Table 1.
Characteristics of included studies
| Source | Trial design | Treatment | Number of patients | Location | Inclusion/exclusion criteria | Background treatment | Study duration | Jadad score |
|---|---|---|---|---|---|---|---|---|
| Bateman27 | RCT, PC, DB, MC | Tiotropium, 5 μg, OD; Tiotropium, 10 μg, OD; Placebo | 670 667 653 |
South Africa, Europe, Canada | ≥ 40 years age; FEV1 ≤ 60%; FEV1 ≤ 70% of FVC; ≥ 10 pack-years; diagnosis of COPD and stable, moderate-to-severe airway obstruction | Allowed: oral and inhaled corticosteroids, theophylline, mucolytic agents and antileukotrienes, salbutamol. Patients on long-acting β-adrenergics and inhaled corticosteroids were switched to a monoproduct inhaled corticosteroid prior to run-in | 48 weeks | 3 |
| Bateman28 | RCT, PC, DB, PG, MC | Tiotropium, 5 μg, OD; Placebo | 1 952 1 965 |
336 centers; 31 countries | FEV1 ≤ 60% prebronchodilator; FEV1/FVC ≤ 70% prebronchodilator; ≥40 years age; ≥ 10 pack-years | Allowed: salbutamol pMDI; all respiratory medications were permitted Not allowed: inhaled anticholinergics |
48 weeks + 1 week run-in | 5 |
| Voshaar42 | RCT, PC, DB, MC | Tiotropium, 5 μg, OD; Tiotropium, 10 μg, OD; Ipratropium, 36 μg, OD; Placebo | 180 180 178 181 |
64 centers; Europe, South Africa, USA, Canada | FEV1 ≤ 60% prebronchodilator; FEV1/FVC ≤ 70%; ≥ 10 pack-years | Allowed: salbutamol, oral corticosteroids, orally inhaled corticosteroids, theophyllines, and mucolytics Not allowed: anticholinergics, inhaled β-adrenergics other than salbutamol, fixed combination inhalers |
12 weeks | 3 |
| Brusasco25 | RCT, PC, DB, MC, DD | Tiotropium, 18 μg, OD; Salmeterol, 50 μg, BID; Placebo | 402 405 400 |
18 countries | FEV1 ≤ 65%; FEV1/FVC ≤ 70%; > 40 years of age; > 10 pack-years | NR | 24 weeks | 4 |
| Casaburi30 | RCT, PC, DB, MC | Tiotropium, 18 μg, OD; Placebo | 279 191 |
25 centers; USA | FEV1 ≤ 65%; FEV1/FVC ≤ 70%; ≥40 years of age; diagnosis of COPD defined by ATS; smoking history of > 10 pack-years | Allowed: stable doses of theophylline, ICS, oral prednisone Not allowed: other inhaled or oral bronchodilators |
13 weeks | 3 |
| Casaburi31 | 2 RCTs, PC, DB, MC | Tiotropium; 18 μg; OD; Placebo | 550 371 |
50 centers | FEV1 ≤ 65%; FEV1/FVC ≤ 70% | Allowed: stable doses of theophylline, ICS, oral prednisone | 56 weeks | 3 |
| Chan32 | RCT, PC, DB, MC | Tiotropium, 18 μg, OD; Placebo | 608 305 |
101 centers; Canada | FEV1 ≤ 65%; FEV1/FVC ≤ 70%; ≥ 1 exacerbation previous year but not 6 weeks prior to randomization | Allowed: stable dose oral corticosteroids, ICS, theophylline preparations, mucolytic preparations (not containing bronchodilators), LABAs | 48 weeks | 4 |
| Covelli33 | RCT, PC, DB, MC | Tiotropium, 18 μg, OD; Placebo | 100 96 |
12 centers; USA | FEV1 ≤ 60%; FEV1/FVC ≤ 70% excluded if exacerbation in prior 6 weeks | Allowed: ICS, LABAs and theophyllines Not allowed: cromones, leukotriene antagonists, and inhaled anticholinergics |
12 weeks | 4 |
| Donohue34 | RCT, PC, DB, MC, DD | Tiotropium, 18 μg, OD; Salmeterol, 50 μg, BID; Placebo | 209 213 201 |
39 countries; 12 countries | FEV1 ≤ 60%; FEV1/FVC ≤ 70%; ≥40 years of age; smoking history of > 10 pack-years | Allowed: usual ICS and oral steroids Not allowed: Inhaled anticholinergic LABAs |
24 weeks | 4 |
| Donohue35 | RCT, PC, DB,** MC, DD | Indacaterol, 150 μg, OD; Indacaterol, 300 μg, OD; Tiotropium, 18 μg, OD; Placebo | 420 418 420 425 |
USA, Europe | FEV1 30%–80% postbronchodilator; FEV1/FVC < 70%; ≥40 years age; ≥20 pack-years; diagnosis of moderate-to-severe COPD (GOLD criteria) | ICS monotherapy, albuterol, treatment with anticholinergic bronchodilators or [β2-agonists was discontinued with appropriate washout; patients receiving fixed-combination [β2-agonist/ICS were switched to ICS monotherapy at an equivalent dose | 26 weeks | 4 |
| Moita36 | RCT, PC, DB, MC | Tiotropium, 18 μg, OD; Placebo | 147 164 |
31 centers; Portugal | FEV1 ≤ 70%; FEV1/FVC ≤ 70%, excluded if ≥3 exacerbations previous year or exacerbation in 6 weeks prior | Allowed: LABAs, theophylline, mucolytics, ICS, stable doses oral corticosteroids. Temporary increases in theophylline or oral steroids for exacerbations; Not allowed: theophylline 24-hour preparations |
12 weeks | 4 |
| Niewoehner37 | RCT, PC, DB, MC | Tiotropium, 18 μg, OD; Placebo | 914 915 |
26 centers; USA | FEV1 ≤ 60%; FEV1/FVC ≤ 70% excluded if not recovered from exacerbation ≥30 days prior | Allowed: all other respiratory medications (including ICS and LABAs) Not allowed: open-label anticholinergic bronchodilator |
24 weeks | 4 |
| Tashkin (UPLIFT)38 | RCT, PC, DB, MC | Tiotropium, 18 μg, OD; Placebo | 2 987 3 006 |
490 centers; 37 countries | FEV1 ≤ 70%; FEV1/FVC ≤ 70%; excluded if exacerbation 4 weeks prior | Allowed: all respiratory medications, except other inhaled anticholinergic drugs | 4 years | 5 |
| Tonnel (TIPHON)35 | RCT, PC, DB, MC | Tiotropium, 18 μg, OD; Placebo | 266 288 |
123 centers; France | FEV1 20%–70%; FEV1/SVC ≤ 70% | Allowed: stable doses of theophylline preparations (excluding 24-hour preparations), mucolytics, ICS, and oral steroids | 36 weeks | 5 |
| Verkindre40 | RCT, PC, DB, MC | Tiotropium; 18 μg, OD; Placebo | 46 54 |
10 centers; France | FEV1 ≤ 50%; FEV1/FVC ≤ 70%; residual volume ≥ 125%; excluded if unstable doses oral corticosteroid 6 weeks prior | Allowed: stable doses oral corticosteroids, ICS, theophylline preparations, mucolytic agents Not allowed: use of SABAs, oral ß2-agonists, or LABAs |
12 weeks | 3 |
| Vogelmeier41 | RCT, PC, DB,* MC | Formoterol, 12 meg BID + Tiotropium, 18 meg, OD; Formoterol, 12 μg, BID; Tiotropium, 18 μg, OD; Placebo | 207 210 221 209 |
86 centers; 8 countries Europe | FEV1 < 70%; FEV1/FVC < 70%; stable COPD; aged 40 years at COPD onset; ≥ 10 pack-years | Allowed: salbutamol, ICS monotherapy | 24 weeks | 3 |
| CSR ACCORD I22 | RCT, MC, PC, DB | Aclidinium, 200 μg, BID; Aclidinium, 400 μg, BID; Placebo | 185 190 187 |
106 centers; USA, Canada | ≥40 years of age, ≥ 10 pack-years; stable, moderate-to-severe COPD as defined by criteria of GOLD; FEV1 30%–80% postsalbutamol; FEV1/FVC < 70% Excluded: patients with asthma; respiratory tract infection or COPD exacerbation in the 6 weeks before visit 1 |
ICS allowed; LABA discontinued | 12 weeks | 4 |
| CSR ACCORD II24 | RCT, MC, PC, DB | Aclidinium, 200 μg, BID; Aclidinium, 400 μg, BID; Placebo | 184 178 182 |
103 centers; USA Canada | ≥40 years of age, ≥ 10 pack-years; stable, moderate-to-severe COPD as defined by criteria of GOLD; FEV1 30%–80% postsalbutamol; FEV1/FVC < 70% Excluded: patients with asthma; respiratory tract infection or COPD exacerbation in the 6 weeks before visit 1 |
ICS allowed; LABA discontinued | 12 weeks | 4 |
| CSR ATTAIN25 | RCT, MC, PC, DB | Aclidinium, 200 μg, BID; Aclidinium, 400 μg, BID; Placebo | 277 269 273 |
103; Europe, South America, Russia, South Africa | ≥ 10 pack-years; FEV1 30%–80% postsalbutamol; FEV1/FVC < 70% | NR | 24 weeks | 4 |
| GLOW 143 | RCT, DB, PC, MC | Glycopyrronium, 50 meg, OD; Placebo | 552 270 | 128; US, Europe, Australia, SE Asia, South America | postbronchodilator FEV1 ≥ 30% and < 80%; postbronchodilator FEV1/FVC < 0.7; ≥ 10 pack-years | Allowed: ICS monotherapy, short acting β2-agonists as required Not allowed: LABAs, LAMAs, theophylline |
26 weeks | 3 |
| GLOW 244 | RCT, MC, PC, DB** | Glycopyrronium, 50 μg, OD; Tiotropium, 18 μg, OD; Placebo | 529 268 269 |
NR | Men and woman aged ≥40 years, smoking history ≥10 pack-years, moderate-to-severe stable COPD (2008 GOLD guidelines), postbronchodilator FEV1 ≥ 30% and < 80% of the predicted normal, and postbronchodilator FEV1/FVC < 0.70 were enrolled | Allowed: concomitant medications (inhaled or intranasal corticosteroids and H1 antagonists) and salbutamol/albuterol inhaler to be used as rescue medication during the study Not allowed: LABA LAMA |
52 weeks | 3 |
Notes:
*
Tiotropium versus placebo is not DB;
**
open label for tiotropium arm. + indicates that the first two lines of this cell (Formoterol and Tiotropium) were administered simultaneously.
Abbreviations: BID, twice daily; COPD, chronic obstructive pulmonary disease; CSR, clinical study report; UPLIFT, Understanding Potential Long-term Impacts on Function with Tiotropium; TIPHON, Tiotropium: Influence sur la Perception de l’amelioration des activites Habituelles Objectivee par une echelle Numerique; ACCORD, ACIidinium in Chronic Obstructive Respiratory Disease COPD; ATTAIN, Aclidinium To Treat Airway obstruction IN COPD patients; GLOW, GLycopyrroniurn bromide in COPD airways clinical study 1; DB, double blind; DD, double dummy; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global initiative for chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; LABA, long acting β-agonist; LAMA, long-acting muscarinic antagonist; MC, multicenter; NR, not reported; OD, once daily; OL, open label; PC, placebo controlled; RCT, randomized controlled trial; S, south; SE, southeast; USA, United States of America; pMDI, pressurized metered-dose inhaler; ATS, American Thoracic Society.