Appendix 1: Existing systematic reviews considered to identify randomized trials
1. Nannini L, Cates C, Lasserson T, Poole P: Combined corticosteroid and longacting beta-agonist in one inhaler versus placebo for chronic obstructive
pulmonary disease. Cochrane Database Syst Rev 2007, CD003794.
2. Yang IA, Fong KM, Sim EH, Black PN, Lasserson TJ: Inhaled corticosteroids for
stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2007,
CD002991.
3. Wilt TJ, Niewoehner D, Macdonald R, Kane RL: Management of Stable Chronic
Obstructive Pulmonary Disease: A Systematic Review for a Clinical Practice
Guideline. Annals of internal medicine 2007, 147(9):639-653.
4. Nannini L, Cates C, Lasserson T, Poole P: Combined corticosteroid and longacting beta-agonist in one inhaler versus long-acting beta-agonists for chronic
obstructive pulmonary disease. Cochrane Database Syst Rev 2007, CD006829.
5. Nannini L, Cates C, Lasserson T, Poole P: Combined corticosteroid and longacting beta-agonist in one inhaler versus inhaled steroids for chronic
obstructive pulmonary disease. Cochrane Database Syst Rev 2007, CD006826.
6. Appleton S, Poole P, Smith B, Veale A, Lasserson TJ, Chan MM. Long-acting beta2agonists for poorly reversible chronic obstructive pulmonary disease. Cochrane
Database Syst Rev. 2006, CD001104.
1
Appendix 2: Excluded studies
Study
Reason for
exclusion
1.
Aalbers R, Ayres J, Backer V, et al. Formoterol in patients with chronic
Exacerbations
obstructive pulmonary disease: a randomized, controlled, 3-month trial. European
not assessed.
Respiratory Journal 2002;19(5):936-43.
2.
Auffarth B, Postma DS, De Monchy JGR, Van der Mark TW, Boorsma M,
Exacerbations
Koeter GH. Effects of inhaled budesonide on spirometric values, reversibility, airway
not assessed.
responsiveness, and cough threshold in smokers with chronic obstructive lung disease.
Thorax 1991(5):372-7.
3.
Casaburi R, Briggs DD, Jr., Donohue JF, Serby CW, Menjoge SS, Witek TJ, Jr.
Exacerbations
The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-
not assessed.
week multicenter trial. The US Tiotropium Study Group. Chest 2000;118(5):1294-302.
4.
Celli B, ZuWallack R, Wang S, Kesten S. Improvement in resting inspiratory
Exacerbations
capacity and hyperinflation with tiotropium in COPD patients with increased static lung
not assessed.
volumes. Chest;2003 Nov; 124(5):1743-8.
5.
Fukuchi Y, Nagai A, Seyama K, et al. Clinical efficacy and safety of transdermal
Exacerbations
tulobuterol in the treatment of stable COPD: An open-label comparison with inhaled
not assessed.
salmeterol. Treatments in Respiratory Medicine 2005(6):447-55.
6.
Gupta RK, Chhabra SK. An evaluation of salmeterol in the treatment of chronic
Exacerbations
obstructive pulmonary diseases. Indian Journal of Chest Diseases & Allied Sciences
not assessed.
2002;44(3):165-72.
7.
Jones PW, Bosh TK. Quality of life changes in COPD patients treated with
salmeterol.
American
Journal
of
Respiratory
&
Critical
Care
Exacerbations
Medicine
not assessed.
McNicholas WT, Calverley PM, Lee A, Edwards JC, Tiotropium Sleep Study in
No comparison
1997;155(4):1283-9.
8.
CI. Long-acting inhaled anticholinergic therapy improves sleeping oxygen saturation in
of different
COPD. European Respiratory Journal 2004;23(6):825-31.
9.
drugs.
Mirici A, Bektas Y, Ozbakis G, Erman Z. Effect of inhaled corticosteroids on
Exacerbations
respiratory function tests and airway inflammation in stable chronic obstructive
not assessed.
pulmonary disease: A randomised, double-blind, placebo-controlled clinical trial.
Clinical Drug Investigation 2001(12):835-42.
2
10.
O'Donnell DE, Fluge T, Gerken F, et al. Effects of tiotropium on lung
Exacerbations
hyperinflation, dyspnoea and exercise tolerance in COPD. European Respiratory
not assessed.
Journal 2004;23(6):832-40.
11.
Ozol D, Aysan T, Solak ZA, Mogulkoc N, Veral A, Sebik F. The effect of inhaled
Exacerbations
corticosteroids on bronchoalveolar lavage cells and IL-8 levels in stable COPD patients.
not assessed.
Respiratory Medicine 2005;99(12):1494-500.
12.
Pauwels RA, Lofdahl CG, Laitinen LA, et al. Long-term treatment with inhaled
Exacerbations
budesonide in persons with mild chronic obstructive pulmonary disease who continue
not assessed.
smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary
Disease. New England Journal of Medicine 1999;340(25):1948-53.
13.
Renkema TE, Schouten JP, Koeter GH, Postma DS. Effects of long-term
treatment with corticosteroids in COPD. Chest 1996;109(5):1156-62.
≥1 exacerbation
per person not
available.
14.
with
Rutgers SR, Koeter GH, van der Mark TW, Postma DS. Short-term treatment
budesonide
does
not
improve
hyperresponsiveness
to
adenosine
5'-
Exacerbations
not assessed.
monophosphate in COPD. American Journal of Respiratory & Critical Care Medicine
1998; 157: 880-886.
15.
Thompson AB, Mueller MB, Heires AJ, et al. Aerosolized beclomethasone in
Exacerbations
chronic bronchitis. Improved pulmonary function and diminished airway inflammation.
not assessed.
American Review of Respiratory Disease 1992;146(2):389-95.
16.
Verhoeven GT, Hegmans JPJJ, Mulder PGH, Bogaard JM, Hoogsteden HC,
Exacerbations
Prins JB. Effects of fluticasone propionate in COPD patients with bronchial
not assessed.
hyperresponsiveness. Thorax 2002(8):694-700.
17.
Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Long-term effect of
inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a
randomised controlled trial. Lancet 1999;353(9167):1819-23.
18.
≥1 exacerbation
per person not
available.
Yildiz F, Basyigit I, Yildirim E, Boyaci H, Ilgazli A. Does addition of inhaled
Exacerbations
steroid to combined bronchodilator therapy affect health status in patients with COPD?
not assessed.
Respirology 2004;9(3):352-5.
19.
The Lung Health Study: Effect of inhaled triamcinolone on the decline in
Exacerbations
pulmonary function in chronic obstructive pulmonary disease. The New England journal
not assessed.
of medicine 2000;343(26):1902-9.
3
Appendix 3: Quality assessment
Description of
Method of
randomisation
Concealment of
random
allocation
Inclusion
criteria
specified
Blinding of
patient
Blinding of
treatment
provider
Intention to
treat analysis
Baumgartner 2007(48)
0
0
1
1
1
1
Beeh 2006(21)
0
0
1
1
1
1
Bourbeau 1998(22)
1
1
1
1
1
0
Boyd 1997(23)
0
0
1
1
1
0
Briggs 2005(49)
0
0
1
1
1
0
Brusasco 2003(24)
0
0
1
1
1
0
Burge 2000(25)
1
1
1
1
1
0
Calverley 2003(26)
1
1
1
1
1
1
Calverley 2003(27)
0
0
1
1
1
1
Calverley 2003(28)
0
0
1
1
1
0
Calverley 2007(14)
1
1
1
1
1
1
Campbell 2005(29)
1
0
1
1
1
1
Casaburi 2002(50)
0
0
1
1
1
0
Celli 2003(30)
1
1
1
1
1
0
Chapman 2002(31)
1
0
1
1
1
1
Covelli 2004(32)
0
0
1
1
1
0
Dahl 2001(33)
0
0
1
1
1
1
Dusser 2006(34)
0
0
1
1
1
1
Hanania 2003(51)
0
0
1
1
1
0
Kardos 2007(52)
0
1
1
1
1
1
Littner 2000(36)
0
0
1
1
1
0
Mahler 1999(37)
0
0
1
1
1
0
Mahler 2002(38)
0
0
1
1
1
0
Niewoehner 2005(39)
1
1
1
1
1
1
Paggiaro 1998(40)
1
1
1
1
1
1
Paggiaro 2006(41)
0
0
1
1
1
0
Rossi 2002(42)
0
0
1
1
1
1
Stockley 2006(43)
1
1
1
1
1
1
Szafranski 2000(44)
0
0
1
1
1
1
Van der Boom 2001(53)
0
0
0
0
0
0
Van der Valk 2002(45)
1
0
1
1
1
1
Van Noord 2000(46)
0
0
1
1
1
0
Wadbo 2002(47)
0
0
0
0
0
0
Wedzicha 2008(54)
1
1
1
1
1
1
Weir 1999(55)
0
0
0
0
0
0
Study
0 = not adequalety described; 1 = adequalety described
4
Appendix 4: Approach to create new data set with n data entries where n is the
total number of included patients
Step 1: 2x2 table
Study 1: 805 patients with mean age 64 years and mean FEV1 38% predicted
Number of patients
without exacerbation
with exacerbation
Placebo
a: 244
b: 156
Salmeterol
c: 263
d: 142
Odds ratio: 0.84
Step 2: Creating new data set with individual data entries
Study
a
Treatment
0
64
38
1
Placebo
0
64
38
1
Placebo
0
64
38
.
.
.
.
.
.
.
.
.
.
.
1
Placebo
1
64
38
1
Placebo
1
64
38
1
Placebo
1
64
38
.
.
.
.
.
.
.
.
.
1
.
.
1
Salmeterol
0
64
38
1
Salmeterol
0
64
38
1
Salmeterol
0
64
38
1
.
.
.
.
.
.
.
.
.
.
.
1
Salmeterol
1
64
38
1
Salmeterol
1
64
38
1
Salmeterol
1
64
38
1
.
.
.
.
.
.
.
.
.
.
.
 another 153 entries
 another 260 entries
d
 another 139 entries
a
FEV1
Placebo
 another 241 entries
c
Age
1
1
b
Exacerbation
2
Tiotroopium bromide
0
62
46
2
Tiotroopium bromide
0
62
46
2
Tiotroopium bromide
0
62
46
.
.
.
.
.
.
.
.
.
2
.
.
 another 397 entries
5