-1.83 0.00 5 2753
Indacaterol/Glycopyrronium vs Placebo 0.26 0.01-6.63 0.00-49.40 - - - -
Indacaterol/Tiotropium vs Placebo 2.00 0.23-16.97 0.06-64.48 - - - -
Salmeterol vs Placebo 0.63 0.45-0.88 0.36-1.09 0.60 0.42-0.87 0.00 4 5171
Tiotropium vs Placebo 1.26 0.82-1.93 0.63-2.52 0.88 0.37-2.10 0.00 5 4241
Tiotropium Respimat vs Placebo 1.46 0.93-2.29 0.70-3.03 1.86 0.92-3.76 -- 1 3917
Triamcinolone Acetonide vs Placebo 3.01 0.61-14.98 0.22-40.76 3.01 0.61-
14.98
-- 1 1116
Umeclidinium vs Placebo 1.12 0.09-13.59 0.02-64.54 - - - -
Vilanterol/Umeclidinium vs Placebo 2.19 0.39-12.12 0.14-35.26 2.04 0.08-
50.25
-- 1 693
Vilanterol vs Placebo 1.60 0.37-6.92 0.15-17.22 1.01 0.10-9.75 0.00 2 1521
Aclidinium vs AZD3199 (Ultra LABA) 7.50 0.08-668.55 0.01-
10996.94
- - - -
Budesonide vs AZD3199 (Ultra LABA) 2.63 0.09-78.91 0.01-657.90 - - - -
Formoterol/Budesonide vs AZD3199 (Ultra LABA) 5.84 0.15-222.91 0.02-
2161.81
- - - -
Fluticasone vs AZD3199 (Ultra LABA) 2.04 0.09-48.09 0.01-345.00 - - - -
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Salmeterol/Fluticasone vs AZD3199 (Ultra LABA) 1.91 0.08-45.05 0.01-323.30 - - - -
Vilanterol/Fluticasone vs AZD3199 (Ultra LABA) 2.24 0.06-85.46 0.01-827.83 - - - -
Formoterol vs AZD3199 (Ultra LABA) 2.01 0.07-57.97 0.01-471.72 - - - -
Glycopyrronium vs AZD3199 (Ultra LABA) 0.58 0.01-31.78 0.00-387.79 - - - -
Indacaterol vs AZD3199 (Ultra LABA) 1.86 0.07-49.85 0.01-387.15 - - - -
Indacaterol/Glycopyrronium vs AZD3199 (Ultra LABA) 0.65 0.01-58.53 0.00-969.44 - - - -
Indacaterol/Tiotropium vs AZD3199 (Ultra LABA) 4.90 0.11-219.81 0.01-
2356.05
- - - -
Salmeterol vs AZD3199 (Ultra LABA) 1.54 0.07-36.44 0.01-261.85 - - - -
Tiotropium vs AZD3199 (Ultra LABA) 3.09 0.13-73.67 0.02-532.92 - - - -
Tiotropium Respimat vs AZD3199 (Ultra LABA) 3.58 0.15-85.61 0.02-620.54 - - - -
Triamcinolone Acetonide vs AZD3199 (Ultra LABA) 7.39 0.22-252.24 0.02-
2280.00
- - - -
Umeclidinium vs AZD3199 (Ultra LABA) 2.74 0.05-152.16 0.00-
1862.07
- - - -
Vilanterol/Umeclidinium vs AZD3199 (Ultra LABA) 5.37 0.15-192.61 0.02-
1796.31
- - - -
Vilanterol vs AZD3199 (Ultra LABA) 3.94 0.12-126.20 0.01-
1097.02
- - - -
Budesonide vs Aclidinium 0.35 0.01-11.46 0.00-100.86 - - - -
Formoterol/Budesonide vs Aclidinium 0.78 0.02-35.35 0.00-382.09 - - - -
Fluticasone vs Aclidinium 0.27 0.01-6.81 0.00-50.76 - - - -
Salmeterol/Fluticasone vs Aclidinium 0.25 0.01-6.38 0.00-47.57 - - - -
Vilanterol/Fluticasone vs Aclidinium 0.30 0.01-12.01 0.00-120.23 - - - -
Formoterol vs Aclidinium 0.27 0.01-10.05 0.00-96.34 - - - -
Glycopyrronium vs Aclidinium 0.08 0.00-4.44 0.00-55.88 - - - -
Indacaterol vs Aclidinium 0.25 0.01-7.13 0.00-57.84 - - - -
Indacaterol/Glycopyrronium vs Aclidinium 0.09 0.00-8.14 0.00-138.53 - - - -
Indacaterol/Tiotropium vs Aclidinium 0.65 0.01-30.82 0.00-341.04 - - - -
Salmeterol vs Aclidinium 0.21 0.01-5.16 0.00-38.53 - - - -
Tiotropium vs Aclidinium 0.41 0.02-10.43 0.00-78.40 - - - -
Tiotropium Respimat vs Aclidinium 0.48 0.02-12.12 0.00-91.28 - - - -
Triamcinolone Acetonide vs Aclidinium 0.99 0.03-35.50 0.00-331.99 - - - -
Umeclidinium vs Aclidinium 0.37 0.01-21.28 0.00-268.33 - - - -
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Vilanterol/Umeclidinium vs Aclidinium 0.72 0.02-27.09 0.00-261.29 - - - -
Vilanterol vs Aclidinium 0.52 0.02-17.78 0.00-160.02 - - - -
Formoterol/Budesonide vs Budesonide 2.22 0.24-20.44 0.06-81.70 4.93 0.24-
103.12
-- 1 556
Fluticasone vs Budesonide 0.78 0.19-3.17 0.08-7.62 - - - -
Salmeterol/Fluticasone vs Budesonide 0.73 0.18-2.97 0.07-7.15 - - - -
Vilanterol/Fluticasone vs Budesonide 0.85 0.09-8.43 0.02-35.21 - - - -
Formoterol vs Budesonide 0.76 0.11-5.55 0.03-19.11 2.92 0.12-
71.87
-- 1 559
Glycopyrronium vs Budesonide 0.22 0.01-3.76 0.00-22.14 - - - -
Indacaterol vs Budesonide 0.71 0.13-3.81 0.05-10.90 - - - -
Indacaterol/Glycopyrronium vs Budesonide 0.25 0.01-8.18 0.00-72.62 - - - -
Indacaterol/Tiotropium vs Budesonide 1.86 0.15-23.66 0.03-115.54 - - - -
Salmeterol vs Budesonide 0.59 0.14-2.41 0.06-5.82 - - - -
Tiotropium vs Budesonide 1.17 0.28-4.93 0.11-12.09 - - - -
Tiotropium Respimat vs Budesonide 1.36 0.32-5.76 0.13-14.17 - - - -
Triamcinolone Acetonide vs Budesonide 2.81 0.34-23.20 0.09-86.58 - - - -
Umeclidinium vs Budesonide 1.04 0.06-18.02 0.01-106.63 - - - -
Vilanterol/Umeclidinium vs Budesonide 2.04 0.23-18.30 0.06-71.94 - - - -
Vilanterol vs Budesonide 1.50 0.20-11.11 0.06-38.80 - - - -
Fluticasone vs Formoterol/Budesonide 0.35 0.04-2.84 0.01-10.50 - - - -
Salmeterol/Fluticasone vs Formoterol/Budesonide 0.33 0.04-2.66 0.01-9.84 - - - -
Vilanterol/Fluticasone vs Formoterol/Budesonide 0.38 0.02-6.12 0.00-34.40 - - - -
Formoterol vs Formoterol/Budesonide 0.34 0.05-2.28 0.02-7.39 0.49 0.04-5.47 -- 1 565
Glycopyrronium vs Formoterol/Budesonide 0.10 0.00-2.52 0.00-18.99 - - - -
Indacaterol vs Formoterol/Budesonide 0.32 0.03-3.05 0.01-12.46 - - - -
Indacaterol/Glycopyrronium vs Formoterol/Budesonide 0.11 0.00-5.12 0.00-55.85 - - - -
Indacaterol/Tiotropium vs Formoterol/Budesonide 0.84 0.04-16.51 0.01-105.77 - - - -
Salmeterol vs Formoterol/Budesonide 0.26 0.03-2.16 0.01-7.98 - - - -
Tiotropium vs Formoterol/Budesonidesonide 0.53 0.06-4.38 0.02-16.39 - - - -
Tiotropium Respimat vs Formoterol/Budesonidesonide 0.61 0.07-5.10 0.02-19.14 - - - -
Triamcinolone Acetonide vs Formoterol/Budesonide 1.27 0.09-17.41 0.02-89.29 - - - -
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Umeclidinium vs Formoterol/Budesonide 0.47 0.02-12.07 0.00-91.35 - - - -
Vilanterol/Umeclidinium vs Formoterol/Budesonide 0.92 0.06-13.52 0.01-72.29 - - - -
Vilanterol vs Formoterol/Budesonide 0.67 0.05-8.52 0.01-41.42 - - - -
Salmeterol/Fluticasone vs Fluticasone 0.94 0.67-1.32 0.54-1.63 0.98 0.69-1.41 0.00 3 3410
Vilanterol/Fluticasone vs Fluticasone 1.10 0.17-6.94 0.05-21.94 - - - -
Formoterol vs Fluticasone 0.99 0.18-5.50 0.06-16.06 - - - -
Glycopyrronium vs Fluticasone 0.28 0.02-3.46 0.00-16.53 - - - -
Indacaterol vs Fluticasone 0.91 0.32-2.58 0.17-4.92 - - - -
Indacaterol/Glycopyrronium vs Fluticasone 0.32 0.01-7.99 0.00-59.66 - - - -
Indacaterol/Tiotropium vs Fluticasone 2.40 0.28-20.71 0.07-79.38 - - - -
Salmeterol vs Fluticasone 0.76 0.52-1.09 0.42-1.37 0.73 0.49-1.08 0.00 2 3135
Tiotropium vs Fluticasone 1.51 0.92-2.48 0.68-3.38 - - - -
Tiotropium Respimat vs Fluticasone 1.75 1.04-2.94 0.75-4.07 - - - -
Triamcinolone Acetonide vs Fluticasone 3.62 0.71-18.57 0.25-51.47 - - - -
Umeclidinium vs Fluticasone 1.34 0.11-16.54 0.02-79.17 - - - -
Vilanterol/Umeclidinium vs Fluticasone 2.63 0.47-14.82 0.16-43.57 - - - -
Vilanterol vs Fluticasone 1.93 0.44-8.44 0.18-21.20 3.03 0.12-
74.80
-- 1 818
Vilanterol/Fluticasone vs Salmeterol/Fluticasone 1.17 0.19-7.38 0.06-23.26 2.97 0.12-
73.14
-- 1 528
Formoterol vs Salmeterol/Fluticasone 1.05 0.19-5.87 0.06-17.17 - - - -
Glycopyrronium vs Salmeterol/Fluticasone 0.30 0.02-3.69 0.01-17.59 - - - -
Indacaterol vs Salmeterol/Fluticasone 0.97 0.35-2.75 0.18-5.25 - - - -
Indacaterol/Glycopyrronium vs Salmeterol/Fluticasone 0.34 0.01-8.38 0.00-61.86 0.34 0.01-8.38 -- 1 522
Indacaterol/Tiotropium vs Salmeterol/Fluticasone 2.56 0.30-21.95 0.08-83.79 - - - -
Salmeterol vs Salmeterol/Fluticasone 0.81 0.56-1.16 0.45-1.45 0.84 0.47-1.48 0.0552 3 4367
Tiotropium vs Salmeterol/Fluticasone 1.61 1.02-2.56 0.76-3.42 2.12 0.95-4.72 -- 1 1448
Tiotropium Respimat vs Salmeterol/Fluticasone 1.87 1.14-3.06 0.84-4.16 - - - -
Triamcinolone Acetonide vs Salmeterol/Fluticasone 3.87 0.75-19.84 0.27-55.04 - - - -
Umeclidinium vs Salmeterol/Fluticasone 1.44 0.12-17.64 0.02-84.37 - - - -
Vilanterol/Umeclidinium vs Salmeterol/Fluticasone 2.81 0.50-15.81 0.17-46.48 - - - -
Vilanterol vs Salmeterol/Fluticasone 2.06 0.47-9.05 0.19-22.77 - - - -
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Formoterol vs Vilanterol/Fluticasone 0.90 0.07-10.89 0.02-51.67 - - - -
Glycopyrronium vs Vilanterol/Fluticasone 0.26 0.01-5.65 0.00-38.83 - - - -
Indacaterol vs Vilanterol/Fluticasone 0.83 0.10-6.70 0.03-24.63 - - - -
Indacaterol/Glycopyrronium vs Vilanterol/Fluticasone 0.29 0.01-11.67 0.00-117.04 - - - -
Indacaterol/Tiotropium vs Vilanterol/Fluticasone 2.19 0.13-36.32 0.02-209.56 - - - -
Salmeterol vs Vilanterol/Fluticasone 0.69 0.11-4.40 0.03-13.98 - - - -
Tiotropium vs Vilanterol/Fluticasone 1.38 0.21-8.94 0.07-28.69 - - - -
Tiotropium Respimat vs Vilanterol/Fluticasone 1.59 0.24-10.43 0.08-33.63 - - - -
Triamcinolone Acetonide vs Vilanterol/Fluticasone 3.30 0.29-37.79 0.06-172.95 - - - -
Umeclidinium vs Vilanterol/Fluticasone 1.22 0.06-24.97 0.01-163.73 - - - -
Vilanterol/Umeclidinium vs Vilanterol/Fluticasone 2.40 0.22-25.69 0.05-112.87 - - - -
Vilanterol vs Vilanterol/Fluticasone 1.76 0.22-14.00 0.06-51.11 3.03 0.12-
74.80
-- 1 818
Glycopyrronium vs Formoterol 0.29 0.01-5.81 0.00-37.98 - - - -
Indacaterol vs Formoterol 0.93 0.14-6.09 0.04-19.69 2.99 0.12-
73.51
-- 1 871
Indacaterol/Glycopyrronium vs Formoterol 0.32 0.01-12.27 0.00-118.66 - - - -
Indacaterol/Tiotropium vs Formoterol 2.44 0.16-37.25 0.03-204.03 - - - -
Salmeterol vs Formoterol 0.77 0.14-4.30 0.05-12.59 - - - -
Tiotropium vs Formoterol 1.53 0.27-8.77 0.09-26.00 - - - -
Tiotropium Respimat vs Formoterol 1.78 0.31-10.22 0.10-30.41 - - - -
Triamcinolone Acetonide vs Formoterol 3.68 0.36-37.84 0.08-162.01 - - - -
Umeclidinium vs Formoterol 1.36 0.07-27.85 0.01-182.79 - - - -
Vilanterol/Umeclidinium vs Formoterol 2.67 0.24-29.61 0.05-132.83 - - - -
Vilanterol vs Formoterol 1.96 0.21-18.30 0.05-73.79 - - - -
Indacaterol vs Glycopyrronium 3.24 0.22-47.20 0.04-251.10 - - - -
Indacaterol/Glycopyrronium vs Glycopyrronium 1.13 0.02-65.94 0.00-833.90 - - - -
Indacaterol/Tiotropium vs Glycopyrronium 8.51 0.33-222.12 0.04-
1698.51
- - - -
Salmeterol vs Glycopyrronium 2.68 0.22-32.94 0.05-157.50 - - - -
Tiotropium vs Glycopyrronium 5.36 0.44-65.17 0.09-309.53 - - - -
Tiotropium Respimat vs Glycopyrronium 6.21 0.51-76.08 0.11-363.10 - - - -
Triamcinolone Acetonide vs Glycopyrronium 12.84 0.66-248.48 0.10-
1577.10
- - - -
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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
- - - -
Vilanterol vs Glycopyrronium 6.84 0.38-121.89 0.06-734.82 - - - -
Indacaterol/Glycopyrronium vs Indacaterol 0.35 0.01-10.13 0.00-82.82 - - - -
Indacaterol/Tiotropium vs Indacaterolacaterol 2.63 0.25-27.65 0.06-119.88 - - - -
Salmeterol vs Indacaterol 0.83 0.29-2.33 0.15-4.44 0.25 0.03-2.29 0.00 2 1784
Tiotropium vs Indacaterol 1.66 0.57-4.81 0.29-9.34 2.99 0.12-
73.38
-- 1 1593
Tiotropium Respimat vs Indacaterol 1.92 0.65-5.64 0.33-11.04 - - - -
Triamcinolone Acetonide vs Indacaterol 3.97 0.60-26.27 0.18-85.38 - - - -
Umeclidinium vs Indacaterol 1.47 0.10-21.61 0.02-115.37 - - - -
Vilanterol/Umeclidinium vs Indacaterol 2.88 0.40-20.80 0.12-71.39 - - - -
Vilanterol vs Indacaterol 2.11 0.36-12.36 0.12-37.16 - - - -
Indacaterol/Tiotropium vs
Indacaterolacaterol/Glycopyrronium
7.55 0.16-357.46 0.01-
3965.59
- - - -
Salmeterol vs Indacaterol/Glycopyrronium 2.37 0.09-59.75 0.01-446.73 - - - -
Tiotropium vs Indacaterol/Glycopyrronium 4.75 0.19-121.10 0.02-912.78 - - - -
Tiotropium Respimat vs Indacaterol/Glycopyrronium 5.50 0.21-140.91 0.03-
1065.04
- - - -
Triamcinolone Acetonide vs Indacaterol/Glycopyrronium 11.38 0.31-415.80 0.03-
3922.96
- - - -
Umeclidinium vs Indacaterol/Glycopyrronium 4.22 0.07-247.43 0.01-
3133.71
- - - -
Vilanterol/Umeclidinium vs Indacaterol/Glycopyrronium 8.26 0.22-315.30 0.02-
3055.92
- - - -
Vilanterol vs Indacaterol/Glycopyrronium 6.06 0.18-206.94 0.02-
1871.33
- - - -
Salmeterol vs Indacaterol/Tiotropium 0.31 0.04-2.71 0.01-10.38 - - - -
Tiotropium vs Indacaterol/Tiotropium 0.63 0.08-5.12 0.02-18.95 0.63 0.08-5.12 0.00 2 2273
Tiotropium Respimat vs Indacaterol/Tiotropium 0.73 0.09-6.03 0.02-22.53 - - - -
Triamcinolone Acetonide vs Indacaterol/Tiotropium 1.51 0.10-21.89 0.02-116.08 - - - -
Umeclidinium vs Indacaterol/Tiotropium 0.56 0.02-14.60 0.00-111.66 - - - -
Vilanterol/Umeclidinium vs Indacaterol/Tiotropium 1.10 0.07-16.48 0.01-89.41 - - - -
Vilanterol vs Indacaterol/Tiotropium 0.80 0.06-10.50 0.01-52.18 - - - -
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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 - - - -
Umeclidinium vs Salmeterol 1.78 0.14-21.96 0.03-105.32 - - - -
Vilanterol/Umeclidinium vs Salmeterol 3.48 0.61-19.73 0.21-58.22 - - - -
Vilanterol vs Salmeterol 2.55 0.58-11.31 0.23-28.60 - - - -
Tiotropium Respimat vs Tiotropium 1.16 0.89-1.50 0.76-1.76 1.12 0.85-1.47 -- 1 11405
Triamcinolone Acetonide vs Tiotropium 2.40 0.46-12.61 0.16-35.53 - - - -
Umeclidinium vs Tiotropium 0.89 0.07-10.81 0.02-51.35 - - - -
Vilanterol/Umeclidinium vs Tiotropium 1.74 0.31-9.70 0.11-28.34 2.96 0.12-
73.01
-- 1 852
Vilanterol vs Tiotropium 1.28 0.29-5.64 0.11-14.26 3.00 0.12-
74.07
-- 1 417
Triamcinolone Acetonide vs Tiotropium Respimat 2.07 0.39-10.95 0.14-30.97 - - - -
Umeclidinium vs Tiotropium Respimat 0.77 0.06-9.41 0.01-44.96 - - - -
Vilanterol/Umeclidinium vs Tiotropium Respimat 1.50 0.27-8.48 0.09-24.94 - - - -
Vilanterol vs Tiotropium Respimat 1.10 0.25-4.93 0.10-12.54 - - - -
Umeclidinium vs Triamcinolone Acetonide 0.37 0.02-7.23 0.00-46.05 - - - -
Vilanterol/Umeclidinium vs Triamcinolone Acetonide 0.73 0.07-7.59 0.02-32.81 - - - -
Vilanterol vs Triamcinolone Acetonide 0.53 0.06-4.67 0.02-18.08 - - - -
Vilanterol/Umeclidinium vs Umeclidinium 1.96 0.18-20.93 0.04-91.76 3.04 0.12-
74.93
-- 1 1270
Vilanterol vs Umeclidinium 1.44 0.11-18.58 0.02-91.79 - - - -
Vilanterol vs Vilanterol/Umeclidinium 0.73 0.14-3.79 0.05-10.54 0.62 0.08-5.08 0.00 2 1255
Common within-network heterogeneity variance 0.00
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity variance)
11.79 (27,0.995,0.00)
Pneumonia: 54 studies (1 five-arm, 1 four-arm, 2 three-arm, 23 two-arm), 21 treatments, 61551 patients
Budesonide vs Placebo 0.75 0.44-1.27 0.39-1.45 1.01 0.44-2.28 0.20 3 1378
Fluticasone vs Placebo 1.66 1.32-2.08 1.20-2.30 1.60 1.32-1.95 0.00 5 4258
Mometasone vs Placebo 1.23 0.51-2.96 0.42-3.60 1.75 0.64-4.81 0.00 3 1514
Formoterol vs Placebo 0.91 0.59-1.41 0.52-1.59 1.46 0.70-3.03 0.30 7 3499
Indacaterol vs Placebo 0.97 0.63-1.50 0.56-1.69 0.59 0.23-1.52 0.00 6 2787
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Salmeterol vs Placebo 1.11 0.91-1.37 0.82-1.51 1.09 0.88-1.35 0.00 3 3829
Vilanterol vs Placebo 1.14 0.53-2.45 0.45-2.92 2.08 0.56-7.67 0.00 2 820
Aclidinium vs Placebo 0.68 0.32-1.42 0.27-1.69 0.68 0.32-1.41 0.00 2 1647
Glycopyrronium vs Placebo 0.82 0.55-1.23 0.49-1.38 0.61 0.32-1.17 0.00 3 2315
Tiotropium vs Placebo 0.95 0.78-1.14 0.71-1.26 0.99 0.84-1.17 0.00 6 11522
Umeclidinium vs Placebo 0.74 0.11-4.99 0.07-7.44 - - - -
Beclomethasone/Formoterol vs Placebo 1.13 0.33-3.84 0.26-4.99 - - - -
Budesonide/Formoterol vs Placebo 1.26 0.80-2.00 0.70-2.26 1.45 0.50-4.18 0.55 3 2066
Fluticasone/Vilanterol vs Placebo 2.13 0.98-4.64 0.82-5.54 1.87 0.50-6.97 0.00 2 822
Fluticasone/Salmeterol vs Placebo 1.90 1.53-2.34 1.39-2.59 1.75 1.44-2.13 <0.0001 4 3872
Mometasone/Formoterol vs Placebo 0.88 0.31-2.51 0.24-3.16 1.66 0.39-7.11 0.00 2 894
Indacaterol/Glycopyrronium vs Placebo 0.85 0.53-1.36 0.47-1.54 1.62 0.10-
26.65
2.81 2 1044
Umeclidinium/Vilanterol vs Placebo 0.61 0.12-3.21 0.08-4.55 - - - -
Tiotropium/Fluticasone/Salmeterol vs Placebo 1.56 0.29-8.27 0.21-11.75 - - - -
Tiotropium/Budesonide/Formoterol vs Placebo 0.94 0.19-4.78 0.13-6.73 - - - -
Fluticasone vs Budesonide 2.21 1.25-3.92 1.08-4.51 - - - -
Mometasone vs Budesonide 1.63 0.60-4.43 0.48-5.52 - - - -
Formoterol vs Budesonide 1.21 0.67-2.17 0.58-2.51 1.19 0.51-2.79 0.00 2 1071
Indacaterol vs Budesonide 1.29 0.65-2.58 0.55-3.03 - - - -
Salmeterol vs Budesonide 1.48 0.84-2.62 0.73-3.01 - - - -
Vilanterol vs Budesonide 1.52 0.60-3.84 0.49-4.72 - - - -
Aclidinium vs Budesonide 0.90 0.36-2.23 0.30-2.73 - - - -
Glycopyrronium vs Budesonide 1.09 0.56-2.13 0.48-2.49 - - - -
Tiotropium vs Budesonide 1.26 0.71-2.22 0.62-2.55 - - - -
Umeclidinium vs Budesonide 0.99 0.14-7.14 0.09-10.81 - - - -
Beclomethasone/Formoterol vs Budesonide 1.50 0.42-5.39 0.32-7.09 - - - -
Budesonide/Formoterol vs Budesonide 1.68 0.93-3.03 0.80-3.49 1.51 0.67-3.39 0.00 2 1067
Fluticasone/Vilanterol vs Budesonide 2.83 1.10-7.25 0.90-8.93 - - - -
Fluticasone/Salmeterol vs Budesonide 2.52 1.44-4.43 1.25-5.09 - - - -
Mometasone/Formoterol vs Budesonide 1.17 0.37-3.66 0.29-4.68 - - - -
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Indacaterol/Glycopyrronium vs Budesonide 1.13 0.55-2.30 0.47-2.72 - - - -
Umeclidinium/Vilanterol vs Budesonide 0.82 0.14-4.64 0.10-6.69 - - - -
Tiotropium/Fluticasone/Salmeterol vs Budesonide 2.07 0.36-11.95 0.25-17.28 - - - -
Tiotropium/Budesonide/Formoterol vs Budesonide 1.25 0.23-6.92 0.16-9.93 - - - -
Mometasone vs Fluticasone 0.74 0.30-1.83 0.24-2.24 - - - -
Formoterol vs Fluticasone 0.55 0.33-0.90 0.29-1.02 - - - -
Indacaterol vs Fluticasone 0.58 0.36-0.95 0.32-1.07 - - - -
Salmeterol vs Fluticasone 0.67 0.54-0.84 0.49-0.93 0.68 0.56-0.83 0.00 2 3174
Vilanterol vs Fluticasone 0.69 0.32-1.47 0.27-1.75 1.18 0.39-3.54 0.00 2 818
Aclidinium vs Fluticasone 0.41 0.19-0.88 0.16-1.06 - - - -
Glycopyrronium vs Fluticasone 0.49 0.31-0.78 0.28-0.88 - - - -
Tiotropium vs Fluticasone 0.57 0.43-0.75 0.39-0.83 - - - -
Umeclidinium vs Fluticasone 0.45 0.07-3.03 0.04-4.53 - - - -
Beclomethasone/Formoterol vs Fluticasone 0.68 0.20-2.36 0.15-3.08 - - - -
Budesonide/Formoterol vs Fluticasone 0.76 0.45-1.27 0.40-1.44 - - - -
Fluticasone/Vilanterol vs Fluticasone 1.28 0.59-2.78 0.49-3.32 1.01 0.32-3.24 0.00 2 820
Fluticasone/Salmeterol vs Fluticasone 1.14 0.91-1.43 0.83-1.57 1.08 0.90-1.29 0.00 3 3441
Mometasone/Formoterol vs Fluticasone 0.53 0.18-1.55 0.14-1.96 - - - -
Indacaterol/Glycopyrronium vs Fluticasone 0.51 0.31-0.85 0.27-0.97 - - - -
Umeclidinium/Vilanterol vs Fluticasone 0.37 0.07-1.95 0.05-2.77 - - - -
Tiotropium/Fluticasone/Salmeterol vs Fluticasone 0.94 0.18-5.04 0.12-7.18 - - - -
Tiotropium/Budesonide/Formoterol vs Fluticasone 0.57 0.11-2.91 0.08-4.11 - - - -
Formoterol vs Mometasone 0.74 0.30-1.82 0.25-2.22 1.91 0.20-
18.09
1.55 2 915
Indacaterol vs Mometasone 0.79 0.30-2.12 0.24-2.64 - - - -
Salmeterol vs Mometasone 0.91 0.37-2.25 0.30-2.75 - - - -
Vilanterol vs Mometasone 0.93 0.29-2.99 0.23-3.85 - - - -
Aclidinium vs Mometasone 0.55 0.17-1.75 0.14-2.24 - - - -
Glycopyrronium vs Mometasone 0.67 0.25-1.77 0.20-2.19 - - - -
Tiotropium vs Mometasone 0.77 0.31-1.91 0.26-2.33 - - - -
Umeclidinium vs Mometasone 0.61 0.07-4.94 0.05-7.68 - - - -
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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 - - - -
Salmeterol vs Formoterol 1.23 0.75-2.00 0.66-2.27 - - - -
Vilanterol vs Formoterol 1.25 0.52-3.03 0.43-3.69 - - - -
Aclidinium vs Formoterol 0.74 0.31-1.76 0.26-2.14 - - - -
Glycopyrronium vs Formoterol 0.90 0.49-1.66 0.42-1.92 - - - -
Tiotropium vs Formoterol 1.04 0.64-1.70 0.56-1.93 - - - -
Umeclidinium vs Formoterol 0.82 0.12-5.78 0.08-8.72 - - - -
Beclomethasone/Formoterol vs Formoterol 1.24 0.38-4.07 0.29-5.26 5.13 0.59-
44.24
-- 1 474
Budesonide/Formoterol vs Formoterol 1.39 0.95-2.03 0.85-2.26 1.49 0.98-2.26 0.04 6 4646
Fluticasone/Vilanterol vs Formoterol 2.34 0.95-5.73 0.78-7.00 - - - -
Fluticasone/Salmeterol vs Formoterol 2.09 1.29-3.37 1.14-3.83 - - - -
Mometasone/Formoterol vs Formoterol 0.96 0.34-2.71 0.27-3.39 0.66 0.18-2.36 0.11 2 898
Indacaterol/Glycopyrronium vs Formoterol 0.93 0.49-1.80 0.42-2.10 - - - -
Umeclidinium/Vilanterol vs Formoterol 0.68 0.12-3.75 0.08-5.38 - - - -
Tiotropium/Fluticasone/Salmeterol vs Formoterol 1.72 0.30-9.65 0.21-13.90 - - - -
Tiotropium/Budesonide/Formoterol vs Formoterol 1.03 0.19-5.59 0.13-7.98 - - - -
Salmeterol vs Indacaterol 1.15 0.73-1.81 0.64-2.05 - - - -
Vilanterol vs Indacaterol 1.17 0.49-2.81 0.40-3.42 - - - -
Aclidinium vs Indacaterol 0.70 0.29-1.65 0.24-2.00 - - - -
Glycopyrronium vs Indacaterol 0.84 0.50-1.44 0.43-1.65 1.01 0.20-5.01 -- 1 949
Tiotropium vs Indacaterol 0.97 0.65-1.45 0.58-1.62 0.90 0.60-1.35 0.00 2 4395
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Umeclidinium vs Indacaterol 0.76 0.11-5.31 0.07-7.97 - - - -
Beclomethasone/Formoterol vs Indacaterol 1.17 0.32-4.29 0.24-5.68 - - - -
Budesonide/Formoterol vs Indacaterol 1.30 0.68-2.48 0.58-2.89 - - - -
Fluticasone/Vilanterol vs Indacaterol 2.19 0.91-5.30 0.74-6.46 - - - -
Fluticasone/Salmeterol vs Indacaterol 1.95 1.20-3.17 1.06-3.60 - - - -
Mometasone/Formoterol vs Indacaterol 0.90 0.29-2.83 0.23-3.62 - - - -
Indacaterol/Glycopyrronium vs Indacaterol 0.88 0.49-1.57 0.42-1.81 1.00 0.20-5.00 -- 1 950
Umeclidinium/Vilanterol vs Indacaterol 0.63 0.12-3.43 0.08-4.90 - - - -
Tiotropium/Fluticasone/Salmeterol vs Indacaterol 1.61 0.29-8.83 0.20-12.65 - - - -
Tiotropium/Budesonide/Formoterol vs Indacaterol 0.97 0.18-5.11 0.13-7.25 - - - -
Vilanterol vs Salmeterol 1.02 0.47-2.22 0.40-2.65 - - - -
Aclidinium vs Salmeterol 0.61 0.28-1.31 0.24-1.56 - - - -
Glycopyrronium vs Salmeterol 0.74 0.48-1.13 0.43-1.27 - - - -
Tiotropium vs Salmeterol 0.85 0.68-1.06 0.61-1.17 0.78 0.57-1.08 -- 1 7376
Umeclidinium vs Salmeterol 0.67 0.10-4.49 0.07-6.71 - - - -
Beclomethasone/Formoterol vs Salmeterol 1.01 0.29-3.51 0.22-4.58 - - - -
Budesonide/Formoterol vs Salmeterol 1.13 0.68-1.88 0.60-2.14 - - - -
Fluticasone/Vilanterol vs Salmeterol 1.91 0.87-4.19 0.73-5.01 - - - -
Fluticasone/Salmeterol vs Salmeterol 1.70 1.38-2.09 1.25-2.31 1.69 1.40-2.04 0.00 8 7613
Mometasone/Formoterol vs Salmeterol 0.79 0.27-2.30 0.21-2.90 - - - -
Indacaterol/Glycopyrronium vs Salmeterol 0.76 0.47-1.25 0.41-1.42 - - - -
Umeclidinium/Vilanterol vs Salmeterol 0.55 0.11-2.89 0.07-4.10 - - - -
Tiotropium/Fluticasone/Salmeterol vs Salmeterol 1.40 0.26-7.45 0.18-10.60 - - - -
Tiotropium/Budesonide/Formoterol vs Salmeterol 0.84 0.17-4.30 0.12-6.08 - - - -
Aclidinium vs Vilanterol 0.59 0.20-1.72 0.16-2.17 - - - -
Glycopyrronium vs Vilanterol 0.72 0.31-1.70 0.25-2.06 - - - -
Tiotropium vs Vilanterol 0.83 0.38-1.81 0.32-2.16 2.03 0.18-
22.56
-- 1 408
Umeclidinium vs Vilanterol 0.65 0.09-4.97 0.06-7.61 - - - -
Beclomethasone/Formoterol vs Vilanterol 0.99 0.23-4.19 0.17-5.70 - - - -
Budesonide/Formoterol vs Vilanterol 1.11 0.45-2.70 0.37-3.29 - - - -
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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 - - - -
Glycopyrronium vs Aclidinium 1.21 0.52-2.83 0.43-3.42 - - - -
Tiotropium vs Aclidinium 1.40 0.65-3.01 0.55-3.59 - - - -
Umeclidinium vs Aclidinium 1.10 0.14-8.49 0.09-13.03 - - - -
Beclomethasone/Formoterol vs Aclidinium 1.67 0.40-6.99 0.30-9.47 - - - -
Budesonide/Formoterol vs Aclidinium 1.87 0.78-4.47 0.64-5.43 - - - -
Fluticasone/Vilanterol vs Aclidinium 3.15 1.07-9.24 0.85-11.68 - - - -
Fluticasone/Salmeterol vs Aclidinium 2.81 1.30-6.07 1.09-7.24 - - - -
Mometasone/Formoterol vs Aclidinium 1.30 0.36-4.70 0.27-6.19 - - - -
Indacaterol/Glycopyrronium vs Aclidinium 1.26 0.52-3.03 0.43-3.69 - - - -
Umeclidinium/Vilanterol vs Aclidinium 0.91 0.15-5.57 0.10-8.15 - - - -
Tiotropium/Fluticasone/Salmeterol vs Aclidinium 2.31 0.37-14.33 0.25-21.03 - - - -
Tiotropium/Budesonide/Formoterol vs Aclidinium 1.39 0.23-8.31 0.16-12.11 - - - -
Tiotropium vs Glycopyrronium 1.15 0.80-1.67 0.71-1.87 1.06 0.71-1.58 <0.0001 4 3385
Umeclidinium vs Glycopyrronium 0.90 0.13-6.25 0.09-9.38 - - - -
Beclomethasone/Formoterol vs Glycopyrronium 1.38 0.38-5.02 0.29-6.63 - - - -
Budesonide/Formoterol vs Glycopyrronium 1.54 0.82-2.86 0.71-3.32 - - - -
Fluticasone/Vilanterol vs Glycopyrronium 2.59 1.09-6.18 0.90-7.51 - - - -
Fluticasone/Salmeterol vs Glycopyrronium 2.31 1.47-3.64 1.30-4.11 - - - -
Mometasone/Formoterol vs Glycopyrronium 1.07 0.35-3.31 0.27-4.22 - - - -
Indacaterol/Glycopyrronium vs Glycopyrronium 1.04 0.66-1.63 0.58-1.84 0.93 0.59-1.48 0.00 2 2416
Umeclidinium/Vilanterol vs Glycopyrronium 0.75 0.14-4.04 0.10-5.76 - - - -
Tiotropium/Fluticasone/Salmeterol vs Glycopyrronium 1.90 0.35-10.39 0.24-14.87 - - - -
Tiotropium/Budesonide/Formoterol vs Glycopyrronium 1.15 0.22-6.01 0.15-8.52 - - - -
Umeclidinium vs Tiotropium 0.78 0.12-5.23 0.08-7.79 0.97 0.14-6.94 -- 1 437
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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 - - - -
Indacaterol/Glycopyrronium vs
Beclomethasone/Formoterol
0.75 0.20-2.80 0.15-3.71 - - - -
Umeclidinium/Vilanterol vs Beclomethasone/Formoterol 0.54 0.07-4.26 0.05-6.55 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Beclomethasone/Formoterol
1.38 0.17-10.93 0.11-16.87 - - - -
Tiotropium/Budesonide/Formoterol vs
Beclomethasone/Formoterol
0.83 0.11-6.37 0.07-9.77 - - - -
Fluticasone/Vilanterol vs Budesonide/Formoterol 1.69 0.68-4.18 0.56-5.11 - - - -
Fluticasone/Salmeterol vs Budesonide/Formoterol 1.50 0.91-2.48 0.80-2.82 - - - -
Mometasone/Formoterol vs Budesonide/Formoterol 0.70 0.24-2.04 0.19-2.58 - - - -
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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 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Budesonide/Formoterol
1.24 0.22-7.00 0.15-10.09 - - - -
Tiotropium/Budesonide/Formoterol vs
Budesonide/Formoterol
0.75 0.14-4.05 0.10-5.79 - - - -
Fluticasone/Salmeterol vs Fluticasone/Vilanterol 0.89 0.41-1.96 0.34-2.34 2.04 0.18-
22.62
-- 1 528
Mometasone/Formoterol vs Fluticasone/Vilanterol 0.41 0.11-1.53 0.08-2.02 - - - -
Indacaterol/Glycopyrronium vs Fluticasone/Vilanterol 0.40 0.16-0.98 0.13-1.20 - - - -
Umeclidinium/Vilanterol vs Fluticasone/Vilanterol 0.29 0.05-1.73 0.03-2.52 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Fluticasone/Vilanterol
0.73 0.12-4.60 0.08-6.76 - - - -
Tiotropium/Budesonide/Formoterol vs
Fluticasone/Vilanterol
0.44 0.07-2.67 0.05-3.89 - - - -
Mometasone/Formoterol vs Fluticasone/Salmeterol 0.46 0.16-1.35 0.13-1.70 - - - -
Indacaterol/Glycopyrronium vs Fluticasone/Salmeterol 0.45 0.27-0.75 0.24-0.85 0.11 0.01-2.09 -- 1 522
Umeclidinium/Vilanterol vs Fluticasone/Salmeterol 0.32 0.06-1.71 0.04-2.43 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Fluticasone/Salmeterol
0.82 0.15-4.41 0.11-6.29 - - - -
Tiotropium/Budesonide/Formoterol vs
Fluticasone/Salmeterol
0.50 0.10-2.55 0.07-3.60 - - - -
Indacaterol/Glycopyrronium vs Mometasone/Formoterol 0.97 0.31-3.08 0.24-3.95 - - - -
Umeclidinium/Vilanterol vs Mometasone/Formoterol 0.70 0.10-4.98 0.07-7.51 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Mometasone/Formoterol
1.78 0.25-12.79 0.16-19.35 - - - -
Tiotropium/Budesonide/Formoterol vs
Mometasone/Formoterol
1.07 0.15-7.44 0.10-11.18 - - - -
Umeclidinium/Vilanterol vs Indacaterol/Glycopyrronium 0.72 0.13-3.97 0.09-5.68 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Indacaterol/Glycopyrronium
1.84 0.33-10.21 0.23-14.66 - - - -
Tiotropium/Budesonide/Formoterol vs
Indacaterol/Glycopyrronium
1.11 0.21-5.90 0.15-8.41 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Umeclidinium/Vilanterol
2.54 0.25-26.17 0.15-42.60 - - - -
Tiotropium/Budesonide/Formoterol vs
Umeclidinium/Vilanterol
1.53 0.15-15.30 0.09-24.76 - - - -
Tiotropium/Budesonide/Formoterol vs
Tiotropium/Fluticasone/Salmeterol
0.60 0.06-6.09 0.04-9.87 - - - -
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Common within-network heterogeneity variance 0.01
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity variance)
34.33 (31,0.311,0.00)
Arrhythmia: 26 studies (1 five-arm, 1 four-arm, 2 three-arm, 22 two-arm), 12 treatments, 27407 patients
Budesonide vs Placebo 1.97 0.35-11.19 0.17-23.08 1.09 0.15-7.80 -- 1 575
Formoterol vs Placebo 1.50 0.66-3.43 0.47-4.83 1.63 0.70-3.84 0.02 6 3053
Indacaterol vs Placebo 1.44 0.61-3.40 0.43-4.85 1.48 0.44-4.99 0.00 2 1081
Salmeterol vs Placebo 0.99 0.39-2.54 0.26-3.75 0.90 0.27-2.99 0.37 4 1213
Aclidinium vs Placebo 1.13 0.44-2.86 0.30-4.22 1.13 0.44-2.87 0.00 2 1647
Glycopyrronium vs Placebo 1.52 0.63-3.62 0.44-5.21 2.92 0.35-
24.37
0.00 2 1522
Tiotropium vs Placebo 1.17 0.71-1.93 0.58-2.38 1.37 0.50-3.72 0.37 4 8729
Budesonide/Formoterol vs Placebo 2.75 0.87-8.64 0.54-13.93 2.93 0.27-
32.10
1.50 2 1556
Fluticasone/Vilanterol vs Placebo 8.88 0.33-240.14 0.08-948.41 - - - -
Fluticasone/Salmeterolvs Placebo 0.80 0.17-3.86 0.09-7.43 - - - -
Indacaterol/Glycopyrronium vs Placebo 1.63 0.68-3.89 0.48-5.60 2.46 0.12-
51.45
-- 1 706
Formoterol vs Budesonide 0.77 0.13-4.37 0.06-9.03 0.48 0.04-5.35 -- 1 559
Indacaterol vs Budesonide 0.73 0.11-5.10 0.05-11.43 - - - -
Salmeterol vs Budesonide 0.51 0.07-3.64 0.03-8.30 - - - -
Aclidinium vs Budesonide 0.57 0.08-4.12 0.03-9.37 - - - -
Glycopyrronium vs Budesonide 0.77 0.11-5.39 0.05-12.12 - - - -
Tiotropium vs Budesonide 0.60 0.10-3.64 0.05-7.73 - - - -
Budesonide/Formoterol vs Budesonide 1.40 0.24-8.11 0.12-16.87 0.98 0.14-7.00 -- 1 556
Fluticasone/Vilanterol vs Budesonide 4.52 0.11-187.86 0.02-887.62 - - - -
Fluticasone/Salmeterolvs Budesonide 0.41 0.04-4.26 0.01-11.29 - - - -
Indacaterol/Glycopyrronium vs Budesonide 0.83 0.12-5.80 0.05-13.04 - - - -
Indacaterol vs Formoterol 0.96 0.29-3.15 0.18-5.16 - - - -
Salmeterol vs Formoterol 0.66 0.19-2.30 0.11-3.87 - - - -
Aclidinium vs Formoterol 0.75 0.22-2.60 0.13-4.36 - - - -
Glycopyrronium vs Formoterol 1.01 0.30-3.34 0.18-5.50 - - - -
Tiotropium vs Formoterol 0.78 0.30-2.04 0.20-3.05 - - - -
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Budesonide/Formoterol vs Formoterol 1.83 0.67-4.98 0.44-7.57 2.12 0.69-6.54 0.00 3 2364
Fluticasone/Vilanterol vs Formoterol 5.91 0.20-176.66 0.05-727.72 - - - -
Fluticasone/Salmeterolvs Formoterol 0.53 0.09-3.15 0.04-6.58 - - - -
Indacaterol/Glycopyrronium vs Formoterol 1.08 0.33-3.59 0.20-5.92 - - - -
Salmeterol vs Indacaterol 0.69 0.20-2.42 0.12-4.09 - - - -
Aclidinium vs Indacaterol 0.78 0.22-2.77 0.13-4.69 - - - -
Glycopyrronium vs Indacaterol 1.05 0.38-2.89 0.25-4.40 0.67 0.11-4.02 -- 1 949
Tiotropium vs Indacaterol 0.81 0.35-1.87 0.25-2.65 0.87 0.24-3.08 0.02 2 4395
Budesonide/Formoterol vs Indacaterol 1.91 0.46-7.97 0.25-14.46 - - - -
Fluticasone/Vilanterol vs Indacaterol 6.16 0.21-182.74 0.05-750.24 - - - -
Fluticasone/Salmeterolvs Indacaterol 0.56 0.10-3.23 0.05-6.71 - - - -
Indacaterol/Glycopyrronium vs Indacaterol 1.13 0.41-3.10 0.27-4.72 0.67 0.11-4.02 -- 1 950
Aclidinium vs Salmeterol 1.13 0.30-4.25 0.17-7.37 - - - -
Glycopyrronium vs Salmeterol 1.52 0.43-5.34 0.26-9.01 - - - -
Tiotropium vs Salmeterol 1.18 0.41-3.36 0.27-5.21 - - - -
Budesonide/Formoterol vs Salmeterol 2.77 0.63-12.16 0.34-22.52 - - - -
Fluticasone/Vilanterol vs Salmeterol 8.94 0.36-220.89 0.10-840.28 - - - -
Fluticasone/Salmeterolvs Salmeterol 0.81 0.21-3.19 0.12-5.64 1.01 0.15-6.83 1.07 3 1875
Indacaterol/Glycopyrronium vs Salmeterol 1.64 0.48-5.66 0.28-9.47 - - - -
Glycopyrronium vs Aclidinium 1.35 0.38-4.83 0.22-8.21 - - - -
Tiotropium vs Aclidinium 1.04 0.36-3.00 0.23-4.66 - - - -
Budesonide/Formoterol vs Aclidinium 2.44 0.56-10.70 0.30-19.80 - - - -
Fluticasone/Vilanterol vs Aclidinium 7.89 0.26-242.89 0.06-
1012.35
- - - -
Fluticasone/Salmeterolvs Aclidinium 0.71 0.12-4.44 0.05-9.49 - - - -
Indacaterol/Glycopyrronium vs Aclidinium 1.45 0.40-5.19 0.24-8.83 - - - -
Tiotropium vs Glycopyrronium 0.77 0.36-1.68 0.26-2.33 0.75 0.31-1.80 0.00 2 2430
Budesonide/Formoterol vs Glycopyrronium 1.81 0.43-7.65 0.24-13.94 - - - -
Fluticasone/Vilanterol vs Glycopyrronium 5.86 0.20-171.85 0.05-701.95 - - - -
Fluticasone/Salmeterolvs Glycopyrronium 0.53 0.09-3.00 0.05-6.18 - - - -
Indacaterol/Glycopyrronium vs Glycopyrronium 1.08 0.50-2.31 0.37-3.18 1.10 0.50-2.42 0.00 2 2416
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Budesonide/Formoterol vs Tiotropium 2.35 0.67-8.19 0.40-13.79 - - - -
Fluticasone/Vilanterol vs Tiotropium 7.58 0.27-209.82 0.07-836.67 - - - -
Fluticasone/Salmeterolvs Tiotropium 0.69 0.14-3.46 0.07-6.79 - - - -
Indacaterol/Glycopyrronium vs Tiotropium 1.39 0.64-3.01 0.47-4.16 1.46 0.62-3.45 0.00 2 2420
Fluticasone/Vilanterol vs Budesonide/Formoterol 3.23 0.10-105.98 0.02-453.67 - - - -
Fluticasone/Salmeterolvs Budesonide/Formoterol 0.29 0.04-2.04 0.02-4.59 - - - -
Indacaterol/Glycopyrronium vs Budesonide/Formoterol 0.59 0.14-2.50 0.08-4.55 - - - -
Fluticasone/Salmeterolvs Fluticasone/Vilanterol 0.09 0.00-1.65 0.00-5.51 0.09 0.00-1.65 -- 1 528
Indacaterol/Glycopyrronium vs Fluticasone/Vilanterol 0.18 0.01-5.27 0.00-21.36 - - - -
Indacaterol/Glycopyrronium vs Fluticasone/Salmeterol 2.03 0.37-11.01 0.18-22.28 3.08 0.12-
75.99
-- 1 522
Common within-network heterogeneity variance 0.00
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity variance)
3.06 (11,0.9899,0.36)
Abbreviations and symbols: OR, Odds Ratio, NMA, Network Meta-analysis, MA, Meta-analysis, CI, Confidence Interval; PrI, Predictive Interval; LABA, long acting
beta agonists, χ², Chi Square Test, d.f., degrees of freedom
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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
Treatment Comparison Odds
Ratio CI
Odds
Ratio CI # studies # patients
Exacerbations: 25 studies (2 four-arm, 6 three-arm, 17 two-arm), 20 treatments, 33211 patients
Fluticasone vs Placebo 0.28 0.13-0.62 0.21 0.09-0.48 2.00 541.00
Vilanterol vs Fluticasone 3.88 1.68-8.93 4.86 1.62-14.64 1.00 407.00
Fluticasone/Vilanterol vs Fluticasone 2.86 1.23-6.64 3.40 1.09-10.62 1.00 408.00
Fluticasone/Vilanterol vs Vilanterol 0.74 0.59-0.92 0.75 0.62-0.91 3.00 2031.00
Indacaterol/Glycopyrronium vs
Glycopyrronium 0.62 0.47-0.82 0.63 0.51-0.77 1.00 1469.00
Indacaterol/Glycopyrronium vs Tiotropium 0.73 0.57-0.94 0.74 0.60-0.91 1.00 1466.00
Indacterol/Tiotropium vs Placebo 0.67 0.46-0.98
Indacaterol/Glycopyrronium vs Placebo 0.60 0.43-0.84
Indacaterol vs Fluticasone 3.30 1.44-7.55
Salmeterol vs Fluticasone 3.40 1.49-7.72
Glycopyrronium vs Fluticasone 3.44 1.47-8.07
Tiotropium vs Fluticasone 2.93 1.30-6.57
Umeclidinium vs Fluticasone 4.71 1.71-12.96
Fluticasone/Salmeterol vs Fluticasone 3.14 1.37-7.20 1.19 0.31-4.59 1.00 179.00
Tiotropium/Salmeterol vs Fluticasone 3.20 1.23-8.29
Indacterol/Tiotropium vs Fluticasone 2.41 1.02-5.73
Umeclidinium/Vilanterol vs Fluticasone 4.37 1.73-11.05
Tiotropium/Fluticasone/Salmeterol vs
Fluticasone 2.60 1.00-6.73
Indacaterol/Glycopyrronium vs Indacaterol 0.65 0.47-0.90
Indacaterol/Glycopyrronium vs Salmeterol 0.63 0.46-0.86
Indacaterol/Glycopyrronium vs Vilanterol 0.55 0.33-0.92
Indacaterol/Glycopyrronium vs
Umeclidinium 0.46 0.23-0.90
Indacaterol/Glycopyrronium vs
Fluticasone/Salmeterol 0.68 0.50-0.93 0.67 0.44-1.03 1.00 522.00
Umeclidinium/Vilanterol vs
Indacterol/Tiotropium 1.81 1.00-3.27
Common within-network heterogeneity
variance
0.01
Design-by-treatment interaction model
for inconsistency χ² (d.f., P-value,
heterogeneity variance)
13.51(12,0.333,0.00)
Mortality Overall: 23 studies (3 four-arm, 5 three-arm, 15 two-arm), 21 treatments, 33624 patients
Salmeterol/Fluticasone vs Placebo 0.50 0.29-0.88
Salmeterol vs Salmeterol/Fluticasone 2.25 1.20-4.20
Tiotropium vs Salmeterol/Fluticasone 1.84 1.07-3.15 1.84 1.07 1 1323
Vilanterol vs Salmeterol/Fluticasone 3.56 1.03-12.38
Common within-network heterogeneity 0.00
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variance
Design-by-treatment interaction model
for inconsistency χ² (d.f., P-value,
heterogeneity variance)
9.51 (12, 0.659,0.00)
Pneumonia: 19 studies (2 four-arm, 4 three-arm, 13 two-arm), 18 treatments, 28763 patients
Budesonide/Formoterol vs Placebo 8.39 1.16-60.69
Fluticasone/Salmeterol vs Placebo 2.45 1.48-4.07
Salmeterol vs Budesonide 2.15 1.00-4.61
Beclomethasone/Formoterol vs Budesonide 11.02
1.05-
116.02
Budesonide/Formoterol vs Budesonide 13.42
1.66-
108.72
Fluticasone/Salmeterol vs Budesonide 3.92 1.68-9.15
Budesonide/Formoterol vs Mometasone 25.06
1.24-
506.42
Budesonide/Formoterol vs Formoterol 2.72 1.38-5.37 2.72 1.38-5.37 2.00 1290.00
Fluticasone/Salmeterol vs Indacaterol 2.08 1.10-3.93
Fluticasone/Salmeterol vs Salmeterol 1.82 1.02-3.26
Fluticasone/Vilanterol vs Vilanterol 2.06 1.27-3.34 2.10 1.28-3.44 3.00 2031.00
Fluticasone/Salmeterol vs Glycopyrronium 2.24 1.14-4.41
Budesonide/Formoterol vs Tiotropium 7.97 1.10-57.95
Fluticasone/Salmeterol vs Tiotropium 2.33 1.43-3.78 2.20 1.33-3.62 1.00 1323.00
Mometasone/Formoterol vs
Budesonide/Formoterol 0.12 0.02-0.88
Indacaterol/Glycopyrronium vs
Budesonide/Formoterol 0.12 0.02-0.91
Indacaterol/Glycopyrronium vs
Fluticasone/Salmeterol 0.41 0.21-0.80 0.11 0.01-2.09 1.00 522.00
Common within-network heterogeneity
variance
0.00
Design-by-treatment interaction model
for inconsistency χ² (d.f., P-value,
heterogeneity variance)
4.88 (7, 0.675, 0.00)
Abbreviations: CI, Confidence Interval; d.f., degrees of freedom
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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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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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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,
budesonide/formoterol/ipratropium bromide; TIOT+Resp, Tiotropium Respimat (Soft Mist Inhaler).
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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, 2013 NO YES
Bateman, 2012 NO NO
Bateman , 2008 NO NO
Bedard, 2012 NO NO
Beier, 2013 NO NO
Beier, 2007 NO NO
Bogdan, 2011 NO NO
Bolukbas, 2011 NO NO
Bourbeau, 2007 YES NO
Bourbeau, 1998 YES YES
Boyd, 1997 NO NO
Briggs, 2005 NO NO
Buhl, 2011 NO NO
Burge, 2000 YES YES
Caillaud, 2007 NO NO
Calverley, 2010 YES YES
Calverley, 2003 YES YES
Calverley, 2007 YES YES
Calverley, 2003 NO NO
Calverley, 2003 YES YES
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
Maltais , 2005 NO NO
Mansori, 2010 NO NO
Martinez, 2013 YES NO
Mathioudakis, 2013 NO NO
McNicholas, 2004 NO NO
Mirici, 2001 YES NO
Moita , 2008 NO NO
Mroz, 2013 NO NO
Nicolini , 2012 NO NO
Niewoehner, 2005 NO YES
O'Donnell, 2006 NO NO
O'Donnell, 2004 NO NO
Ozol, 2005 YES YES
Paggiaro, 1998 YES YES
Pasqua, 2010 NO NO
Pauwels, 1999 YES YES
Perng, 2009 NO NO
Powrie , 2007 NO YES
Pukhta, 2010 NO NO
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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
Wedzicha, 2008 NO YES
Weir, 1999 NO NO
Welte, 2008 NO NO
Welte , 2009 NO NO
Wesseling, 1991 NO NO
Wielders, 2013 NO NO
Wise, 2013 NO NO
Woolhouse , 2001 NO NO
Wouters, 2005 NO NO
Yao, 2014 NO NO
Yildiz, 2004 YES NO
Zheng , 2007 NO YES
Zhong, 2012 NO YES
Included unpublished studies (n= 20)
GlaxoSmithKline, 2005 NO NO
GlaxoSmithKline, 2005 NO NO
GlaxoSmithKline, 2005 NO NO
GlaxoSmithKline, 2006 NO YES
GlaxoSmithKline, 2005 YES 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
Calverley, 2003 NO YES
GlaxoSmithKline, 2008 YES NO
GlaxoSmithKline, 2008 YES YES
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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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist
Page 1 of 2
Section/topic # Checklist item Reported on page #
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
indacaterol/glycopyrronium, tiotropium/fluticasone/salmeterol, and 243
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
File format: Adobe Acrobat Document (.pdf) 427
Title of the Data: Appendix 1-15 428
429
Description of Data: Protocol 430
File name: Protocol.pdf 431
File format: Adobe Acrobat Document (.pdf) 432
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 . . . .
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 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
Between –study heterogeneity 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
Between –study heterogeneity 0.00
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity) 11.79 (27,0.995,0.00)
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 . . . .
Between –study heterogeneity 0.01
Design-by-treatment interaction model for
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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32. Thomas N. Overview: OpenBUGS website. http://www.openbugs.net/w/Overview. Accessed: 610
January 2015. 611
33. Turner RM, Davey J, Clarke MJ et al. Predicting the extent of heterogeneity in meta-analysis, 612
using empirical data from the Cochrane Database of Systematic Reviews. Int J Epidemiol. 2012; 613
41(3):818-827. 614
34. Troosters T, Sciurba FC, Decramer M et al. Tiotropium in patients with moderate COPD naive to 615
maintenance therapy: a randomised placebo-controlled trial. NPJ Prim Care Respir Med. 2014; 616
24:14003. 617
35. Tieu J, Bain E, Middleton P et al. Interconception care for women with a history of gestational 618
diabetes for improving maternal and infant outcomes. In: Cochrane Database of Systematic 619
Reviews. John Wiley & Sons, Ltd; 2013. 620
36. Andrade-Castellanos Carlos A, Colunga-Lozano Luis E, Delgado-Figueroa N et al. Subcutaneous 621
rapid-acting insulin analogues for diabetic ketoacidosis. In: Cochrane Database of Systematic 622
Reviews. John Wiley & Sons, Ltd; 2014. 623
37. Shen W, Li Y, Zhang Y et al. Acupuncture for adults with type 2 diabetes mellitus. In: Cochrane 624
Database of Systematic Reviews. John Wiley & Sons, Ltd; 2013. 625
38. Sekiya M, Kawayama T, Fukuchi Y et al. Safety and efficacy of NVA237 once daily in Japanese 626
patients: the GLOW4 trial. European Respiratory Journal. 2012; 40(Suppl 56):P2103. 627
39. Brown J, Crawford Tineke J, Alsweiler J et al. Myo-inositol for preventing gestational diabetes. 628
In: Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd; 2015. 629
40. Crawford Tineke J, Brown J, Alsweiler J et al. Different intensities of glycaemic control for 630
women with gestational diabetes mellitus. In: Cochrane Database of Systematic Reviews. John 631
Wiley & Sons, Ltd; 2015. 632
41. Flowers N, Hartley L, Todkill D et al. Co-enzyme Q10 supplementation for the primary 633
prevention of cardiovascular disease. In: Cochrane Database of Systematic Reviews. John Wiley 634
& Sons, Ltd; 2014. 635
42. Decramer M, Anzueto A, Kerwin E et al. Efficacy and safety of umeclidinium plus vilanterol 636
versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with 637
chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised 638
controlled trials. The Lancet Respiratory Medicine. 2014; 2(6):472-486. 639
43. Wadbo M, Lofdahl CG, Larsson K et al. Effects of formoterol and ipratropium bromide in 640
COPD: a 3-month placebo-controlled study. Eur Respir J. 2002; 20(5):1138-1146. 641
44. Hanania NA, Feldman G, Zachgo W et al. The efficacy and safety of the novel long-acting beta2 642
agonist vilanterol in patients with COPD: a randomized placebo-controlled trial. Chest. 2012; 643
142(1):119-127. 644
45. Wielders PL, Ludwig-Sengpiel A, Locantore N et al. A new class of bronchodilator improves 645
lung function in COPD: a trial with GSK961081. Eur Respir J. 2013; 42(4):972-981. 646
46. Martinez FJ, Boscia J, Feldman G et al. Fluticasone furoate/vilanterol (100/25; 200/25 mug) 647
improves lung function in COPD: a randomised trial. Respir Med. 2013; 107(4):550-559. 648
47. Dong YH, Lin HH, Shau WY et al. Comparative safety of inhaled medications in patients with 649
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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
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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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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
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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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
Generic name(s)* Trade name(s)*
We will exclude the following formulations:
Long-acting beta2-agonists (LABA) in nebulizer and transdermal form
formoterol (when in nebulizer form)
arformoterol
tulobuterol
Inhaled corticosteroids (ICS) in nebulizer form
beclomethasone (when in nebulizer form)
budesonide (when in nebulizer form)
We will exclude ALL of the following agents:
Short-acting beta2-agonists (SABA) (inhaled, nebulizer, oral, injection)
fenoterol
levosalbutamol or levalbuterol Xopenex
salbutamol or albuterol Ventolin
terbutaline Bricanyl
Short-acting muscarinic anticholinergics (SAMA) (inhaler, nebulizer)
ipratropium bromide Combivent, Atrovent
oxitropium bromide
Combo SABA plus anticholinergic in one inhaler (inhaler, nebulizer)
fenoterol/ipratropium
salbutamol/ipratropium
Methylxanthines (oral, injection)
aminophylline
theophylline
Systemic corticosteroids (oral)
prednisone
methyl-prednisolone
Phosphodiesterase-4 (PDE4) inhibitors (oral)
roflumilast
Note: *This is not an exhausitve list.
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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.
22 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (beta-2-agonist* or beta-2agonist* or beta-2-adrenergic* or adrenergic
beta-2-receptor* or beta-2-receptor agonist* or beta-2-adrenoceptor agonist*)).tw.
23 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (beta2-agonist* or beta2agonist* or beta2-adrenergic* or adrenergic beta2-
receptor* or beta2-receptor agonist* or beta2- adrenoceptor agonist*)).tw.
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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.
25 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (B2-agonist* or B2-adrenergic* or adrenergic B2-receptor* or B2-receptor
agonist* or B2-adrenoceptor agonist*)).tw.
26 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (B-2-agonist* or B-2-adrenergic* or adrenergic B-2-receptor* or B-2-
receptor agonist* or B-2-adrenoceptor agonist*)).tw.
27 (LABA or LABAs or Ultra-LABA* or UltraLABA*).tw.
28 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and bronchodilator*).tw.
29 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (betamimetic* or beta-mimetic*)).tw.
30 exp Adrenergic beta-Agonists/ or Bronchodilator Agents/
31 (longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting).tw.
32 30 and 31
33 or/21-29,32
34 Administration, Inhalation/
35 exp Aerosols/
36 (inhal* or aerosol*).tw.
37 or/34-36
38 33 and 37
39 or/8-20,38 )
40 Beclomethasone/
41 (Aerobec or AeroBec Forte or Aldecin or Apo-Beclomethasone or Ascocortonyl or
AsmabecClickhaler).tw.
42 (Beclamet or Beclazone or BecloAsma or Beclo AZU or Beclocort or Becloforte or
Beclomet or Beclometason* or Beclomethasone or Beclorhinol or Becloturmant or Beclovent or
Becodisk* or Beconase or Becotide or BemedrexEasyhaler or Bronchocort).tw.
43 (Ecobec or Filair or Junik or Nasobec Aqueous or Prolair or Propaderm or Qvar or
Respocort or Sanasthmax or Sanasthmyl or Vancenase or Vanceril or Ventolair or Viarin).tw.
44 (BMJ 5800 or EINECS 224-585-9 or UNII-KGZ1SLC28Z).tw.
45 4419-39-0.rn.
46 Budesonide/
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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.
75 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (anticholinergic* or anti-cholinergic* or cholinolytic* or cholinergic-
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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/
102 ((chronic adj2 obstructi*) and (pulmonary or airway* or air way* or lung$1 or airflow* or
air flow*)).tw.
103 (COPD or COAD).tw.
104 (chronic adj2 bronchitis).tw.
105 emphysema*.tw.
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106 or/100-105
107 formoterol/ or formoterolfumarate/
108 (BD 40A or HSDB 7287 or Oxis or UNII-5ZZ84GCW8B).tw.
109 (eformoterol or Foradil or formoterol).tw.
110 (73573-87-2 or 183814-30-4).rn.
111 indacaterol/
112 (Arcapta or Onbrez or indacaterol or QAB 149 or QAB149 or UNII-8OR09251MQ).tw.
113 312753-06-3.rn.
114 salmeterol/
115 (Aeromax or Astmerole or "GR 33343 X" or "GR 33343X" or HSDB 7315 or Salmeterol
or SN408D or UNII-2I4BC502BT).tw.
116 89365-50-4.rn.
117 salmeterolxinafoate/
118 (Arial or Asmerole or Beglan or Betamican or Dilamax or Inaspir or Salmetedur or
Salmeterolxinafoate or Serevent or Ultrabeta or UNII-6EW8Q962A5).tw.
119 94749-08-3.rn.
120 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (beta-agonist* or betaagonist* or beta-adrenergic* or adrenergic beta-
receptor* or beta-receptor agonist* or beta-adrenoceptor agonist*)).tw.
121 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (beta-2-agonist* or beta-2agonist* or beta-2-adrenergic* or adrenergic
beta-2-receptor* or beta-2-receptor agonist* or beta-2-adrenoceptor agonist*)).tw.
122 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (beta2-agonist* or beta2agonist* or beta2-adrenergic* or adrenergic beta2-
receptor* or beta2-receptor agonist* or beta2- adrenoceptor agonist*)).tw.
123 ((longacting or long-acting) and ("beta(2)-agonist*" or "beta(2)-agonist*" or "beta(2)-
adrenergic*" or "adrenergic beta(2)-receptor*" or "beta(2)-receptor agonist*" or "beta(2)-
adrenoceptor agonist*")).tw.
124 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (B2-agonist* or B2-adrenergic* or adrenergic B2-receptor* or B2-receptor
agonist* or B2-adrenoceptor agonist*)).tw.
125 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (B-2-agonist* or B-2-adrenergic* or adrenergic B-2-receptor* or B-2-
receptor agonist* or B-2-adrenoceptor agonist*)).tw.
126 (LABA or LABAs or Ultra-LABA* or UltraLABA*).tw.
127 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and bronchodilator*).tw.
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128 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (betamimetic* or beta-mimetic*)).tw.
129 exp beta adrenergic receptor stimulating agent/ or brochodilating agent/
130 (longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting).tw.
131 129 and 130
132 or/120-128,131
133 inhalational drug administration/
134 aerosol/
135 (inhal* or aerosol*).tw.
136 or/133-135
137 132 and 136
138 or/107-119,137
139 beclometasone/
140 (Aerobec or AeroBec Forte or Aldecin or Apo-Beclomethasone or Ascocortonyl or
AsmabecClickhaler).tw.
141 (Beclamet or Beclazone or BecloAsma or Beclo AZU or Beclocort or Becloforte or
Beclomet or Beclometason* or Beclomethasone or Beclorhinol or Becloturmant or Beclovent or
Becodisk* or Beconase or Becotide or BemedrexEasyhaler or Bronchocort).tw.
142 (Ecobec or Filair or Junik or Nasobec Aqueous or Prolair or Propaderm or Qvar or
Respocort or Sanasthmax or Sanasthmyl or Vancenase or Vanceril or Ventolair or Viarin).tw.
143 (BMJ 5800 or EINECS 224-585-9 or UNII-KGZ1SLC28Z).tw.
144 4419-39-0.rn.
145 budesonide/
146 (Budesonide or Micronyl or Preferid or Pulmicort or Respules or Rhinocort or "S 1320"
or Spirocort or Uceris or UNII-Q3OKS62Q6X).tw.
147 51333-22-3.rn.
148 fluticasone/ or fluticasone propionate/
149 (Cutivate or Flixonase or Flixotide or Flonase or Flovent or Fluticason* or HSDB 7740 or
UNII-CUT2W21N7U).tw.
150 (90566-53-3 or 80474-14-2).rn.
151 glucocorticoid/
152 glucocorticoid*.tw.
153 corticosteroid/
154 (corticoid* or corticosteroid* or cortico-steroid*).tw.
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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/
160 (Adoair or Advair or Foxair or "Quikhale SF" or Seretide or Viani).tw.
161 (fluticasone adj3 salmeterol).tw.
162 136112-01-1.rn.
163 formoterolfumarate plus mometasonefuroate/
164 (formoterol adj3 mometasone).tw.
165 (Zenhale or Dulera).tw.
166 budesonide plus formoterol/
167 (formoterol adj3 budesonide).tw.
168 (Rilast or Symbicord or Symbicort or Vannair).tw.
169 150693-37-1.rn.
170 fluticasone furoate plus vilanterol/
171 (vilanterol adj3 fluticasone).tw.
172 Breo Ellipta.tw.
173 or/159-172
174 tiotropium bromide/
175 (BA 679 BR or BA 679BR or Spiriva or tiotropium or UNII-0EB439235F or UNII-
XX112XZP0J).tw.
176 (186691-13-4 or 136310-93-5).rn.
177 aclidinium bromide/
178 (LAS 34273 or LAS W-330 or BretarisGenuair or EkliraGenuair or TudorzaPressair or
UNII-UQW7UF9N91).tw.
179 320345-99-1.rn.
180 glycoyrronium bromide.tw.
181 (erythro-glycopyrronium bromide or UNII-9SFK0PX55W).tw.
182 ((longacting or long-acting or ultra-longacting or ultra-long-acting or ultralongacting or
ultralong-acting) and (anticholinergic* or anti-cholinergic* or cholinolytic* or cholinergic-
blocking or antimuscarinic* or anti-muscarinic* or ((cholinergic or acetylcholine or muscarinic)
adj3 antagonist*))).tw.
183 (LAMA or LAMAs or Ultra-LAMA* or UltraLAMA*).tw.
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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
multi-center 12 12 4 687
Aaron, 2007[167] Canada multi-center 52 52 3 449
Abrahams,
2013[133]
10 countries multi-center 24 24 2 856
Agusti, 2014[178] Europe, Asia (not specified) multi-center 12 12 2 528
Ambrosino,
2008[164]
Italy multi-center 25 25 2 234
Anzueto, 2009[46] USA, Canada multi-center 52 52 2 797
Auffarth, 1991[61] Netherlands NR 8 8 2 24
Barnes, 2006[23] NR multi-center 13 13 2 140
Bateman, 2008[36] South Africa multi-center 6 6 2 107
Bateman, 2010[7]
CR:[210]
31 countries multi-center 52 48 2 3917
Bateman, 2012[83] NR multi-center 4 4 6 576
Bateman, 2013[174] NR multi-center 30 26 5 2144
Bedard, 2012[166] Canada single center 3 3 2 36
Beier, 2007[136] Belgium, Germany, France,
the Netherlands, Slovakia
multi-center 5 4 3 163
Beier, 2013[70] Czech Republic, Germany,
Hungary, Poland
multi-center 6 6 3 414
Bogdan, 2011[77] Japan, Romania, Russia,
Ukraine
multi-center 12 12 3 613
Bolukbas, 2011[142] Germany multi-center 12 1 2 46
Bourbeau,
1998[128]
Canada single center 26 26 2 79
Bourbeau, 2007[52] Canada multi-center 12 12 3 60
Boyd, 1997[19] 18 countries multi-center 18 16 3 674
Briggs, 2005[102] Finland, Greece, Italy,
Portugal, Sweden, Turkey,
UK, USA
multi-center 12 12 2 653
Buhl, 2011[27] USA, Austria, Belgium,
Canada, Columbia,
Denmark, Finland, France,
Germany, Greece, Hungary,
Israel, Italy, Mexico,
Norway, Poland, Russia,
Slovakia, Spain,
Switzerland, Turkey, UK
multi-center 12 12 2 1598
Burge, 2000 [129]
CR:[204-208]
UK multi-center 156.53 156.53 2 751
Caillaud, 2007[4] France multi-center 3 3 8 202
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Calverley, 2003[34]
CR:[214-216, 261]
25 countries multi-center 54 52 4 1465
Calverly, 2003[53] NR multi-center 6 6 3 121
Calverly, 2003[119] NR (15 countries) multi-center 52 52 4 1022
Calverley,
2007[138] CR: [234-
242]
42 countries (not specified) multi-center 158 156 4 6112
Calverly, 2008[124] 11 countries multi-center 52 52 3 911
Calverley, 2010[25] 8 countries across Europe multi-center 48 48 3 718
Campbell, 2007[32] USA multi-center 8 8 2 204
Casaburi, 2005[103]
CR:[243]
USA multi-center 25 25 2 108
Cazzola, 2000[17] Italy NR 12 12 3 69
Cazzola, 2007[8] Italy NR 12 12 3 90
Celli, 2003[146] USA NR 5 4 2 81
Celli, 2003[104] 15 countries (not specified) multi-center 16 12 2 824
Chan, 2007[11] Canada multi-center 48 48 2 913
Chanez, 2010[15] Europe and Russia multi-center 4 4 7 460
Chapman,
2002[147]
Canada, Denmark, The
Netherlands, Russia,
Sweden, UK
multi-center 26 24 2 408
Chapman,
2011[115] CR: [249-
251]
USA, Argentina, Canada,
Germany, India, Italy,
Spain, Sweden, Turkey
multi-center 52 52 3 414
Choudhury,
2007[173]
UK multi-center 52 52 2 260
Cooper, 2013[170] 11 countries multi-center 96 96 2 519
Cote, 2009[93] USA multi-center 4 4 2 266
Covelli, 2005[13] USA multi-center 12 12 2 196
Criner, 2008[92] USA multi-center 8 8 2 166
D’Urzo, 2011[79] NR NR 30.29 26 2 822
Dahl, 2001[111] 8 countries multi-center 12 12 3 586
Dahl, 2010[88] Argentina, Chile, Columbia,
Czech, Denmark, Ecuador,
Egypt, Estonia, France,
Germany, Hungary, Israel,
Italy, Korea, Latvia,
Lithuania, Netherlands,
Peru, Romania, Russia,
Slovakia, Spain,
Switzerland, Turkey, UK
multi-center 52 52 4 1732
Dahl, 2013[82] Denmark multi-center 4 4 2 193
Dahl, 2013[131] Europe (not specified),
Canada, India, Korea, South
Africa
multi-center 52 52 2 338
Dal Negro,
2003[137]
Italy single center 52 52 3 18
Decramer,
2013[122]
Argentina, Australia,
Austria, Belgium, Brazil,
Canada, China, Columbia,
multi-center 52 52 2 3439
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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,
Slovakia, South Africa,
Spain, Sweden, Switzerland,
Taiwan, Thailand, Turkey,
UK, Venzuela
Decramer,
2014[183]a
Germany, Italy, Mexico,
Peru, Poland, Romania,
Russia, Ukraine, USA
multi-centre 25 24 4 843
Decramer,
2014[183]b
Argentina, Australia,
Canada, Chile, Germany,
Mexico, Romania, South
Africa, South Korea, USA
multi-centre 25 24 4 869
Doherty, 2012 North, Central and South
America, Europe, Africa,
Asia (not specified)
multi-center 52 26 5 1196
Donohue, 2002[3]
CR:[257, 258]
12 countries multi-center 24 24 3 623
Donohue, 2013[81] USA, Bulgaria, Canada,
Chile, Czech Republic,
Greece, Japan, Mexico,
Poland, Russia, South
Africa, Spain, Thailand
multi-center 24 24 4 1532
Dransfield, 2011[47] USA multi-center 16 16 2 249
Dransfield,
2013[180]a
15 countries multi-center 52 52 4 1622
Dransfield,
2013[180]b
15 countries multi-center 52 52 4 1633
Dusser, 2006[154] France multi-center 50 48 2 1010
Engel, 1989[12] Denmark single center 12 12 2 18
Feldman, 2010[76] USA, New Zealand,
Belgium
multi-center 12 12 2 416
Feldman, 2012[1] USA multi-center 5 4 2 51
Ferguson, 2008[45] USA, Canada multi-center 52 52 2 782
Freeman, 2007[84] UK multi-center 12 12 2 374
Fukuchi, 2013[31] Japan, Korea, Taiwan,
Philippines, Vietnam, India,
Russia, Poland, Ukraine
multi-center 12 12 2 1293
Gelb, 2013[179] USA, Canada multi-center 54 52 2 602
Gupta, 2002[20] India single center 8 8 2 33
Hagedorn,
2013[109]
Germany multi-center 52 52 2 212
Hanania, 2003[160] USA multi-center 24 24 4 723
Hanania, 2012[26] USA multi-center 24 24 2 342
Hanania, 2012[161] NR multi-center 4 4 6 602
Hasani, 2004[153] UK single center 3 3 2 34
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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
multi-center 16 16 3 283
Jones, 2011[176]a
NR - 16 European countries multi-center 52 52 2 843
Jones, 2011[176]b NR - 7 mostly North
American countries
multi-center 52 52 2 804
Jones, 2012[85] 9 European countries (not
specified), South Africa
multi-center 24 24 3 819
Jung, 2012[39] Republic of Korea multi-center 24 24 2 479
Kardos, 2007[101] Germany multi-center 44 44 2 994
Kaushik, 1999[57] India NR 1 1 2 30
Kerwin, 2011[177]a
USA multi-center 12 12 2 323
Kerwin, 2011[177]b
USA multi-center 12 12 2 318
Kerwin, 2012[68]
CR:[244]
USA, Canada multi-center 12 12 3 560
Kerwin, 2012[78] USA, Argentina, Canada,
Chile, France, Germany,
Hungary, Israel, Italy,
Korea, Mexico,
Netherlands, New Zealand,
Peru, Poland, Russia
multi-center 52 52 3 1066
Kerwin, 2013[10] Chile, Estonia, Germany,
Japan, Korea, Philippines,
Poland, Russian Federation,
USA
multi-center 24 24 5 1030
Kinoshita, 2012[75]
CR: [253]
Hong Kong, India, Japan,
Korea, Singapore, Taiwan
multi-center 12 12 3 347
Korn, 2011[108] USA, Czech, Germany,
Hungary, India, Slovakia,
Spain, Turkey
multi-center 12 12 2 1123
Kornmann,
2011[123]
15 countries (not specified) multi-center 27 26 3 998
Koser, 2010[132] USA multi-center 12 12 2 247
Kuna, 2013[71] Bulgaria, Canada, Japan,
Poland, Russia
multi-center 4 4 5 329
Lapperre, 2009[49]
CR:[252]
The Netherlands multi-center 120 (24
weeks
for one
group)
120 (24
weeks
for one
group)
4 75
Littner, 2000[112] USA multi-center 7.14 4.14 5 169
Llewellyn-Jones,
1996[44]
UK NR 14 8 2 16
Lomas, 2012[21] Estonia, Finland, Germany,
South Korea, Latvia,
Lithuania, The Netherlands,
New Zealand, Russia,
multi-center 12 12 2 197
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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
multi-center 12 12 2 472
Mahler, 1999[91] USA multi-center 12 12 2 278
Mahler, 2002[56] Lebanon multi-center 24 24 4 645
Mahler, 2012[175]a
Argentina, Australia,
Colombia, Denmark,
Germany, Greece,
Guatemala, Mexico, Peru,
Philippines, South Africa,
Spain, Turkey, USA
multi-center 12 12 2 1131
Mahler, 2012[175]b Argentina, Canada,
Colombia, Czech Republic,
Hungary, India,
Netherlands, Philippines,
Slovakia, Spain, USA
multi-center 12 12 2 1142
Maltais, 2005[105] NR multi-center 6 6 2 261
Maltais, 2011[14] Canada, USA multi-center 6 6 2 181
Mansori, 2010[152] Iran single center 24 12 2 40
Martinez, 2013[94] Czech Republic, Germany,
Japan, Poland, Romania,
Russian Federation,
Ukraine, USA
multi-center 24 24 6 1224
Mathioudakis,
2013[100]
Greece single center 208 208 5 564
McNicholas,
2004[113]
UK, Ireland, The
Netherlands
multi-center 4 4 3 95
Mirici, 2001[50] Turkey single center 12 12 2 50
Moita, 2008[165] Portugal multi-center 12 12 2 304
Mroz, 2013[107] Poland single center 12 12 2 34
Nicolini, 2012[140] Italy single center 0.14 0.14 2 100
Niewoehner,
2005[126] CR:[211,
212]
USA multi-center 26 24 2 1829
O'Donnell, 2004[65] Canada, USA, Germany multi-center 6 6 2 187
O'Donnell, 2006[48] USA, Canada multi-center 8 8 3 185
Ozol, 2005[150] Turkey NR 24 24 2 26
Paggiaro, 1998[120] 13 European countries (not
specified), New Zealand,
South Africa
multi-center 24 24 2 281
Pasqua, 2010[35] Italy NR 4 4 2 22
Pauwels, 1999[117]
CR:[245, 246]
Belgium, Denmark, Finland,
Italy, the Netherlands,
Norway, Spain, Sweden,
UK
multi-center 156 144 2 1277
Perng, 2009[24] Taiwan multi-center 12 12 3 99
Powrie, 2007[55] UK single center 52 52 2 142
Pukhta, 2010[9] India single center 2 2 2 60
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Rabe, 2008[37] Austria, Belgium, Denmark,
France, Germany,
Netherlands, South Africa,
Sweden
multi-center 6 6 2 605
Reid, 2008[29] Australia NR 24 24 2 34
Renkema, 1996[62] The Netherlands NR 104 104 2 39
Rennard, 2001[171] USA multi-center 12 12 2 267
Rennard, 2009[87] USA, Mexico, Europe (not
specified)
multi-center 56 52 4 1964
Rossi, 2002[38] Austria, Belgium, Czech
Republic, France, Germany,
Greece, Hungary, Italy,
Slovakia, South Africa,
Spain, USA
multi-center 52 52 3 854
Rubin, 2008[99] Brazil single center 0.14 0.003
(30
minutes)
2 40
Rutgers, 1998[143] The Netherlands single center 6 6 2 44
Rutten-van,
1999[18]
The Netherlands multi-center 12 12 2 97
Santus, 2012[30] Italy NR 4 4 2 24
Schermer,
2007[118]
The Netherlands multi-center 12 12 2 40
Scherr, 2012[130] Switzerland single center 12 12 2 68
Sechaud, 2012[125] Germany, Denmark multi-center 2 2 5 41
Senderovitz,
1999[144]
Denmark multi-center 24 24 2 26
Shaker, 2009[151]
CR:[256]
Denmark single center 208 104 -208 2 254
Sharafkhaneh,
2012[42]
USA, Central and South
America, South Africa
multi-center 54 52 3 1219
Sin, 2008[156] Canada multi-center 4 4 3 224
Sposato, 2008[139] Italy single center 0.05 0.34 2 37
Sridevi, 2012[134] India single center 14 14 2 60
Stahl, 2001[98] Sweden multi-center 12 12 2 121
Stockley, 2006[16] Austria, Bulgaria, Belgium,
Croatia, Czech Republic,
Denmark, Ireland, Estonia,
France, Germany, Holland,
Hungary, Latvia, Poland,
Spain, Slovak Republic,
Slovenia, Ukraine, UK
multi-center 52 52 2 634
Struijs, 1997[158] The Netherlands NR 52 52 2 33
Sugiura, 2003[40] Japan single center 4 4 2 18
Suzuki, 2010[90] Japan single center 52 52 2 20
Szafranski, 2003[73]
CR:[259]
Argentina, Brazil, Denmark,
Finland, UK, Italy, Mexico,
Poland, Portugal, South
Africa, Spain
multi-center 52 52 4 812
Tashkin, 2008 [2]
CR: [217-224, 227-
37 countries multi-center 208 208 2 5992
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232]
Tashkin, 2008[72] USA, Czech Republic, The
Netherlands, Poland, South
Africa
multi-center 28 26 6 1704
Tashkin, 2009[95] USA multi-center 12 12 2 255
Tashkin, 2012[69] South America, Asia,
Africa, Europe, North
America (not specified)
multi-center 52 26 5 1055
The Lung Health
Study Research
Group, 2000 [51]
CR: [209]
NR multi-center 208 mean
160
2 1116
Tonnel, 2008 France multi-center 36 36 2 554
Troosters, 2014[182] Belgium, Canada, Czech
Republic, Germany, Great
Britain, Greece, the
Netherlands, Portugal,
Ukraine, USA
multi-center 24 24 2 457
Tzani, 2011[58] Italy multi-center 12 12 2 18
Ulubay, 2005[163] Turkey single center 4 4 2 25
Um, 2007[148] Korea single center 6 6 2 81
Van de Maele,
2010[33]
Belgium multi-center 2 2 5 255
van Den Boom,
2001[149] CR: [247,
248]
The Netherlands single center 52 52 2 74
van den Broek,
2008[89]
Netherlands single center 104 0.006 2 77
van der Valk,
2002[43]
The Netherlands single center 24 24 2 244
van Noord,
2000[116]
The Netherlands multi-center 14 12 2 97
Verhoeven,
2002[59] CR: [254,
255]
The Netherlands NR 24 24 2 23
Verkindre,
2006[155]
France multi-center 14 12 2 100
Vestbo, 1999[114] Denmark single center 144 144 2 290
Vogelmeier,
2008[97]
8 countries multi-center 24 24 4 847
Vogelmeier,
2010[135]
Germany, France, the
Netherland, Spain, Turkey,
USA
multi-center 4 4 3 281
Vogelmeier,
2011[169] CR: [213]
25 countries multi-center 52 52 2 7376
Vogelmeier,
2013[80]
Belgium, Czech, Estonia,
Germany, Hungary, Korea,
Lithuania, Norway, Spain,
South Africa
multi-center 26
efficacy,
30 safety
26 2 523
Wadbo, 2002[60] Sweden multi-center 12 12 2 121
Watkins, 2013[141] USA single center 6 6 3 365
Wedzicha, 2008[22]
CR:[233]
Austria, Belgium, Czech
Republic, Denmark,
multi-center 104 104 2 1323
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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]
The Netherlands single center 6 6 2 35
Wielders, 2013[6] 9 countries multi-center 5 4 8 436
Wise, 2013[168] USA, UK, France,
Denmark, Germany and
other countries not specified
multi-center mean
119.6
median
119.28
3 17135
Woolhouse,
2001[145]
UK NR 2 2 2 23
Wouters, 2005[172] The Netherlands multi-center 52 52 2 373
Yao, 2014[181] China, Australia, India multi-center 26 26 3 561
Yildiz, 2004[41] Turkey single center 12 12 2 38
Zheng, 2007[159] China multi-center 26 24 2 445
Zhong, 2012[74] China multi-center 24 24 2 308
Unpublished Studies (n= 20)
Calverley,
2003†[186] USA NR 52 52 2 631
Cheng, 2012†[198] Taiwan NR 52 52 2 78
da Fonseca Reis,
2010†[200] NR NR 12 12 2 18
Dawber, 2005†[189] NR single center 3 3 2 59
GlaxoSmithKline,
2005
(SCO100470)†[193]
Australia, Bulgaria, Croatia,
Czech Republic, France,
Germany, Greece, Italy,
Latvia, Lithuania,
Netherlands, Philippines,
Poland, Romania, Russian
Federation, Slovakia,
Slovenia, Sweden, Thailand,
UK multi-center
24 24 2 1050
GlaxoSmithKline,
2005
(SCO40034)†[195] The Netherlands multi-center
12 12 2 125
GlaxoSmithKline,
2005 (SLMF
4010)†[187] France multi-center
24 24 2 34
GlaxoSmithKline,
2005
(SMS40298)†[197] Canada multi-center
16 16 2 347
GlaxoSmithKline,
2005 USA multi-center 4 8 2 316
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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]
Adult & elderly (≥18) 27.65 COPD NR moderate to very severe† NR
Calverly, 2003[53] Adult & elderly (≥18) 38 non-asthmatic COPD NR severe† NR
Calverly, 2003[119] Adult & elderly (≥18) 24.51 COPD III and IV moderate to very severe† > 24
Calverley,
2007[138] CR:
[234-242]
Adult & elderly (≥18) 24.23 COPD NR moderate to very severe† NR
Calverly, 2008 Adult & elderly (≥18) 31.72 COPD I-IV mild to very severe† NR
Calverley, 2010 Adult & elderly (≥18) 19.35 COPD severe stable COPD
according to the
GOLD guidelines
severe† >24
Campbell, 2007 Adult & elderly (≥18) 48.04 COPD NR moderate to very severe† NR
Casaburi, 2005[103]
CR:[243]
Adult & elderly (≥18) 43.5 COPD NR moderate to very severe† NR
Cazzola, 2000 Adult & elderly (≥18) 8.75 COPD NR mild to very severe† NR
Cazzola, 2007 Adult & elderly (≥18) 11.11 COPD a baseline FEV1 of
less than 50% of
predicted, and a
post-bronchodilator
FEV1/ FVC<70%
following
salbutamol 400 mg
according with the
GOLD criteria of
severity
severe to very severe NR
Celli, 2003[146] Adult & elderly (≥18) 38.27 COPD NR NR NR
Celli, 2003[104] Adult & elderly (≥18) 25.02 COPD NR moderate to very severe† > 24
Chan , 2007 Adult & elderly (≥18) 40.33 COPD NR moderate to very severe† NR
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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
moderate to very severe† NR
Donohue, 2002[3]
CR:[257, 258]
Adult & elderly (≥18) 25 COPD NR moderate† NR
Donohue, 2013 Adult & elderly (≥18) 29.31 COPD II, III, IV mod to very severe† NR
Dransfield, 2011 Adult & elderly (≥18) 42.98 COPD NR moderate to severe NR
Dransfield, 2013a Adult & elderly (≥18) 40.57 COPD NR moderate to very severe† NR
Dransfield, 2013b Adult & elderly (≥18) 44.52 COPD NR moderate to very severe† NR
Dusser, 2006 Adult & elderly (≥18) 12.01 non-asthmatic COPD NR moderate to severe† NR
Engel, 1989 Adult (18-64) 55.56 cough and expectoration
for at least three months
a year during at least the
NR mild to moderate† at least the
preceding 2
years
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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
Adult & elderly (≥18) 4.87 COPD NR moderate to very severe† NR
Nicolini, 2012 Adult & elderly (≥18) 32 COPD stages 2, 3, 4 stable NR
Niewoehner,
2005[126] CR:[211,
212]
Adult & elderly (≥18) 1.48 COPD NR moderate to very severe† NR
O'Donnell, 2004 Adult & elderly (≥18) 26.2 COPD NR moderate to very severe† NR
O'Donnell, 2006 Adult & elderly (≥18) 30.12 COPD NR moderate to very severe† NR
Ozol, 2005 Adult & elderly (≥18) 18.18 COPD NR mild to moderate NR
Paggiaro, 1998 Adult & elderly (≥18) 22.78 COPD: "as a disorder
characterised by
decreased maximum
NR mild to severe† NR
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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)
NR moderate to very severe† NR
Sposato, 2008 Adult & elderly (≥18) 32.43 COPD moderate-to-severe
COPD as per
GOLD
moderate to severe, stable NR
Sridevi, 2012 Adult & elderly (≥18) stable or exacerbated
COPD
NR moderate to very severe† NR
Stahl, 2001 Adult & elderly (≥18) 46.99 COPD NR moderate to severe NR
Stockley, 2006 Adult & elderly (≥18) 24.04 COPD NR moderate to very severe† NR
Struijs, 1997 Adult & elderly (≥18) 39.39 COPD NR NR NR
Sugiura, 2002 Adult & elderly (≥18) 11.11 COPD NR NR NR
Suzuki, 2010 Adult & elderly (≥18) 10 COPD I; II-III moderate to severe NR
Szafranski,
2003[73] CR:[259]
Adult & elderly (≥18) 21.26 COPD moderate-to-severe moderate to very severe† ≥24
Tashkin DP, 2012 Adult & elderly (≥18) 22.46 COPD NR moderate to very severe† ≥24
Tashkin, 2008[2]
CR: [217-224, 227-
232]
Adult & elderly (≥18) 25 COPD II (44.5%); III
(44%); IV (8.5%)
moderate to very severe† NR
Tashkin, 2008[72] Adult & elderly (≥18) 31.87 COPD who had previous
exacerbations
NR moderate to verey severe† >24
Tashkin, 2009 Adult & elderly (≥18) 33.73 COPD NR severe to very severe† NR
The Lung Health
Study Research
Group, 2000[51]
CR: [209]
Adult & elderly (≥18) 36.95 COPD NR mild to severe† NR
Tonnel, 2008 Adult & elderly (≥18) 13.9 non-asthmatic COPD NR moderate to very severe† NR
Troosters, 2014 Adult & elderly (≥18) 31.5 non-asthmatic COPD II moderate† NR
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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
NR moderate to very severe† NR
Unpublished Studies (n=20)
Calverley,
2003*[186] NR NR COPD NR moderate to very severe† NR
Cheng, 2012* NR NR COPD NR NR NR
da Fonseca Reis,
2010* NR NR COPD III Severe NR
Dawber, 2005* NR NR COPD NR moderate to severe NR
GlaxoSmithKline,
2005 (SCO100470)* Adult & elderly (≥18) 22.19 COPD II NR† NR
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GlaxoSmithKline,
2005 (SCO40034)* Adult & elderly (≥18) 25.6 COPD NR moderate to very severe†
NR
GlaxoSmithKline,
2005 (SLMF 4010)* Adult (18-64) 11.76 COPD NR moderate to severe†
NR
GlaxoSmithKline,
2005 (SMS40298)* Adult & elderly (≥18) 41.21 COPD NR moderate to very severe†
NR
GlaxoSmithKline,
2005 (SMS40315)* Adult & elderly (≥18) 39.18 COPD NR moderate to severe†
NR
GlaxoSmithKline,
2005 ,SFCT01
(SCO30002)* Adult & elderly (≥18) 17.57 COPD NR moderate to very severe†
NR
GlaxoSmithKline,
2006 (SCO100540)* Adult & elderly (≥18) 10.79 COPD NR moderate to very severe†
NR
GlaxoSmithKline,
2007 (SCO104925)* Adult & elderly (≥18) 23.6 bronchitis and COPD NR moderate to severe†
NR
GlaxoSmithKline,
2008 (SCO40041)* Adult & elderly (≥18) 38.71 COPD NR moderate to very severe†
NR
Kelleher, 2011* NR NR COPD NR NR† NR
Maltais, 2010* NR 45.5 COPD NR NR NR
Novartis, 2006
(CQAB149B2205)* Adult & elderly (≥18) 33.23 COPD NR moderate to severe†
NR
Ohar, 2013* Adult (18-64) 45.5 COPD NR NR† NR
Sekiya, 2012* Adult & elderly (≥18) 2.45 COPD II, III moderate to severe† NR
Sricharoenchai,
2008* NR NR COPD NR NR
NR
To, 2011* NR NR COPD NR moderate to severe† NR
Note: † As determined by a clinician (SES), *Unpublished data (n=20 studies)
Abbreviations: NR, not reported; CR, Companion report; FEV1, Forced expiratory volume; FVC, Forced vital capacity, ; ATS, American Thoracic Society;
GOLD, Global Initiative for Chronic Obstructive Lung Disease; GOLD I,II, III,IV: Mild, Moderate, Severe, Very Severe
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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
Calverley, 2010 Low Low Low Low Low Low High
Campbell, 2007 Unclear Unclear Low Low Low Unclear High
Casaburi, 2005 Unclear Unclear Low Low Low Unclear High
Cazzola, 2000 Low Unclear Low Unclear High Unclear Unclear
Cazzola, 2007 Unclear Unclear Low Low Unclear Unclear Unclear
Celli, 2003[146] Unclear Unclear Low Low Low Unclear High
Celli, 2003[104] Low Unclear Low Low Low High High
Chan, 2007 Low Unclear Low Low Low Unclear High
Chanez, 2010 Unclear Unclear Low Low Low Unclear Unclear
Chapman, 2002 Low Unclear Low Low Low Unclear Unclear
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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)
Unclear Unclear Low Low Low Unclear Unclear
GlaxoSmithKline, 2005
(SMS40315)
Unclear Unclear Low Low Low Unclear Unclear
GlaxoSmithKline,
2005(SCO40034)
Unclear Unclear Low Low Low Unclear Unclear
GlaxoSmithKline, 2005
(SCO100470)
Unclear Unclear Low Low Low Low High
GlaxoSmithKline, 2005
(SCO30002)
Unclear Unclear Low Low Low Low High
GlaxoSmithKline, 2005
(SLMF4010)
Unclear Unclear Low Low Low Unclear High
GlaxoSmithKline, 2006
(SCO100540)
Unclear Unclear Low Low Low Unclear Unclear
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Glaxo 2007 (SCO104925) Unclear Unclear Low Low Unclear Unclear High
Glaxo 2008 (SCO40041) Unclear Unclear Low Low Unclear Unclear High
Gupta, 2002 Low Unclear Low Low Low Unclear Unclear
Hagedorn , 2013 Unclear Unclear Low Low Low Low High
Hanania, 2003 Unclear Unclear Low Low Unclear Unclear Unclear
Hanania, 2012[26] Unclear Unclear Low Low Low Low High
Hanania, 2012[161] Low Unclear Low Low Low Low High
Hasani, 2004 Unclear Unclear Low Low Low Unclear High
Hattotuwa, 2002 Low Unclear Low Low High Unclear Unclear
Hoshino, 2011 Unclear Unclear Low Low Unclear Low Low
Hoshino, 2013 Low Unclear Low Low Unclear Unclear Unclear
Johansson, 2008 Unclear Unclear Low Low Low Unclear Unclear
Jones, 1997 Unclear Unclear Low Low Unclear Unclear High
Jones, 2011a Unclear Unclear Low Low Low Low High
Jones, 2011b Unclear Unclear Low Low Low Low High
Jones, 2012 Unclear Unclear Low Low Low Low High
Jung, 2012 Low Unclear Low Low Low Unclear High
Kardos, 2007 Low Unclear Low Low Low Unclear Unclear
Kaushik, 1999 Unclear Unclear Low Low Unclear Unclear Unclear
Kelleher, 2011 Unclear Unclear Low Low High Unclear Unclear
Kerwin, 2011a Low Low Low Low Low Low High
Kerwin, 2011b Low Low Low Low Low Low High
Kerwin, 2012[78] Unclear Unclear Low Low Low High High
Kerwin, 2012[68] Unclear Unclear Low Low Low Low High
Kerwin, 2013 Low Unclear Low Low Low Low Unclear
Kinoshita, 2012 Low Unclear Low Low Low Low High
Korn, 2011 Low Low Low Low Low Low High
Kornmann, 2011 Low Unclear Low Low Low Low High
Koser, 2010 Unclear Unclear Low Low Low Low High
Kuna, 2013 Unclear Unclear Low Low Low Low High
Lapperre, 2009 Unclear Unclear Low Low Unclear High Unclear
Littner, 2000 Unclear Unclear Low Low Low Unclear Unclear
Llewellyn-Jones, 1996 Unclear Unclear Low Low Low Unclear Unclear
Lomas, 2012 Low Unclear Low Low Low High High
Lötvall, 2012 Low Low Low Low Low Low High
Magnussen, 2008 Unclear Unclear Low Low Low Unclear High
Mahler, 1999 Unclear Unclear Low Low Unclear Unclear Unclear
Mahler, 2002 Unclear Unclear Low Low High Unclear Unclear
Mahler, 2012a Low Low Low Low Low Unclear High
Mahler, 2012b Low Low Low Low Low Low High
Maltais, 2005 Unclear Unclear Low Low High Unclear Unclear
Maltais, 2010 Unclear Unclear Low Low Low Unclear Unclear
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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
Unclear Unclear Low Low Low Unclear Unclear
To, 2011 Unclear Unclear Low Unclear Low Unclear Unclear
Tonnel, 2008 Low Unclear Low Low High Unclear High
Troosters, 2014 Low Unclear Low Low Low Low Unclear
Tzani, 2011 Low Unclear Low Low Low Low High
Ulubay, 2005 Unclear Unclear Low Low Unclear Unclear Unclear
Um, 2007 Low Unclear High Low High Unclear Low
Van de Maele, 2010 Low Unclear Low Low Low Unclear Unclear
van Den Boom, 2001 Unclear Unclear Low Low Low Unclear Low
van den Broek , 2008 Low Unclear Low Low Low Unclear Unclear
van der Valk, 2002 Low Unclear Low Low Low Unclear Unclear
van Noord, 2000 Unclear Unclear Low Low Low Unclear High
Verhoeven, 2002 Unclear Unclear Low Low Low Low Unclear
Verkindre, 2006 Unclear Unclear Low Low Low Unclear High
Vestbo, 1999 Low Low Low Low Low Unclear Unclear
Vogelmeier, 2008 Unclear Unclear Low Low Low Low High
Vogelmeier, 2010 Unclear Unclear Low Low Low Low High
Vogelmeier, 2011 Low Low Low Low Low Low High
Vogelmeier, 2013 Low Low Low Low Low Low High
Wadbo, 2002 Unclear Unclear Low Low High Unclear Unclear
Watkins, 2013 Unclear Unclear Low Low Low Low High
Wedzicha, 2008 Low Low Low Low Low Low Unclear
Wedzicha, 2013 Low Low Low Low Low Low High
Weir, 1999 Unclear Unclear Low Low High Unclear Unclear
Welte, 2008 Unclear Unclear Low Low Low Unclear High
Welte, 2009 Low Unclear Low Low Low Low High
Wesseling, 1991 Unclear Unclear Low Low Low Unclear Unclear
Wielders, 2013 Unclear Unclear Low Low Low Low High
Wise, 2013 Unclear Unclear Low Low Low Low Low
Woolhouse, 2001 Unclear Unclear Low Low Low Unclear Unclear
Wouters, 2005 Low Unclear Low Low High Unclear High
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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
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
Beclomethasone/Formoterol
0.78 0.39-1.58 - - - - -
Tiotropium/Budesonide/Formoterol vs
Beclomethasone/Formoterol
0.32 0.15-0.65 - - - - -
Fluticasone/Vilanterol vs Budesonide/Formoterol 0.88 0.27-2.88 - - - - -
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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 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Budesonide/Formoterol
0.90 0.49-1.66 - - - - -
Tiotropium/Budesonide/Formoterol vs
Budesonide/Formoterol
0.36 0.19-0.69 - - - - -
Fluticasone/Salmeterol vs Fluticasone/Vilanterol 1.19 0.39-3.59 - 1.19 0.39-3.59 -- 1 528
Tiotropium/Salmeterol vs Fluticasone/Vilanterol 1.25 0.37-4.20 - - - - -
Indacaterol/Glycopyrronium vs Fluticasone/Vilanterol 0.85 0.27-2.64 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Fluticasone/Vilanterol
1.02 0.30-3.41 - - - - -
Tiotropium/Budesonide/Formoterol vs
Fluticasone/Vilanterol
0.41 0.12-1.39 - - - - -
Tiotropium/Salmeterol vs Fluticasone/Salmeterol 1.05 0.64-1.72 - - - - -
Indacaterol/Glycopyrronium vs Fluticasone/Salmeterol 0.71 0.55-0.92 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Fluticasone/Salmeterol
0.86 0.52-1.40 - - - - -
Tiotropium/Budesonide/Formoterol vs
Fluticasone/Salmeterol
0.35 0.21-0.58 - - - - -
Indacaterol/Glycopyrronium vs Tiotropium/Salmeterol 0.68 0.41-1.13 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Tiotropium/Salmeterol
0.81 0.51-1.31 - 0.81 0.51-1.30 -- 1 293
Tiotropium/Budesonide/Formoterol vs
Tiotropium/Salmeterol
0.33 0.17-0.65 - - - - -
Tiotropium/Fluticasone/Salmeterol vs
Indacaterol/Glycopyrronium
1.20 0.72-2.00 - - - - -
Tiotropium/Budesonide/Formoterol vs
Indacaterol/Glycopyrronium
0.48 0.28-0.83 - - - - -
Tiotropium/Budesonide/Formoterol vs
Tiotropium/Fluticasone/Salmeterol
0.40 0.21-0.80 - - - - -
Common within-network heterogeneity variance 0.00
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity variance)
3.37 (4,0.498,0.00)
Overall Mortality: 88 studies (1 five-arm, 12 four-arm, 14 three-arm, 61 two-arm), 28 treatments, 97526 patients
AZD3199 (Ultra LABA) vs Placebo 0.46 0.02-10.32 0.02-11.85 0.32 0.01-7.95 -- 1 128
Aclidinium vs Placebo 0.74 0.31-1.72 0.30-1.81 0.74 0.32-1.72 0.00 4 2565
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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
Beclomethasone/Formoterol
3.82 0.11-138.30 0.09-162.06 - - - -
Fluticasone vs Beclomethasone/Formoterol 1.36 0.27-6.88 0.25-7.42 - - - -
Salmeterol/Fluticasone vs Beclomethasone/Formoterol 1.02 0.20-5.17 0.19-5.58 - - - -
Salmeterol/Fluticasone/Tiotropium vs
Beclomethasone/Formoterol
2.07 0.26-16.35 0.24-17.96 - - - -
Fluticasone/Tiotropium vs Beclomethasone/Formoterol 1.19 0.06-22.19 0.06-25.28 - - - -
Vilanterol/Fluticasone vs Beclomethasone/Formoterol 1.60 0.23-11.00 0.21-12.01 - - - -
Formoterol vs Beclomethasone/Formoterol 1.68 0.34-8.20 0.32-8.83 0.20 0.01-4.13 -- 1 465
Formoterol/Tiotropium vs Beclomethasone/Formoterol 0.87 0.06-11.74 0.06-13.19 - - - -
Glycopyrronium vs Beclomethasone/Formoterol 0.98 0.18-5.30 0.17-5.73 - - - -
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Indacaterol vs Beclomethasone/Formoterol 1.07 0.20-5.69 0.19-6.15 - - - -
Indacaterol/Glycopyrronium vs
Beclomethasone/Formoterol
1.12 0.20-6.08 0.19-6.58 - - - -
Indacaterol/Tiotropium vs Beclomethasone/Formoterol 1.41 0.15-13.15 0.14-14.55 - - - -
Mometasone vs Beclomethasone/Formoterol 1.82 0.30-10.87 0.28-11.80 - - - -
Formoterol/Mometasone vs Beclomethasone/Formoterol 0.90 0.12-6.89 0.11-7.56 - - - -
Salmeterol vs Beclomethasone/Formoterol 1.17 0.23-5.89 0.22-6.36 - - - -
Salmeterol/Tiotropium vs Beclomethasone/Formoterol 2.03 0.26-16.00 0.23-17.58 - - - -
Tiotropium vs Beclomethasone/Formoterol 1.26 0.25-6.33 0.23-6.83 - - - -
Tiotropium Respimat vs Beclomethasone/Formoterol 1.27 0.25-6.48 0.23-6.99 - - - -
Triamcinoloneacetonide vs Beclomethasone/Formoterol 1.02 0.18-5.90 0.16-6.39 - - - -
Umeclidinium vs Beclomethasone/Formoterol 1.48 0.17-12.64 0.16-13.93 - - - -
Vilanterol vs Beclomethasone/Formoterol 1.95 0.30-12.69 0.27-13.84 - - - -
Vilanterol/Umeclidinium vs Beclomethasone/Formoterol 1.69 0.23-12.48 0.21-13.67 - - - -
Formoterol/Budesonide vs Budesonide 1.32 0.74-2.35 0.71-2.45 1.19 0.57-2.49 0.00 4 1781
Formoterol/Budesonide/Tiotropium vs Budesonide 3.62 0.14-93.06 0.12-107.46 - - - -
Fluticasone vs Budesonide 1.29 0.77-2.17 0.74-2.26 - - - -
Salmeterol/Fluticasone vs Budesonide 0.97 0.58-1.63 0.56-1.70 - - - -
Salmeterol/Fluticasone/Tiotropium vs Budesonide 1.96 0.49-7.85 0.46-8.39 - - - -
Fluticasone/Tiotropium vs Budesonide 1.13 0.09-13.64 0.08-15.25 - - - -
Vilanterol/Fluticasone vs Budesonide 1.52 0.48-4.87 0.45-5.16 - - - -
Formoterol vs Budesonide 1.59 0.92-2.75 0.89-2.86 1.62 0.79-3.34 0.00 3 1470
Formoterol/Tiotropium vs Budesonide 0.82 0.10-6.78 0.09-7.46 - - - -
Glycopyrronium vs Budesonide 0.93 0.46-1.87 0.44-1.95 - - - -
Indacaterol vs Budesonide 1.02 0.53-1.97 0.51-2.05 - - - -
Indacaterol/Glycopyrronium vs Budesonide 1.06 0.51-2.19 0.49-2.28 - - - -
Indacaterol/Tiotropium vs Budesonide 1.34 0.26-6.79 0.24-7.33 - - - -
Mometasone vs Budesonide 1.72 0.66-4.48 0.63-4.71 - - - -
Formoterol/Mometasone vs Budesonide 0.86 0.22-3.35 0.20-3.58 - - - -
Salmeterol vs Budesonide 1.11 0.67-1.85 0.64-1.93 - - - -
Salmeterol/Tiotropium vs Budesonide 1.92 0.48-7.69 0.45-8.21 - - - -
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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/Tiotropium vs
Formoterol/Budesonide
2.75 0.11-71.01 0.09-82.01 - - - -
Fluticasone vs Formoterol/Budesonide 0.98 0.57-1.69 0.55-1.76 - - - -
Salmeterol/Fluticasone vs Formoterol/Budesonide 0.74 0.43-1.27 0.41-1.32 - - - -
Salmeterol/Fluticasone/Tiotropium vs
Formoterol/Budesonide
1.49 0.37-6.02 0.35-6.44 - - - -
Fluticasone/Tiotropium vs Formoterol/Budesonide 0.86 0.07-10.42 0.06-11.66 - - - -
Vilanterol/Fluticasone vs Formoterol/Budesonide 1.16 0.36-3.74 0.34-3.97 - - - -
Formoterol vs Formoterol/Budesonide 1.21 0.77-1.90 0.74-1.98 1.14 0.69-1.91 0.0587 7 5046
Formoterol/Tiotropium vs Formoterol/Budesonide 0.63 0.08-5.17 0.07-5.69 - - - -
Glycopyrronium vs Formoterol/Budesonide 0.71 0.35-1.45 0.33-1.51 - - - -
Indacaterol vs Formoterol/Budesonide 0.77 0.39-1.52 0.38-1.59 - - - -
Indacaterol/Glycopyrronium vs Formoterol/Budesonide 0.81 0.38-1.69 0.37-1.77 - - - -
Indacaterol/Tiotropium vs Formoterol/Budesonide 1.01 0.20-5.20 0.18-5.62 - - - -
Mometasone vs Formoterol/Budesonide 1.31 0.51-3.35 0.49-3.52 - - - -
Formoterol/Mometasone vs Formoterol/Budesonide 0.65 0.17-2.51 0.16-2.67 - - - -
Salmeterol vs Formoterol/Budesonide 0.84 0.49-1.44 0.47-1.50 - - - -
Salmeterol/Tiotropium vs Formoterol/Budesonide 1.46 0.36-5.90 0.34-6.30 - - - -
Tiotropium vs Formoterol/Budesonide 0.91 0.54-1.54 0.52-1.60 - - - -
Tiotropium Respimat vs Formoterol/Budesonide 0.92 0.52-1.62 0.50-1.69 - - - -
Triamcinoloneacetonide vs Formoterol/Budesonide 0.74 0.31-1.75 0.30-1.83 - - - -
Umeclidinium vs Formoterol/Budesonide 1.07 0.24-4.82 0.22-5.18 - - - -
Vilanterol vs Formoterol/Budesonide 1.41 0.47-4.18 0.45-4.42 - - - -
Vilanterol/Umeclidinium vs Formoterol/Budesonide 1.22 0.33-4.44 0.31-4.73 - - - -
Fluticasone vs Formoterol/Budesonide/Tiotropium 0.36 0.01-8.89 0.01-10.26 - - - -
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Salmeterol/Fluticasone vs
Formoterol/Budesonide/Tiotropium
0.27 0.01-6.68 0.01-7.71 - - - -
Salmeterol/Fluticasone/Tiotropium vs
Formoterol/Budesonide/Tiotropium
0.54 0.02-17.20 0.01-20.04 - - - -
Fluticasone/Tiotropium vs
Formoterol/Budesonide/Tiotropium
0.31 0.01-17.58 0.00-21.00 - - - -
Vilanterol/Fluticasone vs
Formoterol/Budesonide/Tiotropium
0.42 0.01-12.34 0.01-14.33 - - - -
Formoterol vs Formoterol/Budesonide/Tiotropium 0.44 0.02-11.23 0.01-12.97 - - - -
Formoterol/Tiotropium vs
Formoterol/Budesonide/Tiotropium
0.23 0.01-10.28 0.00-12.16 - - - -
Glycopyrronium vs Formoterol/Budesonide/Tiotropium 0.26 0.01-6.60 0.01-7.63 - - - -
Indacaterol vs Formoterol/Budesonide/Tiotropium 0.28 0.01-7.15 0.01-8.26 - - - -
Indacaterol/Glycopyrronium vs
Formoterol/Budesonide/Tiotropium
0.29 0.01-7.54 0.01-8.71 - - - -
Indacaterol/Tiotropium vs
Formoterol/Budesonide/Tiotropium
0.37 0.01-12.96 0.01-15.17 - - - -
Mometasone vs Formoterol/Budesonide/Tiotropium 0.48 0.02-13.21 0.01-15.31 - - - -
Formoterol/Mometasone vs
Formoterol/Budesonide/Tiotropium
0.24 0.01-7.57 0.01-8.82 - - - -
Salmeterol vs Formoterol/Budesonide/Tiotropium 0.31 0.01-7.62 0.01-8.79 - - - -
Salmeterol/Tiotropium vs
Formoterol/Budesonide/Tiotropium
0.53 0.02-16.83 0.01-19.61 - - - -
Tiotropium vs Formoterol/Budesonide/Tiotropium 0.33 0.01-8.16 0.01-9.41 0.33 0.01-8.14 -- 1 660
Tiotropiumropium Respimat vs
Formoterol/Budesonide/Tiotropium
0.33 0.01-8.30 0.01-9.57 - - - -
Triamcinoloneacetonide vs
Formoterol/Budesonide/Tiotropium
0.27 0.01-7.16 0.01-8.29 - - - -
Umeclidinium vs Formoterol/Budesonide/Tiotropium 0.39 0.01-12.95 0.01-15.12 - - - -
Vilanterol vs Formoterol/Budesonide/Tiotropium 0.51 0.02-14.56 0.02-16.88 - - - -
Vilanterol/Umeclidinium vs
Formoterol/Budesonide/Tiotropium
0.44 0.01-13.54 0.01-15.75 - - - -
Salmeterol/Fluticasone vs Fluticasone 0.75 0.60-0.94 0.58-0.98 0.76 0.62-0.93 0.00 3 3752
Salmeterol/Fluticasone/Tiotropium vs Fluticasone 1.52 0.41-5.68 0.38-6.06 - - - -
Fluticasone/Tiotropium vs Fluticasone 0.88 0.08-10.14 0.07-11.32 - - - -
Vilanterol/Fluticasone vs Fluticasone 1.18 0.40-3.44 0.38-3.63 1.36 0.09-
19.56
1.163 2 820
Formoterol vs Fluticasone 1.23 0.76-2.01 0.73-2.09 - - - -
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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/Tiotropium vs
Salmeterol/Fluticasone
2.02 0.54-7.54 0.51-8.04 - - - -
Fluticasone/Tiotropium vs Salmeterol/Fluticasone 1.16 0.10-13.41 0.09-14.97 1.03 0.06-
17.24
-- 1 65
Vilanterol/Fluticasone vs Salmeterol/Fluticasone 1.57 0.54-4.58 0.51-4.84 2.97 0.12-
73.14
-- 1 528
Formoterol vs Salmeterol/Fluticasone 1.64 1.01-2.67 0.97-2.78 - - - -
Formoterol/Tiotropium vs Salmeterol/Fluticasone 0.85 0.11-6.62 0.10-7.27 0.99 0.06-
15.90
-- 1 605
Glycopyrronium vs Salmeterol/Fluticasone 0.96 0.56-1.66 0.54-1.72 - - - -
Indacaterol vs Salmeterol/Fluticasone 1.05 0.64-1.71 0.62-1.78 - - - -
Indacaterol/Glycopyrronium vs Salmeterol/Fluticasone 1.09 0.61-1.95 0.59-2.03 - - - -
Indacaterol/Tiotropium vs Salmeterol/Fluticasone 1.38 0.29-6.60 0.27-7.10 - - - -
Mometasone vs Salmeterol/Fluticasone 1.77 0.73-4.31 0.70-4.52 - - - -
Formoterol/Mometasone vs Salmeterol/Fluticasone 0.88 0.23-3.32 0.22-3.54 - - - -
Salmeterol vs Salmeterol/Fluticasone 1.14 0.93-1.41 0.88-1.48 1.08 0.89-1.31 0.00 8 8202
Salmeterol/Tiotropium vs Salmeterol/Fluticasone 1.98 0.53-7.38 0.50-7.87 - - - -
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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 - - - -
Fluticasone/Tiotropium vs
Salmeterol/Fluticasone/Tiotropium
0.58 0.04-9.14 0.03-10.34 - - - -
Vilanterol/Fluticasone vs
Salmeterol/Fluticasone/Tiotropium
0.78 0.15-4.14 0.13-4.48 - - - -
Formoterol vs Salmeterol/Fluticasone/Tiotropium 0.81 0.21-3.21 0.19-3.43 - - - -
Formoterol/Tiotropium vs
Salmeterol/Fluticasone/Tiotropium
0.42 0.04-4.77 0.03-5.32 - - - -
Glycopyrronium vs Salmeterol/Fluticasone/Tiotropium 0.47 0.12-1.90 0.11-2.03 - - - -
Indacaterol vs Salmeterol/Fluticasone/Tiotropium 0.52 0.13-2.03 0.12-2.17 - - - -
Indacaterol/Glycopyrronium vs
Salmeterol/Fluticasone/Tiotropium
0.54 0.13-2.18 0.12-2.33 - - - -
Indacaterol/Tiotropium vs
Salmeterol/Fluticasone/Tiotropium
0.68 0.09-5.11 0.08-5.60 - - - -
Mometasone vs Salmeterol/Fluticasone/Tiotropium 0.88 0.18-4.18 0.17-4.50 - - - -
Formoterol/Mometasone vs
Salmeterol/Fluticasone/Tiotropium
0.44 0.07-2.76 0.06-3.01 - - - -
Salmeterol vs Salmeterol/Fluticasone/Tiotropium 0.57 0.15-2.10 0.14-2.23 - - - -
Salmeterol/Tiotropium vs
Salmeterol/Fluticasone/Tiotropium
0.98 0.31-3.13 0.29-3.32 0.98 0.31-3.11 -- 1 293
Tiotropium vs Salmeterol/Fluticasone/Tiotropium 0.61 0.17-2.22 0.16-2.36 0.61 0.17-2.21 -- 1 301
Tiotropiumropium Respimat vs
Salmeterol/Fluticasone/Tiotropium
0.62 0.17-2.28 0.16-2.43 - - - -
Triamcinoloneacetonide vs
Salmeterol/Fluticasone/Tiotropium
0.49 0.11-2.17 0.11-2.33 - - - -
Umeclidinium vs Salmeterol/Fluticasone/Tiotropium 0.72 0.10-4.89 0.10-5.34 - - - -
Vilanterol vs Salmeterol/Fluticasone/Tiotropium 0.94 0.19-4.74 0.17-5.12 - - - -
Vilanterol/Umeclidinium vs
Salmeterol/Fluticasone/Tiotropium
0.82 0.14-4.74 0.13-5.14 - - - -
Vilanterol/Fluticasone vs Fluticasone/Tiotropium 1.35 0.09-19.30 0.08-21.74 - - - -
Formoterol vs Fluticasone/Tiotropium 1.41 0.12-16.90 0.11-18.89 - - - -
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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
Common within-network heterogeneity variance 0.00
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity variance)
31.44 (50,0.982,0.00)
Cardiovascular Related Mortality: 37 studies (6 four-arm, 6 three-arm, 25 two-arm), 20 treatments, 55156 patients
AZD3199 (Ultra LABA) vs Placebo 0.41 0.02-9.44 0.00-67.10 0.32 0.01-7.95 -- 1 128
Aclidinium vs Placebo 3.06 0.12-75.35 0.02-556.25 3.06 0.12-
75.35
-- 1 542
Budesonide vs Placebo 1.07 0.27-4.23 0.12-9.95 1.35 0.30-6.08 -- 1 1852
Formoterol/Budesonide vs Placebo 2.38 0.30-18.87 0.08-68.73 5.38 0.26-
112.46
-- 1 581
Fluticasone vs Placebo 0.83 0.61-1.14 0.50-1.38 0.85 0.61-1.17 0.00 4 4962
Salmeterol/Fluticasone vs Placebo 0.78 0.57-1.07 0.47-1.30 0.85 0.60-1.20 0.00 2 3839
Vilanterol/Fluticasone vs Placebo 0.91 0.15-5.73 0.05-18.00 0.33 0.01-8.23 -- 1 822
Formoterol vs Placebo 0.82 0.15-4.45 0.05-12.77 0.69 0.11-4.39 0.00 3 1580
Glycopyrronium vs Placebo 0.23 0.02-2.83 0.00-13.38 0.16 0.01-3.97 -- 1 817
Indacaterol vs Placebo 0.76 0.28-2.06 0.15-3.84 0.48 0.13-1.83 0.00 5 2753
Indacaterol/Glycopyrronium vs Placebo 0.26 0.01-6.63 0.00-49.40 - - - -
Indacaterol/Tiotropium vs Placebo 2.00 0.23-16.97 0.06-64.48 - - - -
Salmeterol vs Placebo 0.63 0.45-0.88 0.36-1.09 0.60 0.42-0.87 0.00 4 5171
Tiotropium vs Placebo 1.26 0.82-1.93 0.63-2.52 0.88 0.37-2.10 0.00 5 4241
Tiotropium Respimat vs Placebo 1.46 0.93-2.29 0.70-3.03 1.86 0.92-3.76 -- 1 3917
Triamcinolone Acetonide vs Placebo 3.01 0.61-14.98 0.22-40.76 3.01 0.61-
14.98
-- 1 1116
Umeclidinium vs Placebo 1.12 0.09-13.59 0.02-64.54 - - - -
Vilanterol/Umeclidinium vs Placebo 2.19 0.39-12.12 0.14-35.26 2.04 0.08-
50.25
-- 1 693
Vilanterol vs Placebo 1.60 0.37-6.92 0.15-17.22 1.01 0.10-9.75 0.00 2 1521
Aclidinium vs AZD3199 (Ultra LABA) 7.50 0.08-668.55 0.01-
10996.94
- - - -
Budesonide vs AZD3199 (Ultra LABA) 2.63 0.09-78.91 0.01-657.90 - - - -
Formoterol/Budesonide vs AZD3199 (Ultra LABA) 5.84 0.15-222.91 0.02-
2161.81
- - - -
Fluticasone vs AZD3199 (Ultra LABA) 2.04 0.09-48.09 0.01-345.00 - - - -
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Salmeterol/Fluticasone vs AZD3199 (Ultra LABA) 1.91 0.08-45.05 0.01-323.30 - - - -
Vilanterol/Fluticasone vs AZD3199 (Ultra LABA) 2.24 0.06-85.46 0.01-827.83 - - - -
Formoterol vs AZD3199 (Ultra LABA) 2.01 0.07-57.97 0.01-471.72 - - - -
Glycopyrronium vs AZD3199 (Ultra LABA) 0.58 0.01-31.78 0.00-387.79 - - - -
Indacaterol vs AZD3199 (Ultra LABA) 1.86 0.07-49.85 0.01-387.15 - - - -
Indacaterol/Glycopyrronium vs AZD3199 (Ultra LABA) 0.65 0.01-58.53 0.00-969.44 - - - -
Indacaterol/Tiotropium vs AZD3199 (Ultra LABA) 4.90 0.11-219.81 0.01-
2356.05
- - - -
Salmeterol vs AZD3199 (Ultra LABA) 1.54 0.07-36.44 0.01-261.85 - - - -
Tiotropium vs AZD3199 (Ultra LABA) 3.09 0.13-73.67 0.02-532.92 - - - -
Tiotropium Respimat vs AZD3199 (Ultra LABA) 3.58 0.15-85.61 0.02-620.54 - - - -
Triamcinolone Acetonide vs AZD3199 (Ultra LABA) 7.39 0.22-252.24 0.02-
2280.00
- - - -
Umeclidinium vs AZD3199 (Ultra LABA) 2.74 0.05-152.16 0.00-
1862.07
- - - -
Vilanterol/Umeclidinium vs AZD3199 (Ultra LABA) 5.37 0.15-192.61 0.02-
1796.31
- - - -
Vilanterol vs AZD3199 (Ultra LABA) 3.94 0.12-126.20 0.01-
1097.02
- - - -
Budesonide vs Aclidinium 0.35 0.01-11.46 0.00-100.86 - - - -
Formoterol/Budesonide vs Aclidinium 0.78 0.02-35.35 0.00-382.09 - - - -
Fluticasone vs Aclidinium 0.27 0.01-6.81 0.00-50.76 - - - -
Salmeterol/Fluticasone vs Aclidinium 0.25 0.01-6.38 0.00-47.57 - - - -
Vilanterol/Fluticasone vs Aclidinium 0.30 0.01-12.01 0.00-120.23 - - - -
Formoterol vs Aclidinium 0.27 0.01-10.05 0.00-96.34 - - - -
Glycopyrronium vs Aclidinium 0.08 0.00-4.44 0.00-55.88 - - - -
Indacaterol vs Aclidinium 0.25 0.01-7.13 0.00-57.84 - - - -
Indacaterol/Glycopyrronium vs Aclidinium 0.09 0.00-8.14 0.00-138.53 - - - -
Indacaterol/Tiotropium vs Aclidinium 0.65 0.01-30.82 0.00-341.04 - - - -
Salmeterol vs Aclidinium 0.21 0.01-5.16 0.00-38.53 - - - -
Tiotropium vs Aclidinium 0.41 0.02-10.43 0.00-78.40 - - - -
Tiotropium Respimat vs Aclidinium 0.48 0.02-12.12 0.00-91.28 - - - -
Triamcinolone Acetonide vs Aclidinium 0.99 0.03-35.50 0.00-331.99 - - - -
Umeclidinium vs Aclidinium 0.37 0.01-21.28 0.00-268.33 - - - -
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Vilanterol/Umeclidinium vs Aclidinium 0.72 0.02-27.09 0.00-261.29 - - - -
Vilanterol vs Aclidinium 0.52 0.02-17.78 0.00-160.02 - - - -
Formoterol/Budesonide vs Budesonide 2.22 0.24-20.44 0.06-81.70 4.93 0.24-
103.12
-- 1 556
Fluticasone vs Budesonide 0.78 0.19-3.17 0.08-7.62 - - - -
Salmeterol/Fluticasone vs Budesonide 0.73 0.18-2.97 0.07-7.15 - - - -
Vilanterol/Fluticasone vs Budesonide 0.85 0.09-8.43 0.02-35.21 - - - -
Formoterol vs Budesonide 0.76 0.11-5.55 0.03-19.11 2.92 0.12-
71.87
-- 1 559
Glycopyrronium vs Budesonide 0.22 0.01-3.76 0.00-22.14 - - - -
Indacaterol vs Budesonide 0.71 0.13-3.81 0.05-10.90 - - - -
Indacaterol/Glycopyrronium vs Budesonide 0.25 0.01-8.18 0.00-72.62 - - - -
Indacaterol/Tiotropium vs Budesonide 1.86 0.15-23.66 0.03-115.54 - - - -
Salmeterol vs Budesonide 0.59 0.14-2.41 0.06-5.82 - - - -
Tiotropium vs Budesonide 1.17 0.28-4.93 0.11-12.09 - - - -
Tiotropium Respimat vs Budesonide 1.36 0.32-5.76 0.13-14.17 - - - -
Triamcinolone Acetonide vs Budesonide 2.81 0.34-23.20 0.09-86.58 - - - -
Umeclidinium vs Budesonide 1.04 0.06-18.02 0.01-106.63 - - - -
Vilanterol/Umeclidinium vs Budesonide 2.04 0.23-18.30 0.06-71.94 - - - -
Vilanterol vs Budesonide 1.50 0.20-11.11 0.06-38.80 - - - -
Fluticasone vs Formoterol/Budesonide 0.35 0.04-2.84 0.01-10.50 - - - -
Salmeterol/Fluticasone vs Formoterol/Budesonide 0.33 0.04-2.66 0.01-9.84 - - - -
Vilanterol/Fluticasone vs Formoterol/Budesonide 0.38 0.02-6.12 0.00-34.40 - - - -
Formoterol vs Formoterol/Budesonide 0.34 0.05-2.28 0.02-7.39 0.49 0.04-5.47 -- 1 565
Glycopyrronium vs Formoterol/Budesonide 0.10 0.00-2.52 0.00-18.99 - - - -
Indacaterol vs Formoterol/Budesonide 0.32 0.03-3.05 0.01-12.46 - - - -
Indacaterol/Glycopyrronium vs Formoterol/Budesonide 0.11 0.00-5.12 0.00-55.85 - - - -
Indacaterol/Tiotropium vs Formoterol/Budesonide 0.84 0.04-16.51 0.01-105.77 - - - -
Salmeterol vs Formoterol/Budesonide 0.26 0.03-2.16 0.01-7.98 - - - -
Tiotropium vs Formoterol/Budesonidesonide 0.53 0.06-4.38 0.02-16.39 - - - -
Tiotropium Respimat vs Formoterol/Budesonidesonide 0.61 0.07-5.10 0.02-19.14 - - - -
Triamcinolone Acetonide vs Formoterol/Budesonide 1.27 0.09-17.41 0.02-89.29 - - - -
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Umeclidinium vs Formoterol/Budesonide 0.47 0.02-12.07 0.00-91.35 - - - -
Vilanterol/Umeclidinium vs Formoterol/Budesonide 0.92 0.06-13.52 0.01-72.29 - - - -
Vilanterol vs Formoterol/Budesonide 0.67 0.05-8.52 0.01-41.42 - - - -
Salmeterol/Fluticasone vs Fluticasone 0.94 0.67-1.32 0.54-1.63 0.98 0.69-1.41 0.00 3 3410
Vilanterol/Fluticasone vs Fluticasone 1.10 0.17-6.94 0.05-21.94 - - - -
Formoterol vs Fluticasone 0.99 0.18-5.50 0.06-16.06 - - - -
Glycopyrronium vs Fluticasone 0.28 0.02-3.46 0.00-16.53 - - - -
Indacaterol vs Fluticasone 0.91 0.32-2.58 0.17-4.92 - - - -
Indacaterol/Glycopyrronium vs Fluticasone 0.32 0.01-7.99 0.00-59.66 - - - -
Indacaterol/Tiotropium vs Fluticasone 2.40 0.28-20.71 0.07-79.38 - - - -
Salmeterol vs Fluticasone 0.76 0.52-1.09 0.42-1.37 0.73 0.49-1.08 0.00 2 3135
Tiotropium vs Fluticasone 1.51 0.92-2.48 0.68-3.38 - - - -
Tiotropium Respimat vs Fluticasone 1.75 1.04-2.94 0.75-4.07 - - - -
Triamcinolone Acetonide vs Fluticasone 3.62 0.71-18.57 0.25-51.47 - - - -
Umeclidinium vs Fluticasone 1.34 0.11-16.54 0.02-79.17 - - - -
Vilanterol/Umeclidinium vs Fluticasone 2.63 0.47-14.82 0.16-43.57 - - - -
Vilanterol vs Fluticasone 1.93 0.44-8.44 0.18-21.20 3.03 0.12-
74.80
-- 1 818
Vilanterol/Fluticasone vs Salmeterol/Fluticasone 1.17 0.19-7.38 0.06-23.26 2.97 0.12-
73.14
-- 1 528
Formoterol vs Salmeterol/Fluticasone 1.05 0.19-5.87 0.06-17.17 - - - -
Glycopyrronium vs Salmeterol/Fluticasone 0.30 0.02-3.69 0.01-17.59 - - - -
Indacaterol vs Salmeterol/Fluticasone 0.97 0.35-2.75 0.18-5.25 - - - -
Indacaterol/Glycopyrronium vs Salmeterol/Fluticasone 0.34 0.01-8.38 0.00-61.86 0.34 0.01-8.38 -- 1 522
Indacaterol/Tiotropium vs Salmeterol/Fluticasone 2.56 0.30-21.95 0.08-83.79 - - - -
Salmeterol vs Salmeterol/Fluticasone 0.81 0.56-1.16 0.45-1.45 0.84 0.47-1.48 0.0552 3 4367
Tiotropium vs Salmeterol/Fluticasone 1.61 1.02-2.56 0.76-3.42 2.12 0.95-4.72 -- 1 1448
Tiotropium Respimat vs Salmeterol/Fluticasone 1.87 1.14-3.06 0.84-4.16 - - - -
Triamcinolone Acetonide vs Salmeterol/Fluticasone 3.87 0.75-19.84 0.27-55.04 - - - -
Umeclidinium vs Salmeterol/Fluticasone 1.44 0.12-17.64 0.02-84.37 - - - -
Vilanterol/Umeclidinium vs Salmeterol/Fluticasone 2.81 0.50-15.81 0.17-46.48 - - - -
Vilanterol vs Salmeterol/Fluticasone 2.06 0.47-9.05 0.19-22.77 - - - -
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Formoterol vs Vilanterol/Fluticasone 0.90 0.07-10.89 0.02-51.67 - - - -
Glycopyrronium vs Vilanterol/Fluticasone 0.26 0.01-5.65 0.00-38.83 - - - -
Indacaterol vs Vilanterol/Fluticasone 0.83 0.10-6.70 0.03-24.63 - - - -
Indacaterol/Glycopyrronium vs Vilanterol/Fluticasone 0.29 0.01-11.67 0.00-117.04 - - - -
Indacaterol/Tiotropium vs Vilanterol/Fluticasone 2.19 0.13-36.32 0.02-209.56 - - - -
Salmeterol vs Vilanterol/Fluticasone 0.69 0.11-4.40 0.03-13.98 - - - -
Tiotropium vs Vilanterol/Fluticasone 1.38 0.21-8.94 0.07-28.69 - - - -
Tiotropium Respimat vs Vilanterol/Fluticasone 1.59 0.24-10.43 0.08-33.63 - - - -
Triamcinolone Acetonide vs Vilanterol/Fluticasone 3.30 0.29-37.79 0.06-172.95 - - - -
Umeclidinium vs Vilanterol/Fluticasone 1.22 0.06-24.97 0.01-163.73 - - - -
Vilanterol/Umeclidinium vs Vilanterol/Fluticasone 2.40 0.22-25.69 0.05-112.87 - - - -
Vilanterol vs Vilanterol/Fluticasone 1.76 0.22-14.00 0.06-51.11 3.03 0.12-
74.80
-- 1 818
Glycopyrronium vs Formoterol 0.29 0.01-5.81 0.00-37.98 - - - -
Indacaterol vs Formoterol 0.93 0.14-6.09 0.04-19.69 2.99 0.12-
73.51
-- 1 871
Indacaterol/Glycopyrronium vs Formoterol 0.32 0.01-12.27 0.00-118.66 - - - -
Indacaterol/Tiotropium vs Formoterol 2.44 0.16-37.25 0.03-204.03 - - - -
Salmeterol vs Formoterol 0.77 0.14-4.30 0.05-12.59 - - - -
Tiotropium vs Formoterol 1.53 0.27-8.77 0.09-26.00 - - - -
Tiotropium Respimat vs Formoterol 1.78 0.31-10.22 0.10-30.41 - - - -
Triamcinolone Acetonide vs Formoterol 3.68 0.36-37.84 0.08-162.01 - - - -
Umeclidinium vs Formoterol 1.36 0.07-27.85 0.01-182.79 - - - -
Vilanterol/Umeclidinium vs Formoterol 2.67 0.24-29.61 0.05-132.83 - - - -
Vilanterol vs Formoterol 1.96 0.21-18.30 0.05-73.79 - - - -
Indacaterol vs Glycopyrronium 3.24 0.22-47.20 0.04-251.10 - - - -
Indacaterol/Glycopyrronium vs Glycopyrronium 1.13 0.02-65.94 0.00-833.90 - - - -
Indacaterol/Tiotropium vs Glycopyrronium 8.51 0.33-222.12 0.04-
1698.51
- - - -
Salmeterol vs Glycopyrronium 2.68 0.22-32.94 0.05-157.50 - - - -
Tiotropium vs Glycopyrronium 5.36 0.44-65.17 0.09-309.53 - - - -
Tiotropium Respimat vs Glycopyrronium 6.21 0.51-76.08 0.11-363.10 - - - -
Triamcinolone Acetonide vs Glycopyrronium 12.84 0.66-248.48 0.10-
1577.10
- - - -
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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
- - - -
Vilanterol vs Glycopyrronium 6.84 0.38-121.89 0.06-734.82 - - - -
Indacaterol/Glycopyrronium vs Indacaterol 0.35 0.01-10.13 0.00-82.82 - - - -
Indacaterol/Tiotropium vs Indacaterolacaterol 2.63 0.25-27.65 0.06-119.88 - - - -
Salmeterol vs Indacaterol 0.83 0.29-2.33 0.15-4.44 0.25 0.03-2.29 0.00 2 1784
Tiotropium vs Indacaterol 1.66 0.57-4.81 0.29-9.34 2.99 0.12-
73.38
-- 1 1593
Tiotropium Respimat vs Indacaterol 1.92 0.65-5.64 0.33-11.04 - - - -
Triamcinolone Acetonide vs Indacaterol 3.97 0.60-26.27 0.18-85.38 - - - -
Umeclidinium vs Indacaterol 1.47 0.10-21.61 0.02-115.37 - - - -
Vilanterol/Umeclidinium vs Indacaterol 2.88 0.40-20.80 0.12-71.39 - - - -
Vilanterol vs Indacaterol 2.11 0.36-12.36 0.12-37.16 - - - -
Indacaterol/Tiotropium vs
Indacaterolacaterol/Glycopyrronium
7.55 0.16-357.46 0.01-
3965.59
- - - -
Salmeterol vs Indacaterol/Glycopyrronium 2.37 0.09-59.75 0.01-446.73 - - - -
Tiotropium vs Indacaterol/Glycopyrronium 4.75 0.19-121.10 0.02-912.78 - - - -
Tiotropium Respimat vs Indacaterol/Glycopyrronium 5.50 0.21-140.91 0.03-
1065.04
- - - -
Triamcinolone Acetonide vs Indacaterol/Glycopyrronium 11.38 0.31-415.80 0.03-
3922.96
- - - -
Umeclidinium vs Indacaterol/Glycopyrronium 4.22 0.07-247.43 0.01-
3133.71
- - - -
Vilanterol/Umeclidinium vs Indacaterol/Glycopyrronium 8.26 0.22-315.30 0.02-
3055.92
- - - -
Vilanterol vs Indacaterol/Glycopyrronium 6.06 0.18-206.94 0.02-
1871.33
- - - -
Salmeterol vs Indacaterol/Tiotropium 0.31 0.04-2.71 0.01-10.38 - - - -
Tiotropium vs Indacaterol/Tiotropium 0.63 0.08-5.12 0.02-18.95 0.63 0.08-5.12 0.00 2 2273
Tiotropium Respimat vs Indacaterol/Tiotropium 0.73 0.09-6.03 0.02-22.53 - - - -
Triamcinolone Acetonide vs Indacaterol/Tiotropium 1.51 0.10-21.89 0.02-116.08 - - - -
Umeclidinium vs Indacaterol/Tiotropium 0.56 0.02-14.60 0.00-111.66 - - - -
Vilanterol/Umeclidinium vs Indacaterol/Tiotropium 1.10 0.07-16.48 0.01-89.41 - - - -
Vilanterol vs Indacaterol/Tiotropium 0.80 0.06-10.50 0.01-52.18 - - - -
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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 - - - -
Umeclidinium vs Salmeterol 1.78 0.14-21.96 0.03-105.32 - - - -
Vilanterol/Umeclidinium vs Salmeterol 3.48 0.61-19.73 0.21-58.22 - - - -
Vilanterol vs Salmeterol 2.55 0.58-11.31 0.23-28.60 - - - -
Tiotropium Respimat vs Tiotropium 1.16 0.89-1.50 0.76-1.76 1.12 0.85-1.47 -- 1 11405
Triamcinolone Acetonide vs Tiotropium 2.40 0.46-12.61 0.16-35.53 - - - -
Umeclidinium vs Tiotropium 0.89 0.07-10.81 0.02-51.35 - - - -
Vilanterol/Umeclidinium vs Tiotropium 1.74 0.31-9.70 0.11-28.34 2.96 0.12-
73.01
-- 1 852
Vilanterol vs Tiotropium 1.28 0.29-5.64 0.11-14.26 3.00 0.12-
74.07
-- 1 417
Triamcinolone Acetonide vs Tiotropium Respimat 2.07 0.39-10.95 0.14-30.97 - - - -
Umeclidinium vs Tiotropium Respimat 0.77 0.06-9.41 0.01-44.96 - - - -
Vilanterol/Umeclidinium vs Tiotropium Respimat 1.50 0.27-8.48 0.09-24.94 - - - -
Vilanterol vs Tiotropium Respimat 1.10 0.25-4.93 0.10-12.54 - - - -
Umeclidinium vs Triamcinolone Acetonide 0.37 0.02-7.23 0.00-46.05 - - - -
Vilanterol/Umeclidinium vs Triamcinolone Acetonide 0.73 0.07-7.59 0.02-32.81 - - - -
Vilanterol vs Triamcinolone Acetonide 0.53 0.06-4.67 0.02-18.08 - - - -
Vilanterol/Umeclidinium vs Umeclidinium 1.96 0.18-20.93 0.04-91.76 3.04 0.12-
74.93
-- 1 1270
Vilanterol vs Umeclidinium 1.44 0.11-18.58 0.02-91.79 - - - -
Vilanterol vs Vilanterol/Umeclidinium 0.73 0.14-3.79 0.05-10.54 0.62 0.08-5.08 0.00 2 1255
Common within-network heterogeneity variance 0.00
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity variance)
11.79 (27,0.995,0.00)
Pneumonia: 54 studies (1 five-arm, 1 four-arm, 2 three-arm, 23 two-arm), 21 treatments, 61551 patients
Budesonide vs Placebo 0.75 0.44-1.27 0.39-1.45 1.01 0.44-2.28 0.20 3 1378
Fluticasone vs Placebo 1.66 1.32-2.08 1.20-2.30 1.60 1.32-1.95 0.00 5 4258
Mometasone vs Placebo 1.23 0.51-2.96 0.42-3.60 1.75 0.64-4.81 0.00 3 1514
Formoterol vs Placebo 0.91 0.59-1.41 0.52-1.59 1.46 0.70-3.03 0.30 7 3499
Indacaterol vs Placebo 0.97 0.63-1.50 0.56-1.69 0.59 0.23-1.52 0.00 6 2787
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Salmeterol vs Placebo 1.11 0.91-1.37 0.82-1.51 1.09 0.88-1.35 0.00 3 3829
Vilanterol vs Placebo 1.14 0.53-2.45 0.45-2.92 2.08 0.56-7.67 0.00 2 820
Aclidinium vs Placebo 0.68 0.32-1.42 0.27-1.69 0.68 0.32-1.41 0.00 2 1647
Glycopyrronium vs Placebo 0.82 0.55-1.23 0.49-1.38 0.61 0.32-1.17 0.00 3 2315
Tiotropium vs Placebo 0.95 0.78-1.14 0.71-1.26 0.99 0.84-1.17 0.00 6 11522
Umeclidinium vs Placebo 0.74 0.11-4.99 0.07-7.44 - - - -
Beclomethasone/Formoterol vs Placebo 1.13 0.33-3.84 0.26-4.99 - - - -
Budesonide/Formoterol vs Placebo 1.26 0.80-2.00 0.70-2.26 1.45 0.50-4.18 0.55 3 2066
Fluticasone/Vilanterol vs Placebo 2.13 0.98-4.64 0.82-5.54 1.87 0.50-6.97 0.00 2 822
Fluticasone/Salmeterol vs Placebo 1.90 1.53-2.34 1.39-2.59 1.75 1.44-2.13 <0.0001 4 3872
Mometasone/Formoterol vs Placebo 0.88 0.31-2.51 0.24-3.16 1.66 0.39-7.11 0.00 2 894
Indacaterol/Glycopyrronium vs Placebo 0.85 0.53-1.36 0.47-1.54 1.62 0.10-
26.65
2.81 2 1044
Umeclidinium/Vilanterol vs Placebo 0.61 0.12-3.21 0.08-4.55 - - - -
Tiotropium/Fluticasone/Salmeterol vs Placebo 1.56 0.29-8.27 0.21-11.75 - - - -
Tiotropium/Budesonide/Formoterol vs Placebo 0.94 0.19-4.78 0.13-6.73 - - - -
Fluticasone vs Budesonide 2.21 1.25-3.92 1.08-4.51 - - - -
Mometasone vs Budesonide 1.63 0.60-4.43 0.48-5.52 - - - -
Formoterol vs Budesonide 1.21 0.67-2.17 0.58-2.51 1.19 0.51-2.79 0.00 2 1071
Indacaterol vs Budesonide 1.29 0.65-2.58 0.55-3.03 - - - -
Salmeterol vs Budesonide 1.48 0.84-2.62 0.73-3.01 - - - -
Vilanterol vs Budesonide 1.52 0.60-3.84 0.49-4.72 - - - -
Aclidinium vs Budesonide 0.90 0.36-2.23 0.30-2.73 - - - -
Glycopyrronium vs Budesonide 1.09 0.56-2.13 0.48-2.49 - - - -
Tiotropium vs Budesonide 1.26 0.71-2.22 0.62-2.55 - - - -
Umeclidinium vs Budesonide 0.99 0.14-7.14 0.09-10.81 - - - -
Beclomethasone/Formoterol vs Budesonide 1.50 0.42-5.39 0.32-7.09 - - - -
Budesonide/Formoterol vs Budesonide 1.68 0.93-3.03 0.80-3.49 1.51 0.67-3.39 0.00 2 1067
Fluticasone/Vilanterol vs Budesonide 2.83 1.10-7.25 0.90-8.93 - - - -
Fluticasone/Salmeterol vs Budesonide 2.52 1.44-4.43 1.25-5.09 - - - -
Mometasone/Formoterol vs Budesonide 1.17 0.37-3.66 0.29-4.68 - - - -
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Indacaterol/Glycopyrronium vs Budesonide 1.13 0.55-2.30 0.47-2.72 - - - -
Umeclidinium/Vilanterol vs Budesonide 0.82 0.14-4.64 0.10-6.69 - - - -
Tiotropium/Fluticasone/Salmeterol vs Budesonide 2.07 0.36-11.95 0.25-17.28 - - - -
Tiotropium/Budesonide/Formoterol vs Budesonide 1.25 0.23-6.92 0.16-9.93 - - - -
Mometasone vs Fluticasone 0.74 0.30-1.83 0.24-2.24 - - - -
Formoterol vs Fluticasone 0.55 0.33-0.90 0.29-1.02 - - - -
Indacaterol vs Fluticasone 0.58 0.36-0.95 0.32-1.07 - - - -
Salmeterol vs Fluticasone 0.67 0.54-0.84 0.49-0.93 0.68 0.56-0.83 0.00 2 3174
Vilanterol vs Fluticasone 0.69 0.32-1.47 0.27-1.75 1.18 0.39-3.54 0.00 2 818
Aclidinium vs Fluticasone 0.41 0.19-0.88 0.16-1.06 - - - -
Glycopyrronium vs Fluticasone 0.49 0.31-0.78 0.28-0.88 - - - -
Tiotropium vs Fluticasone 0.57 0.43-0.75 0.39-0.83 - - - -
Umeclidinium vs Fluticasone 0.45 0.07-3.03 0.04-4.53 - - - -
Beclomethasone/Formoterol vs Fluticasone 0.68 0.20-2.36 0.15-3.08 - - - -
Budesonide/Formoterol vs Fluticasone 0.76 0.45-1.27 0.40-1.44 - - - -
Fluticasone/Vilanterol vs Fluticasone 1.28 0.59-2.78 0.49-3.32 1.01 0.32-3.24 0.00 2 820
Fluticasone/Salmeterol vs Fluticasone 1.14 0.91-1.43 0.83-1.57 1.08 0.90-1.29 0.00 3 3441
Mometasone/Formoterol vs Fluticasone 0.53 0.18-1.55 0.14-1.96 - - - -
Indacaterol/Glycopyrronium vs Fluticasone 0.51 0.31-0.85 0.27-0.97 - - - -
Umeclidinium/Vilanterol vs Fluticasone 0.37 0.07-1.95 0.05-2.77 - - - -
Tiotropium/Fluticasone/Salmeterol vs Fluticasone 0.94 0.18-5.04 0.12-7.18 - - - -
Tiotropium/Budesonide/Formoterol vs Fluticasone 0.57 0.11-2.91 0.08-4.11 - - - -
Formoterol vs Mometasone 0.74 0.30-1.82 0.25-2.22 1.91 0.20-
18.09
1.55 2 915
Indacaterol vs Mometasone 0.79 0.30-2.12 0.24-2.64 - - - -
Salmeterol vs Mometasone 0.91 0.37-2.25 0.30-2.75 - - - -
Vilanterol vs Mometasone 0.93 0.29-2.99 0.23-3.85 - - - -
Aclidinium vs Mometasone 0.55 0.17-1.75 0.14-2.24 - - - -
Glycopyrronium vs Mometasone 0.67 0.25-1.77 0.20-2.19 - - - -
Tiotropium vs Mometasone 0.77 0.31-1.91 0.26-2.33 - - - -
Umeclidinium vs Mometasone 0.61 0.07-4.94 0.05-7.68 - - - -
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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 - - - -
Salmeterol vs Formoterol 1.23 0.75-2.00 0.66-2.27 - - - -
Vilanterol vs Formoterol 1.25 0.52-3.03 0.43-3.69 - - - -
Aclidinium vs Formoterol 0.74 0.31-1.76 0.26-2.14 - - - -
Glycopyrronium vs Formoterol 0.90 0.49-1.66 0.42-1.92 - - - -
Tiotropium vs Formoterol 1.04 0.64-1.70 0.56-1.93 - - - -
Umeclidinium vs Formoterol 0.82 0.12-5.78 0.08-8.72 - - - -
Beclomethasone/Formoterol vs Formoterol 1.24 0.38-4.07 0.29-5.26 5.13 0.59-
44.24
-- 1 474
Budesonide/Formoterol vs Formoterol 1.39 0.95-2.03 0.85-2.26 1.49 0.98-2.26 0.04 6 4646
Fluticasone/Vilanterol vs Formoterol 2.34 0.95-5.73 0.78-7.00 - - - -
Fluticasone/Salmeterol vs Formoterol 2.09 1.29-3.37 1.14-3.83 - - - -
Mometasone/Formoterol vs Formoterol 0.96 0.34-2.71 0.27-3.39 0.66 0.18-2.36 0.11 2 898
Indacaterol/Glycopyrronium vs Formoterol 0.93 0.49-1.80 0.42-2.10 - - - -
Umeclidinium/Vilanterol vs Formoterol 0.68 0.12-3.75 0.08-5.38 - - - -
Tiotropium/Fluticasone/Salmeterol vs Formoterol 1.72 0.30-9.65 0.21-13.90 - - - -
Tiotropium/Budesonide/Formoterol vs Formoterol 1.03 0.19-5.59 0.13-7.98 - - - -
Salmeterol vs Indacaterol 1.15 0.73-1.81 0.64-2.05 - - - -
Vilanterol vs Indacaterol 1.17 0.49-2.81 0.40-3.42 - - - -
Aclidinium vs Indacaterol 0.70 0.29-1.65 0.24-2.00 - - - -
Glycopyrronium vs Indacaterol 0.84 0.50-1.44 0.43-1.65 1.01 0.20-5.01 -- 1 949
Tiotropium vs Indacaterol 0.97 0.65-1.45 0.58-1.62 0.90 0.60-1.35 0.00 2 4395
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Umeclidinium vs Indacaterol 0.76 0.11-5.31 0.07-7.97 - - - -
Beclomethasone/Formoterol vs Indacaterol 1.17 0.32-4.29 0.24-5.68 - - - -
Budesonide/Formoterol vs Indacaterol 1.30 0.68-2.48 0.58-2.89 - - - -
Fluticasone/Vilanterol vs Indacaterol 2.19 0.91-5.30 0.74-6.46 - - - -
Fluticasone/Salmeterol vs Indacaterol 1.95 1.20-3.17 1.06-3.60 - - - -
Mometasone/Formoterol vs Indacaterol 0.90 0.29-2.83 0.23-3.62 - - - -
Indacaterol/Glycopyrronium vs Indacaterol 0.88 0.49-1.57 0.42-1.81 1.00 0.20-5.00 -- 1 950
Umeclidinium/Vilanterol vs Indacaterol 0.63 0.12-3.43 0.08-4.90 - - - -
Tiotropium/Fluticasone/Salmeterol vs Indacaterol 1.61 0.29-8.83 0.20-12.65 - - - -
Tiotropium/Budesonide/Formoterol vs Indacaterol 0.97 0.18-5.11 0.13-7.25 - - - -
Vilanterol vs Salmeterol 1.02 0.47-2.22 0.40-2.65 - - - -
Aclidinium vs Salmeterol 0.61 0.28-1.31 0.24-1.56 - - - -
Glycopyrronium vs Salmeterol 0.74 0.48-1.13 0.43-1.27 - - - -
Tiotropium vs Salmeterol 0.85 0.68-1.06 0.61-1.17 0.78 0.57-1.08 -- 1 7376
Umeclidinium vs Salmeterol 0.67 0.10-4.49 0.07-6.71 - - - -
Beclomethasone/Formoterol vs Salmeterol 1.01 0.29-3.51 0.22-4.58 - - - -
Budesonide/Formoterol vs Salmeterol 1.13 0.68-1.88 0.60-2.14 - - - -
Fluticasone/Vilanterol vs Salmeterol 1.91 0.87-4.19 0.73-5.01 - - - -
Fluticasone/Salmeterol vs Salmeterol 1.70 1.38-2.09 1.25-2.31 1.69 1.40-2.04 0.00 8 7613
Mometasone/Formoterol vs Salmeterol 0.79 0.27-2.30 0.21-2.90 - - - -
Indacaterol/Glycopyrronium vs Salmeterol 0.76 0.47-1.25 0.41-1.42 - - - -
Umeclidinium/Vilanterol vs Salmeterol 0.55 0.11-2.89 0.07-4.10 - - - -
Tiotropium/Fluticasone/Salmeterol vs Salmeterol 1.40 0.26-7.45 0.18-10.60 - - - -
Tiotropium/Budesonide/Formoterol vs Salmeterol 0.84 0.17-4.30 0.12-6.08 - - - -
Aclidinium vs Vilanterol 0.59 0.20-1.72 0.16-2.17 - - - -
Glycopyrronium vs Vilanterol 0.72 0.31-1.70 0.25-2.06 - - - -
Tiotropium vs Vilanterol 0.83 0.38-1.81 0.32-2.16 2.03 0.18-
22.56
-- 1 408
Umeclidinium vs Vilanterol 0.65 0.09-4.97 0.06-7.61 - - - -
Beclomethasone/Formoterol vs Vilanterol 0.99 0.23-4.19 0.17-5.70 - - - -
Budesonide/Formoterol vs Vilanterol 1.11 0.45-2.70 0.37-3.29 - - - -
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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 - - - -
Glycopyrronium vs Aclidinium 1.21 0.52-2.83 0.43-3.42 - - - -
Tiotropium vs Aclidinium 1.40 0.65-3.01 0.55-3.59 - - - -
Umeclidinium vs Aclidinium 1.10 0.14-8.49 0.09-13.03 - - - -
Beclomethasone/Formoterol vs Aclidinium 1.67 0.40-6.99 0.30-9.47 - - - -
Budesonide/Formoterol vs Aclidinium 1.87 0.78-4.47 0.64-5.43 - - - -
Fluticasone/Vilanterol vs Aclidinium 3.15 1.07-9.24 0.85-11.68 - - - -
Fluticasone/Salmeterol vs Aclidinium 2.81 1.30-6.07 1.09-7.24 - - - -
Mometasone/Formoterol vs Aclidinium 1.30 0.36-4.70 0.27-6.19 - - - -
Indacaterol/Glycopyrronium vs Aclidinium 1.26 0.52-3.03 0.43-3.69 - - - -
Umeclidinium/Vilanterol vs Aclidinium 0.91 0.15-5.57 0.10-8.15 - - - -
Tiotropium/Fluticasone/Salmeterol vs Aclidinium 2.31 0.37-14.33 0.25-21.03 - - - -
Tiotropium/Budesonide/Formoterol vs Aclidinium 1.39 0.23-8.31 0.16-12.11 - - - -
Tiotropium vs Glycopyrronium 1.15 0.80-1.67 0.71-1.87 1.06 0.71-1.58 <0.0001 4 3385
Umeclidinium vs Glycopyrronium 0.90 0.13-6.25 0.09-9.38 - - - -
Beclomethasone/Formoterol vs Glycopyrronium 1.38 0.38-5.02 0.29-6.63 - - - -
Budesonide/Formoterol vs Glycopyrronium 1.54 0.82-2.86 0.71-3.32 - - - -
Fluticasone/Vilanterol vs Glycopyrronium 2.59 1.09-6.18 0.90-7.51 - - - -
Fluticasone/Salmeterol vs Glycopyrronium 2.31 1.47-3.64 1.30-4.11 - - - -
Mometasone/Formoterol vs Glycopyrronium 1.07 0.35-3.31 0.27-4.22 - - - -
Indacaterol/Glycopyrronium vs Glycopyrronium 1.04 0.66-1.63 0.58-1.84 0.93 0.59-1.48 0.00 2 2416
Umeclidinium/Vilanterol vs Glycopyrronium 0.75 0.14-4.04 0.10-5.76 - - - -
Tiotropium/Fluticasone/Salmeterol vs Glycopyrronium 1.90 0.35-10.39 0.24-14.87 - - - -
Tiotropium/Budesonide/Formoterol vs Glycopyrronium 1.15 0.22-6.01 0.15-8.52 - - - -
Umeclidinium vs Tiotropium 0.78 0.12-5.23 0.08-7.79 0.97 0.14-6.94 -- 1 437
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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 - - - -
Indacaterol/Glycopyrronium vs
Beclomethasone/Formoterol
0.75 0.20-2.80 0.15-3.71 - - - -
Umeclidinium/Vilanterol vs Beclomethasone/Formoterol 0.54 0.07-4.26 0.05-6.55 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Beclomethasone/Formoterol
1.38 0.17-10.93 0.11-16.87 - - - -
Tiotropium/Budesonide/Formoterol vs
Beclomethasone/Formoterol
0.83 0.11-6.37 0.07-9.77 - - - -
Fluticasone/Vilanterol vs Budesonide/Formoterol 1.69 0.68-4.18 0.56-5.11 - - - -
Fluticasone/Salmeterol vs Budesonide/Formoterol 1.50 0.91-2.48 0.80-2.82 - - - -
Mometasone/Formoterol vs Budesonide/Formoterol 0.70 0.24-2.04 0.19-2.58 - - - -
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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 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Budesonide/Formoterol
1.24 0.22-7.00 0.15-10.09 - - - -
Tiotropium/Budesonide/Formoterol vs
Budesonide/Formoterol
0.75 0.14-4.05 0.10-5.79 - - - -
Fluticasone/Salmeterol vs Fluticasone/Vilanterol 0.89 0.41-1.96 0.34-2.34 2.04 0.18-
22.62
-- 1 528
Mometasone/Formoterol vs Fluticasone/Vilanterol 0.41 0.11-1.53 0.08-2.02 - - - -
Indacaterol/Glycopyrronium vs Fluticasone/Vilanterol 0.40 0.16-0.98 0.13-1.20 - - - -
Umeclidinium/Vilanterol vs Fluticasone/Vilanterol 0.29 0.05-1.73 0.03-2.52 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Fluticasone/Vilanterol
0.73 0.12-4.60 0.08-6.76 - - - -
Tiotropium/Budesonide/Formoterol vs
Fluticasone/Vilanterol
0.44 0.07-2.67 0.05-3.89 - - - -
Mometasone/Formoterol vs Fluticasone/Salmeterol 0.46 0.16-1.35 0.13-1.70 - - - -
Indacaterol/Glycopyrronium vs Fluticasone/Salmeterol 0.45 0.27-0.75 0.24-0.85 0.11 0.01-2.09 -- 1 522
Umeclidinium/Vilanterol vs Fluticasone/Salmeterol 0.32 0.06-1.71 0.04-2.43 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Fluticasone/Salmeterol
0.82 0.15-4.41 0.11-6.29 - - - -
Tiotropium/Budesonide/Formoterol vs
Fluticasone/Salmeterol
0.50 0.10-2.55 0.07-3.60 - - - -
Indacaterol/Glycopyrronium vs Mometasone/Formoterol 0.97 0.31-3.08 0.24-3.95 - - - -
Umeclidinium/Vilanterol vs Mometasone/Formoterol 0.70 0.10-4.98 0.07-7.51 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Mometasone/Formoterol
1.78 0.25-12.79 0.16-19.35 - - - -
Tiotropium/Budesonide/Formoterol vs
Mometasone/Formoterol
1.07 0.15-7.44 0.10-11.18 - - - -
Umeclidinium/Vilanterol vs Indacaterol/Glycopyrronium 0.72 0.13-3.97 0.09-5.68 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Indacaterol/Glycopyrronium
1.84 0.33-10.21 0.23-14.66 - - - -
Tiotropium/Budesonide/Formoterol vs
Indacaterol/Glycopyrronium
1.11 0.21-5.90 0.15-8.41 - - - -
Tiotropium/Fluticasone/Salmeterol vs
Umeclidinium/Vilanterol
2.54 0.25-26.17 0.15-42.60 - - - -
Tiotropium/Budesonide/Formoterol vs
Umeclidinium/Vilanterol
1.53 0.15-15.30 0.09-24.76 - - - -
Tiotropium/Budesonide/Formoterol vs
Tiotropium/Fluticasone/Salmeterol
0.60 0.06-6.09 0.04-9.87 - - - -
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Common within-network heterogeneity variance 0.01
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity variance)
34.33 (31,0.311,0.00)
Arrhythmia: 26 studies (1 five-arm, 1 four-arm, 2 three-arm, 22 two-arm), 12 treatments, 27407 patients
Budesonide vs Placebo 1.97 0.35-11.19 0.17-23.08 1.09 0.15-7.80 -- 1 575
Formoterol vs Placebo 1.50 0.66-3.43 0.47-4.83 1.63 0.70-3.84 0.02 6 3053
Indacaterol vs Placebo 1.44 0.61-3.40 0.43-4.85 1.48 0.44-4.99 0.00 2 1081
Salmeterol vs Placebo 0.99 0.39-2.54 0.26-3.75 0.90 0.27-2.99 0.37 4 1213
Aclidinium vs Placebo 1.13 0.44-2.86 0.30-4.22 1.13 0.44-2.87 0.00 2 1647
Glycopyrronium vs Placebo 1.52 0.63-3.62 0.44-5.21 2.92 0.35-
24.37
0.00 2 1522
Tiotropium vs Placebo 1.17 0.71-1.93 0.58-2.38 1.37 0.50-3.72 0.37 4 8729
Budesonide/Formoterol vs Placebo 2.75 0.87-8.64 0.54-13.93 2.93 0.27-
32.10
1.50 2 1556
Fluticasone/Vilanterol vs Placebo 8.88 0.33-240.14 0.08-948.41 - - - -
Fluticasone/Salmeterolvs Placebo 0.80 0.17-3.86 0.09-7.43 - - - -
Indacaterol/Glycopyrronium vs Placebo 1.63 0.68-3.89 0.48-5.60 2.46 0.12-
51.45
-- 1 706
Formoterol vs Budesonide 0.77 0.13-4.37 0.06-9.03 0.48 0.04-5.35 -- 1 559
Indacaterol vs Budesonide 0.73 0.11-5.10 0.05-11.43 - - - -
Salmeterol vs Budesonide 0.51 0.07-3.64 0.03-8.30 - - - -
Aclidinium vs Budesonide 0.57 0.08-4.12 0.03-9.37 - - - -
Glycopyrronium vs Budesonide 0.77 0.11-5.39 0.05-12.12 - - - -
Tiotropium vs Budesonide 0.60 0.10-3.64 0.05-7.73 - - - -
Budesonide/Formoterol vs Budesonide 1.40 0.24-8.11 0.12-16.87 0.98 0.14-7.00 -- 1 556
Fluticasone/Vilanterol vs Budesonide 4.52 0.11-187.86 0.02-887.62 - - - -
Fluticasone/Salmeterolvs Budesonide 0.41 0.04-4.26 0.01-11.29 - - - -
Indacaterol/Glycopyrronium vs Budesonide 0.83 0.12-5.80 0.05-13.04 - - - -
Indacaterol vs Formoterol 0.96 0.29-3.15 0.18-5.16 - - - -
Salmeterol vs Formoterol 0.66 0.19-2.30 0.11-3.87 - - - -
Aclidinium vs Formoterol 0.75 0.22-2.60 0.13-4.36 - - - -
Glycopyrronium vs Formoterol 1.01 0.30-3.34 0.18-5.50 - - - -
Tiotropium vs Formoterol 0.78 0.30-2.04 0.20-3.05 - - - -
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Budesonide/Formoterol vs Formoterol 1.83 0.67-4.98 0.44-7.57 2.12 0.69-6.54 0.00 3 2364
Fluticasone/Vilanterol vs Formoterol 5.91 0.20-176.66 0.05-727.72 - - - -
Fluticasone/Salmeterolvs Formoterol 0.53 0.09-3.15 0.04-6.58 - - - -
Indacaterol/Glycopyrronium vs Formoterol 1.08 0.33-3.59 0.20-5.92 - - - -
Salmeterol vs Indacaterol 0.69 0.20-2.42 0.12-4.09 - - - -
Aclidinium vs Indacaterol 0.78 0.22-2.77 0.13-4.69 - - - -
Glycopyrronium vs Indacaterol 1.05 0.38-2.89 0.25-4.40 0.67 0.11-4.02 -- 1 949
Tiotropium vs Indacaterol 0.81 0.35-1.87 0.25-2.65 0.87 0.24-3.08 0.02 2 4395
Budesonide/Formoterol vs Indacaterol 1.91 0.46-7.97 0.25-14.46 - - - -
Fluticasone/Vilanterol vs Indacaterol 6.16 0.21-182.74 0.05-750.24 - - - -
Fluticasone/Salmeterolvs Indacaterol 0.56 0.10-3.23 0.05-6.71 - - - -
Indacaterol/Glycopyrronium vs Indacaterol 1.13 0.41-3.10 0.27-4.72 0.67 0.11-4.02 -- 1 950
Aclidinium vs Salmeterol 1.13 0.30-4.25 0.17-7.37 - - - -
Glycopyrronium vs Salmeterol 1.52 0.43-5.34 0.26-9.01 - - - -
Tiotropium vs Salmeterol 1.18 0.41-3.36 0.27-5.21 - - - -
Budesonide/Formoterol vs Salmeterol 2.77 0.63-12.16 0.34-22.52 - - - -
Fluticasone/Vilanterol vs Salmeterol 8.94 0.36-220.89 0.10-840.28 - - - -
Fluticasone/Salmeterolvs Salmeterol 0.81 0.21-3.19 0.12-5.64 1.01 0.15-6.83 1.07 3 1875
Indacaterol/Glycopyrronium vs Salmeterol 1.64 0.48-5.66 0.28-9.47 - - - -
Glycopyrronium vs Aclidinium 1.35 0.38-4.83 0.22-8.21 - - - -
Tiotropium vs Aclidinium 1.04 0.36-3.00 0.23-4.66 - - - -
Budesonide/Formoterol vs Aclidinium 2.44 0.56-10.70 0.30-19.80 - - - -
Fluticasone/Vilanterol vs Aclidinium 7.89 0.26-242.89 0.06-
1012.35
- - - -
Fluticasone/Salmeterolvs Aclidinium 0.71 0.12-4.44 0.05-9.49 - - - -
Indacaterol/Glycopyrronium vs Aclidinium 1.45 0.40-5.19 0.24-8.83 - - - -
Tiotropium vs Glycopyrronium 0.77 0.36-1.68 0.26-2.33 0.75 0.31-1.80 0.00 2 2430
Budesonide/Formoterol vs Glycopyrronium 1.81 0.43-7.65 0.24-13.94 - - - -
Fluticasone/Vilanterol vs Glycopyrronium 5.86 0.20-171.85 0.05-701.95 - - - -
Fluticasone/Salmeterolvs Glycopyrronium 0.53 0.09-3.00 0.05-6.18 - - - -
Indacaterol/Glycopyrronium vs Glycopyrronium 1.08 0.50-2.31 0.37-3.18 1.10 0.50-2.42 0.00 2 2416
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Budesonide/Formoterol vs Tiotropium 2.35 0.67-8.19 0.40-13.79 - - - -
Fluticasone/Vilanterol vs Tiotropium 7.58 0.27-209.82 0.07-836.67 - - - -
Fluticasone/Salmeterolvs Tiotropium 0.69 0.14-3.46 0.07-6.79 - - - -
Indacaterol/Glycopyrronium vs Tiotropium 1.39 0.64-3.01 0.47-4.16 1.46 0.62-3.45 0.00 2 2420
Fluticasone/Vilanterol vs Budesonide/Formoterol 3.23 0.10-105.98 0.02-453.67 - - - -
Fluticasone/Salmeterolvs Budesonide/Formoterol 0.29 0.04-2.04 0.02-4.59 - - - -
Indacaterol/Glycopyrronium vs Budesonide/Formoterol 0.59 0.14-2.50 0.08-4.55 - - - -
Fluticasone/Salmeterolvs Fluticasone/Vilanterol 0.09 0.00-1.65 0.00-5.51 0.09 0.00-1.65 -- 1 528
Indacaterol/Glycopyrronium vs Fluticasone/Vilanterol 0.18 0.01-5.27 0.00-21.36 - - - -
Indacaterol/Glycopyrronium vs Fluticasone/Salmeterol 2.03 0.37-11.01 0.18-22.28 3.08 0.12-
75.99
-- 1 522
Common within-network heterogeneity variance 0.00
Design-by-treatment interaction model for
inconsistency χ² (d.f., P-value, heterogeneity variance)
3.06 (11,0.9899,0.36)
Abbreviations and symbols: OR, Odds Ratio, NMA, Network Meta-analysis, MA, Meta-analysis, CI, Confidence Interval; PrI, Predictive Interval; LABA, long acting
beta agonists, χ², Chi Square Test, d.f., degrees of freedom
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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
Treatment Comparison Odds
Ratio CI
Odds
Ratio CI # studies # patients
Exacerbations: 25 studies (2 four-arm, 6 three-arm, 17 two-arm), 20 treatments, 33211 patients
Fluticasone vs Placebo 0.28 0.13-0.62 0.21 0.09-0.48 2.00 541.00
Vilanterol vs Fluticasone 3.88 1.68-8.93 4.86 1.62-14.64 1.00 407.00
Fluticasone/Vilanterol vs Fluticasone 2.86 1.23-6.64 3.40 1.09-10.62 1.00 408.00
Fluticasone/Vilanterol vs Vilanterol 0.74 0.59-0.92 0.75 0.62-0.91 3.00 2031.00
Indacaterol/Glycopyrronium vs
Glycopyrronium 0.62 0.47-0.82 0.63 0.51-0.77 1.00 1469.00
Indacaterol/Glycopyrronium vs Tiotropium 0.73 0.57-0.94 0.74 0.60-0.91 1.00 1466.00
Indacterol/Tiotropium vs Placebo 0.67 0.46-0.98
Indacaterol/Glycopyrronium vs Placebo 0.60 0.43-0.84
Indacaterol vs Fluticasone 3.30 1.44-7.55
Salmeterol vs Fluticasone 3.40 1.49-7.72
Glycopyrronium vs Fluticasone 3.44 1.47-8.07
Tiotropium vs Fluticasone 2.93 1.30-6.57
Umeclidinium vs Fluticasone 4.71 1.71-12.96
Fluticasone/Salmeterol vs Fluticasone 3.14 1.37-7.20 1.19 0.31-4.59 1.00 179.00
Tiotropium/Salmeterol vs Fluticasone 3.20 1.23-8.29
Indacterol/Tiotropium vs Fluticasone 2.41 1.02-5.73
Umeclidinium/Vilanterol vs Fluticasone 4.37 1.73-11.05
Tiotropium/Fluticasone/Salmeterol vs
Fluticasone 2.60 1.00-6.73
Indacaterol/Glycopyrronium vs Indacaterol 0.65 0.47-0.90
Indacaterol/Glycopyrronium vs Salmeterol 0.63 0.46-0.86
Indacaterol/Glycopyrronium vs Vilanterol 0.55 0.33-0.92
Indacaterol/Glycopyrronium vs
Umeclidinium 0.46 0.23-0.90
Indacaterol/Glycopyrronium vs
Fluticasone/Salmeterol 0.68 0.50-0.93 0.67 0.44-1.03 1.00 522.00
Umeclidinium/Vilanterol vs
Indacterol/Tiotropium 1.81 1.00-3.27
Common within-network heterogeneity
variance
0.01
Design-by-treatment interaction model
for inconsistency χ² (d.f., P-value,
heterogeneity variance)
13.51(12,0.333,0.00)
Mortality Overall: 23 studies (3 four-arm, 5 three-arm, 15 two-arm), 21 treatments, 33624 patients
Salmeterol/Fluticasone vs Placebo 0.50 0.29-0.88
Salmeterol vs Salmeterol/Fluticasone 2.25 1.20-4.20
Tiotropium vs Salmeterol/Fluticasone 1.84 1.07-3.15 1.84 1.07 1 1323
Vilanterol vs Salmeterol/Fluticasone 3.56 1.03-12.38
Common within-network heterogeneity 0.00
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variance
Design-by-treatment interaction model
for inconsistency χ² (d.f., P-value,
heterogeneity variance)
9.51 (12, 0.659,0.00)
Pneumonia: 19 studies (2 four-arm, 4 three-arm, 13 two-arm), 18 treatments, 28763 patients
Budesonide/Formoterol vs Placebo 8.39 1.16-60.69
Fluticasone/Salmeterol vs Placebo 2.45 1.48-4.07
Salmeterol vs Budesonide 2.15 1.00-4.61
Beclomethasone/Formoterol vs Budesonide 11.02
1.05-
116.02
Budesonide/Formoterol vs Budesonide 13.42
1.66-
108.72
Fluticasone/Salmeterol vs Budesonide 3.92 1.68-9.15
Budesonide/Formoterol vs Mometasone 25.06
1.24-
506.42
Budesonide/Formoterol vs Formoterol 2.72 1.38-5.37 2.72 1.38-5.37 2.00 1290.00
Fluticasone/Salmeterol vs Indacaterol 2.08 1.10-3.93
Fluticasone/Salmeterol vs Salmeterol 1.82 1.02-3.26
Fluticasone/Vilanterol vs Vilanterol 2.06 1.27-3.34 2.10 1.28-3.44 3.00 2031.00
Fluticasone/Salmeterol vs Glycopyrronium 2.24 1.14-4.41
Budesonide/Formoterol vs Tiotropium 7.97 1.10-57.95
Fluticasone/Salmeterol vs Tiotropium 2.33 1.43-3.78 2.20 1.33-3.62 1.00 1323.00
Mometasone/Formoterol vs
Budesonide/Formoterol 0.12 0.02-0.88
Indacaterol/Glycopyrronium vs
Budesonide/Formoterol 0.12 0.02-0.91
Indacaterol/Glycopyrronium vs
Fluticasone/Salmeterol 0.41 0.21-0.80 0.11 0.01-2.09 1.00 522.00
Common within-network heterogeneity
variance
0.00
Design-by-treatment interaction model
for inconsistency χ² (d.f., P-value,
heterogeneity variance)
4.88 (7, 0.675, 0.00)
Abbreviations: CI, Confidence Interval; d.f., degrees of freedom
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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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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,
budesonide/formoterol/ipratropium bromide; TIOT+Resp, Tiotropium Respimat (Soft Mist Inhaler).
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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, 2013 NO YES
Bateman, 2012 NO NO
Bateman , 2008 NO NO
Bedard, 2012 NO NO
Beier, 2013 NO NO
Beier, 2007 NO NO
Bogdan, 2011 NO NO
Bolukbas, 2011 NO NO
Bourbeau, 2007 YES NO
Bourbeau, 1998 YES YES
Boyd, 1997 NO NO
Briggs, 2005 NO NO
Buhl, 2011 NO NO
Burge, 2000 YES YES
Caillaud, 2007 NO NO
Calverley, 2010 YES YES
Calverley, 2003[34] YES YES
Calverley, 2007 YES YES
Calverley, 2003[53] NO NO
Calverley, 2003[119] YES YES
Calverley, 2008 NO YES
Campbell, 2007 NO NO
Casaburi, 2005 NO NO
Cazzola, 2007 NO NO
Cazzola, 2000 NO NO
Celli, 2003[146] NO NO
Celli, 2003[104] NO NO
Chan, 2007 NO YES
Chanez, 2010 NO NO
Chapman, 2011 NO NO
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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
Maltais , 2011 NO NO
Maltais , 2005 NO NO
Mansori, 2010 NO NO
Martinez, 2013 YES NO
Mathioudakis, 2013 NO NO
McNicholas, 2004 NO NO
Mirici, 2001 YES NO
Moita , 2008 NO NO
Mroz, 2013 NO NO
Nicolini , 2012 NO NO
Niewoehner, 2005 NO YES
O'Donnell, 2006 NO NO
O'Donnell, 2004 NO NO
Ozol, 2005 YES YES
Paggiaro, 1998 YES YES
Pasqua, 2010 NO NO
Pauwels, 1999 YES YES
Perng, 2009 NO NO
Powrie , 2007 NO YES
Pukhta, 2010 NO NO
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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
Wedzicha, 2013 NO YES
Wedzicha, 2008 NO YES
Weir, 1999 NO NO
Welte, 2008 NO NO
Welte , 2009 NO NO
Wesseling, 1991 NO NO
Wielders, 2013 NO NO
Wise, 2013 NO NO
Woolhouse , 2001 NO NO
Wouters, 2005 NO NO
Yao, 2014 NO NO
Yildiz, 2004 YES NO
Zheng , 2007 NO YES
Zhong, 2012 NO YES
Included unpublished studies (n= 20)
GlaxoSmithKline, 2005(SMS40298) NO NO
GlaxoSmithKline, 2005(SMS40315) NO NO
GlaxoSmithKline, 2005(SCO40034) NO NO
GlaxoSmithKline, 2006(SCO100540) NO YES
GlaxoSmithKline, 2005(SCO100470) YES YES
GlaxoSmithKline, 2005 (SCO30002) YES YES
da Fonseca Reis, 2010 NO NO
Cheng, 2012 NO NO
Sricharoenchai, 2008 NO NO
Ohar, 2013 NO YES
Dawber, 2005 NO NO
Maltais, 2010 NO NO
To, 2011 NO YES
GlaxoSmithKline, 2005 (SLMF4010) NO YES
Kelleher, 2011 NO NO
Calverley, 2003[186] NO YES
GlaxoSmithKline, 2008 YES NO
GlaxoSmithKline, 2008 (SCO40041) YES YES
Novartis, 2006 NO NO
Sekiya, 2012 NO NO
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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
Mortality, Pneumonia,
CVM (for NCT00782210 only)
2014
Koch A, Pizzichini E, Hamilton A, Hart L, Korducki L, De Salvo
MC et al. Lung function efficacy and symptomatic benefit of
olodaterol once daily delivered via Respimat® versus placebo and
formoterol twice daily in patients with GOLD 2–4 COPD: results
from two replicate 48-week studies. International journal of
chronic obstructive pulmonary disease. 2014; 9:697..
Olodaterol Phase III
clinical program in COPD; NCT00793624,
NCT00796653
olodaterol (5 μg Respimat) vs.
formoterol vs. placebo Mortality, Pneumonia
2014
Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A.
Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and
tiotropium 18 mcg in chronic obstructive pulmonary disease:
NCT01777334 umeclidinium/vilanterol vs.
tiotropium
Mortality, Pneumonia,
Serious arrhythmia, CVM
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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
Mod/severe exacerbation, Mortality,
Pneumonia, Serious arrhythmia
2014
Singh D, Jones PW, Bateman ED, Korn S, Serra C, Molins E et al.
Efficacy and safety of aclidinium bromide/formoterol fumarate
fixed-dose combinations compared with individual components
and placebo in patients with COPD (ACLIFORM-COPD): a
multicentre, randomised study. BMC pulmonary medicine. 2014;
14(1):178.
ACLIFORM-COPD; NCT01462942
aclidinium/formoterol (400/12
μg) vs. aclidinium vs. formoterol
vs. placebo
Mod/severe exacerbation, Mortality,
Pneumonia, Serious arrhythmia, CVM
2014
Singh D, Nicolini G, Bindi E, Corradi M, Guastalla D,
Kampschulte J et al. Extrafine Beclomethasone/formoterol
compared to Fluticasone/salmeterol Combination Therapy in
COPD. BMC pulmonary medicine. 2014; 14(1):43.
FUTURE;
NCT01245569
extrafine
beclomethasone/formoterol vs.
fluticasone/salmeterol
Mortality, Pneumonia,
Serious arrhythmia, CVM
2014
Trivedi R, Richard N, Mehta R, Church A. Umeclidinium in
patients with COPD: a randomised, placebo-controlled study.
European Respiratory Journal. 2014; 43(1):72-81.
NCT01387230 umeclidinium (125 μg) vs.
placebo Serious arrhythmia
2014
Wedzicha J, Singh D, Vestbo J, Paggiaro P, Jones P, Bonnet-
Gonod F et al. Extrafine beclomethasone/formoterol in severe
COPD patients with history of exacerbations. Respiratory
medicine. 2014; 108(8):1153-1162.
FORWARD
extrafine
beclomethasone/formoterol vs.
formoterol
Mortality, Pneumonia,
Serious arrhythmia
2014
ZuWallack R, Allen L, Hernandez G, Ting N, Abrahams R.
Efficacy and safety of combining olodaterol Respimat® and
tiotropium HandiHaler® in patients with COPD: results of two
randomized, double-blind, active-controlled studies. International
journal of chronic obstructive pulmonary disease. 2014; 9:1133.
ANHELTO 1 and
ANHELTO 2 ; NCT01694771,
NCT01696058
tiotropium (HandiHaler)+
olodaterol (Respimat) vs.
tiotropium (HandiHaler)+
placebo (Respimat)
Mortality
2013
Rennard SI, Scanlon PD, Ferguson GT, Rekeda L, Maurer BT, Gil
EG et al. ACCORD COPD II: a randomized clinical trial to
evaluate the 12-week efficacy and safety of twice-daily aclidinium
bromide in chronic obstructive pulmonary disease patients.
Clinical drug investigation. 2013; 33(12):893-904.
ACCORD COPD II; NCT01045161
placebo vs. aclidinium (400 μg) Mortality, Serious arrhythmia
Notes: *Outcomes from our NMA that were assessed as outcomes in the trial
Abbreviations: CVM, Cardiovascular related mortality; Mod/severe, Moderate/severe
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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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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist
Page 1 of 2
Section/topic # Checklist item Reported on page #
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.
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