Pharmacotherapies for chronic obstructive pulmonary disease: a multiple treatment comparison meta-analysis

Figures & data

Figure 1 Flow diagram of included studies.

Table 1A Overview of included clinical trials that provide data on the total number of exacerbations and/or the mean annual rate of exacerbations

Reference	Number of patients	Treatment comparisons	Baseline forced expiratory volume in 1 second (FEV1) predicted	Exacerbations	Background treatment	Duration of treatment	Location
Paggiaro et al 1998	139 142	Placebo Fluticasone propionate 250 μg twice daily	FEV1 35%–90%	Defined as worsening of symptoms, requiring changes to normal treatment, including antimicrobial therapy, short courses of oral steroids, and other bronchodilator therapy.	Patients could take short-acting beta 2-agonists for the relief of symptoms as required. Other COPD medications, such as anticholinergics and xanthine derivatives, could be continued without dose changes.	6 months	13 European countries, New Zealand, and South Africa
Burge et al 2000	370 372	Placebo Fluticasone propionate 500 μg twice daily	FEV1 < 85%	Defined as worsening of respiratory symptoms that required treatment with oral corticosteroids or antibiotics, or both.	Nasal and ophthalmic corticosteroids, theophyllines, and all other bronchodilators were allowed during the study.	36 months	18 hospitals in the United Kingdom
Casaburi et al 2002	371 550	Placebo Tiotropium 18 μg once daily	FEV1 ≤ 65%	Defined as a complex of respiratory events (cough, wheezing, dyspnea or sputum production) lasting >3 days and generally requiring treatment with antibiotics and/or oral steroids.	Albuterol metered-dose inhaler, as needed, stable doses of theophylline (ie, unchanging doses that had been used for ≥6 weeks prior to entry), inhaled glucocorticosteroids and the equivalent of ≤10 mg/day oral prednisone throughout the study.	12 months	50 clinical centers
Rossi et al 2002	200 425	Placebo Formoterol	FEV < 70%	Defined as undergoing a course of additional therapy (ie, corticosteroids, antibiotics, or oxygen); and (severe), COPD-related hospitalizations.	Inhaled salbutamol (up to eight puffs per day) was allowed as the rescue medication. Short courses of antibiotics, oral corticosteroids, and/or oxygen were permitted in case of exacerbations or respiratory infection up to two times during the study.	12 months	81 centers worldwide
Brusasco et al 2003	400 402 405	Placebo Tiotropium 18 μg once daily Salmeterol 50 μg twice daily	FEV1 ≤ 65%	Defined as a complex of respiratory symptoms (new onset or an increase in at least one of cough, sputum, dyspnea, wheeze, chest discomfort) lasting at least 3 days and usually associated with therapeutic intervention.	Oral steroid bursts or theopylline for exacerbations.	6 months	18 countries
Calverley et al 2003	256 254 255 257	Placebo Budesonide/formoterol 2 × 160 μg/4.5 μg twice daily Formoterol 2 × 4.5 μg twice daily Budesonide 2 × 200 μg twice daily	FEV1 < 50%	Defined as symptoms requiring medical intervention (oral antibiotics and/or corticosteroids or hospitalization).	Oral corticosteroids (maximum 3 weeks per course) and antibiotics in the event of exacerbations. Parenteral steroids and/or nebulized treatment (single injections/inhalations) at emergency visits.	12 months	109 centers in 15 countries
Calverley et al 2003	361 372 374 358	Placebo Salmeterol 50 μg twice daily Fluticasone 500 μg twice daily Salmeterol/flucticasone 50/500 μg twice daily	FEV1 25%–70%	Defined as a worsening of symptoms that require treatment with antibiotics, oral corticosteroids, or both.	Inhaled salbutamol as relief medication throughout the study, and regular treatment with anticholinergics, mucolytics, and theophylline as needed. All non-COPD medications could be continued if the dose remained constant whenever possible, and if their use would not be expected to affect lung function.	12 months	196 hospitals in 25 countries
Szafranski et al 2003	205 201 208 198	Placebo Formoterol 4.5 μg twice daily Budesonide/formoterol 160/4.5 μg twice daily Budesonide 200 μg twice daily	FEV1 ≤ 50%	Severe exacerbations were defined as the use of oral steroids and/or antibiotics and/or hospitalization due to respiratory symptoms. Mild exacerbations were defined as a day with ≥4 inhalations of reliever medication above the mean run-in use.	Terbutaline 0.5 mg was allowed (no preventative medications allowed).	12 months	89 centers in 11 countries
Niewoehner et al 2005	915 914	Placebo Tiotropium 18 μg once daily	FEV1 < 60%	A complex of respiratory symptoms (increase or new-onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids, hospitalization, or both.	All other respiratory medications (including inhaled corticosteroids and long-acting beta-agonists). Also, antibiotics and systemic steroid prescriptions for exacerbations.	6 months	26 Veterans Affairs medical centers in the United States
Rabe et al 2005 (M2-107)	280 1131	Placebo Roflumilast 250 μg or 500 μg once daily	FEV1 30%–80%	Mild exacerbations were defined as an increase in bronchodilator use on two or more consecutive days (>4 puffs of salbutamol) without the need for additional health care contact. Moderate exacerbations were defined as home management with administration of oral glucocorticosteroid treatment or unscheduled health care contact, or both. Severe exacerbations were defined as the need for hospital admission (or emergency room treatment).	Concomitant respiratory medications permitted included salbutamol as rescue therapy, and short-acting anticholinergics at a constant daily dose. Oral corticosteroids were also permitted for the treatment of exacerbations.	6 months	159 centers in 11 countries
Dusser et al 2006	510 500	Placebo Tiotropium 18 μg once daily	FEV1 30%–65%	Defined as the onset of at least one clinical descriptor (worsening of dyspnea, cough, or sputum production; appearance of purulent sputum; fever (>38°C); appearance of new chest radiograph abnormality) lasting ≥2 days and requiring a new prescription or an increase in dose of beta 2 agonists, antibiotics, corticosteroids, or bronchodilators.	Any additional medication deemed necessary to treat exacerbations (excluding anticholinergics and long-acting beta 2-agonists).	12 months	177 centers in France
Stockley et al 2006	318 316	Placebo Salmeterol 50 μg twice daily	FEV1 < 70%	Defined as a worsening of symptoms requiring a change in medications.	Doses up to 2000 μg/day beclomethasone dipropionate or equivalent or 1000 μg/day fluticasone propionate were allowed during the study, as were usual treatments such as methylxanthines, short-acting anticholinergic agents, and mucolytics.	12 months	19 European countries
Aaron et al 2007	156 148 145	Tiotropium 18 μg once daily plus placebo Tiotropium 18 μg once daily plus salmeterol 2 × 25 μg twice daily Tiotropium 18 μg once daily plus fluticasone/salmeterol 2 × 250/25 μg twice daily	FEV1 < 65%	Defined according to the 2000 Aspen Lung Conference Consensus definition. An exacerbation is “a sustained worsening of the patient’s respiratory condition, from the stable state and beyond normal day-to-day variations, necessitating a change in regular medication in a patient”.	Inhaled abuterol for use when necessary. Use of any treatment with inhaled corticosteroids, long-acting beta 2-agonists, and anticholinergics not permitted. Therapy with other respiratory medications, such as oxygen, antileukotrienes, and methylxanthines permitted.	12 months	27 medical centers in Canada
Calverley et al 2007	1524 1521 1534 1533	Placebo Salmeterol 50 μg twice daily Fluticasone 500 μg twice daily Salmeterol/flucticasone 50 μg/500 μg twice daily	FEV1 < 60%	Defined as a symptomatic deterioration requiring treatment with antibiotic agents, systemic corticosteroids, hospitalization, or a combination.	Continuation of comedications, except for corticosteriods and inhaled long-acting bronchodilators.	36 months	444 centers in 42 countries
Calverley et al 2007 (M2-112)	753 760	Placebo Roflumilast 500 μg once daily	FEV1 ≤ 50%	Moderate exacerbations were defined as symtomatic deteriorations treated with systemic corticosteroids and/or antibiotics. Severe exacerbations were defined as symptoms requiring hospitalizaiton.	Inhaled corticosteroids of 2000 μg or less, beclomethasone dipropionate or equivalent and short-acting anticholinergics allowed. Salbutamol available to patients as rescue therapy.	12 months	159 centers in 14 countries
Chan et al 2007	305 608	Placebo Tiotropium 18 μg once daily	FEV1 < 65%	Defined as a complex of respiratory symptoms (new onset or increase in at least one of cough, sputum, sputum purulence, dyspnea, wheeze, chest discomfort) lasting at least three days and requiring treatment with antibiotics and/or systemic steroids.	Permitted oral corticosteroids (at a stable dose of 10 mg or less of prednisone daily or equivalent), stable doses of inhaled corticosteroids, therophylline preparations, mucolytic preparations (not containing bronchodilators), LABA and, for acute symptom relief, salbutamol as needed.	48 weeks	101 centers in Canada
Kardos et al 2007	487 507	Salmeterol 50 μg twice daily Salmeterol/flucticasone 50/500 μg twice daily	FEV1 < 50%	Defined as an increase in or the new onset of respiratory symptoms that may require oral steroids and/or antibiotics and/or hospitalization.	All non-COPD medications, including pre-existing selective beta-blocker therapy, could be continued if the dose remained constant. Acute moderate and severe exacerbations treated with systemic corticosteroids and/or antibiotics.	44 weeks	95 respiratory centers in Germany
Powrie et al 2007	73 69	Placebo Tiotropium 18 μg once daily	FEV1 < 80%	Defined as the presence, for ≥2 days consecutively, of an increase in any two major symptoms (dyspnea, sputum purulence, and sputum volume) or in one major and one minor symptom (wheeze, sore throat, cough, and symptoms of a common cold).	Except for other anticholinergics, pulmonary drugs were permitted.	12 month	Single center
Ferguson et al 2008	385 391	Salmeterol 50 μg twice daily Fluticasone propionate/salmeterol 250/50 μg twice daily	FEV1 ≤ 50%	Defined as the worsening of two or more major symptoms or one major and one minor symptom for two or more consecutive days.	Oral corticisteroids and antibiotics were allowed for the acute treatment of exacerbations.	12 months	94 research sites in the United States and Canada
Tashkin et al 2008	3006 2987	Placebo Tiotropium 18 μg once daily	FEV1 < 70%	Defined as an increase in or the new onset of >1 respiratory symptom (cough, sputum, sputum purulence, wheezing, or dyspnea) lasting ≥3 days and requiring an antibiotic or corticosteroid.	All respiratory medication allowed, except inhaled anticholinergic drugs.	48 months	487 centers in 37 countries
Tonnel et al 2008	288 266	Placebo Tiotropium 18 μg once daily	FEV1 20%–70%	Defined as a sustained worsening of the patient’s COPD (from the stable state and beyond normal day-to-day variation) that was acute in onset and necessitated a change in regular medication.	Use of theophylline preparations, mucolytics, inhaled corticosteroids, and oral steroids were allowed if dosage was stabilized for 6 or more weeks before study entry. One 10-day course of oral steroids was permitted for treatment exacerbations. Antibiotics could also be used for treatment of exacerbations.	9 months	123 centers in France
Wedzicha et al 2008	658 665	Salmeterol/flucticasone 50/500 μg twice daily Tiotropium 18 μg once daily	FEV1 < 50%	Defined as symptoms that required treatment with oral corticosteroids and/or antibiotics or required hospitalization.	Short acting inhaled beta-agonists for relief therapy and standardized short courses of oral systemic corticosteroids and/or antibiotics where indicated for treatment of exacerbations.	24 months	179 centers in 20 countries
Anzueto et al 2009	393 385	Salmeterol 50 μg twice daily Fluticasone propionate/salmeterol 250/50 μg twice daily	FEV1 ≤ 50%	Defined as the worsening of two or more major symptoms or 1 major and one minor symptom for two or more consecutive days.	Albuterol was provided as-needed. Ipratropium was permitted throughout the study. Oral corticosteroids and antibiotics were allowed for the treatment of exacerbations.	12 months	98 research centers in the United States and Canada
Calverley et al 2009 (M2-124 and M2-125)	1554 1537	Placebo Roflumilast 500 μg once daily	FEV1 ≤ 50%	Moderate exacerbations were defined as symptoms requiring corticosteroids. Severe exacerbations were defined as symptoms requiring hospitalization or death.	Short-acting beta 2-agonists as needed. Long-acting and short-acting anticholinergic drugs at stable doses.	12 months	246 centers in 10 countries (M2-124) and 221 centers in 8 countries (M2-125)
Fabbri et al 2009 (M2-127)	467 466	Salmeterol 50 μg twice daily plus placebo Salmeterol 50 μg twice daily plus roflumilast 500 μg once daily	FEV1 40%–70%	Mild exacerbations were defined as the need for an increase in rescue medication of at least three puffs per day on at least two consecutive days. Moderate exacerbations were defined as the need for oral corticosteroids (not antibiotics). Severe exacerbations were defined as the need for treatment in hospital or death.	Besides tiotropium, no inhaled corticosteroids, shortacting anticholinergic drugs, other long-acting bronchodilator drugs, theophylline, or other respiratory drugs were allowed.	6 months	85 centers in 7 countries
Fabbri et al 2009 (M2-128)	372 371	Tiotropium 18 μg once daily plus placebo Tiotropium 18 μg once daily plus roflumilast 500 μg once daily	FEV1 40%–70%	Mild exacerbations were defined as the need for an increase in rescue medication of at least three puffs per day on at least two consecutive days. Moderate exacerbations were defined as the need for oral corticosteroids (not antibiotics). Severe exacerbations were defined as the need for treatment in hospital or death.	Besides tiotropium, no inhaled corticosteroids, short-acting anticholinergic drugs, other long-acting bronchodilator drugs, theophylline, or other respiratory drugs were allowed.	6 months	85 centers in 7 countries

Table 1B Overview of additional included clinical trials that provide data on the number of patients with at least one exacerbation

Reference	Number of patients	Treatment comparisons	Baseline forced expiratory volume in 1 second (FEV1) predicted	Exacerbations	Background treatment	Duration of treatment	Location
Bourbeau et al 1998	40 39	Placebo Budesonide 400 μg twice daily	FEV1 < 65%	Exacerbations were defined as worsening of symptoms leading to treatment.	Regular treatment with at least one bronchodilator.	12 months	1 outpatient clinic in Canada
Chapman et al 2002	207 201	Placebo Salmeterol 50 μg twice daily	FEV1 ≤ 85%	Defined as a worsening of respiratory disease requiring a change in medication and/or hospital care, emergency room care, or an unscheduled outpatient visit.	Methylxanthines, anticholinergic agents and inhaled steroids were allowed.	6 months	28 centers in Canada, 6 in Denmark, 3 in the Netherlands, 4 in Russia, 4 in Sweden, and 7 in the United Kingdom
Vogelmeier et al 2008	203 204 209 196	Placebo Formoterol 10 μg twice daily Tiotropium 18 μg once daily Formoterol 10 μg twice daily plus Tiotropium 18 μg once daily	FEV1 < 70%	Defined as at least two COPD symptoms, possibly requiring additional treatment or hospitalizations.	Salbutamol was permitted as rescue medication. Inhaled corticosteroids at stable doses were also allowed.	6 months	30 centers in Germany, 19 in Italy, 9 in the Netherlands, 9 in Russia, 7 in Poland, 4 in Czech Republic, 4 in Spain, and 4 in Hungary

Note: These studies are in addition to those listed in Table 1.

Figure 2 Diagram displaying the network of 10 treatments involved in the MTC analyses of the COPD data. Each treatment is a node in the network. The links between nodes are used to indicate a direct comparison between pairs of treatments. The numbers shown along the link lines indicate the number of trials comparing pairs of treatments head-to-head.

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Figure 3 Comparisons of all 10 different treatments for management of COPD. Rate ratios and associated 95% confidence intervals were obtained from a random-effects MTC model without covariates.

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Appendix Table 7 Random effects, direct (head to head) evaluation using DerSimmonian Laird random-effects model. Exacerbation rates

Treatment vs Comparator	Random-effects direct evidence
	Rate ratio	95% CI
Roflumilast vs placebo	0.85	(0.78–0.93)
LABA vs placebo	0.87	(0.79–0.96)
LAMA vs placebo	0.74	(0.64–0.84)
ICS vs placebo	0.81	(0.74–0.90)
ICS + LABA vs placebo	0.72	(0.66–0.79)
LAMA vs LABA	0.91	(0.80–1.06)
Roflumilast + LABA vs LABA	0.79	(0.70–0.91)
ICS + LABA vs LABA	0.81	(0.75–0.86)
ICS + LABA + LAMA vs LAMA	0.91	(0.75–1.11)
Roflumilast + LAMA vs LAMA	0.83	(0.72–0.97)
LABA + LAMA vs LAMA	1.07	(0.94–1.22)
ICS + LABA vs LAMA	0.97	(0.93–1.02)
ICS + LABA + LAMA vs LABA + LAMA	0.85	(0.74–0.97)

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Appendix Table 8 Random effects, direct (head to head) evaluation using DerSimmonian Laird random-effects model. Binomial model

Treatment vs comparator	Random-effects direct evidence
	Relative risk	95% CI
Roflumilast vs placebo	0.90	(0.85–0.95)
LABA vs placebo	0.85	(0.78–0.91)
LAMA vs placebo	0.84	(0.77–0.92)
ICS vs placebo	0.69	(0.57–0.83)
ICS + LABA vs placebo	0.70	(0.57–0.88)
LAMA vs LABA	0.95	(0.82–1.10)
Roflumilast + LABA vs LABA	0.83	(0.83–1.00)
ICS + LABA vs LABA	0.90	(0.83–0.98)
ICS + LABA + LAMA vs LAMA	0.96	(0.80–1.14)
Roflumilast + LAMA vs LAMA	0.73	(0.62–0.87)
LABA + LAMA vs LAMA	0.83	(0.46–1.51)
ICS + LABA vs LAMA	1.05	(0.96–1.15)
ICS + LABA + LAMA vs LABA + LAMA	0.93	(0.82–1.05)

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Table 2 Estimated rate ratios and 95% CI for the relative effects of pairs of treatments, produced by the random-effects MTC model without covariates

Treatment vs comparator	Random-effects MTC model
	Rate ratio	95% CI
Roflumilast vs placebo	0.85	(0.72, 0.97)
LABA vs placebo	0.84	(0.75, 0.93)
LAMA vs placebo	0.74	(0.66, 0.81)
ICS vs placebo	0.80	(0.71, 0.90)
Roflumilast + LABA vs placebo	0.67	(0.48, 0.91)
Roflumilast + LAMA vs placebo	0.62	(0.44, 0.85)
LABA + LAMA vs placebo	0.80	(0.56, 1.12)
ICS + LABA vs placebo	0.69	(0.61, 0.77)
ICS + LAMA + LABA vs placebo	0.68	(0.47, 0.95)
LABA vs roflumilast	0.98	(0.80, 1.19)
LAMA vs roflumilast	0.87	(0.71, 1.05)
ICS vs roflumilast	0.94	(0.76, 1.15)
Roflumilast + LABA vs roflumilast	0.79	(0.54, 1.12)
Roflumilast + LAMA vs roflumilast	0.73	(0.50, 1.04)
LABA + LAMA vs roflumilast	0.94	(0.63, 1.36)
ICS + LABA vs roflumilast	0.81	(0.66, 0.99)
ICS + LAMA + LABA vs roflumilast	0.80	(0.53, 1.16)
LAMA vs LABA	0.88	(0.77, 1.01)
ICS vs LABA	0.96	(0.84, 1.09)
Roflumilast + LABA vs LABA	0.80	(0.59, 1.08)
Roflumilast + LAMA vs LABA	0.75	(0.52, 1.03)
LABA + LAMA vs LABA	0.96	(0.66, 1.35)
ICS + LABA vs LABA	0.82	(0.74, 0.92)
ICS + LAMA + LABA vs LABA	0.82	(0.56, 1.15)
ICS vs LAMA	1.09	(0.93, 1.26)
Roflumilast + LABA vs LAMA	0.91	(0.64, 1.25)
Roflumilast + LAMA vs LAMA	0.84	(0.61, 1.14)
LABA + LAMA vs LAMA	1.09	(0.77, 1.49)
ICS + LABA vs LAMA	0.94	(0.81, 1.07)
ICS + LAMA + LABA vs LAMA	0.92	(0.66, 1.28)
Roflumilast + LABA vs ICS	0.84	(0.60, 1.15)
Roflumilast + LAMA vs ICS	0.78	(0.54, 1.08)
LABA + LAMA vs ICS	1.01	(0.69, 1.42)
ICS + LABA vs ICS	0.86	(0.76, 0.98)
ICS + LAMA + LABA vs ICS	0.86	(0.58, 1.21)
Roflumilast + LAMA vs roflumilast + LABA	0.95	(0.58, 1.46)
LABA + LAMA vs roflumilast + LABA	1.23	(0.74, 1.90)
ICS + LABA vs roflumilast + LABA	1.05	(0.75, 1.43)
LAMA + ICS + LABA vs roflumilast + LABA	1.04	(0.63, 1.63)
LABA + LAMA vs roflumilast + LAMA	1.32	(0.82, 2.03)
ICS + LABA vs roflumilast + LAMA	1.14	(0.80, 1.58)
ICS + LAMA + LABA vs roflumilast + LAMA	1.12	(0.70, 1.72)
ICS + LABA vs LABA + LAMA	0.88	(0.61, 1.24)
ICS + LAMA + LABA vs LABA + LAMA	0.86	(0.61, 1.18)
ICS + LAMA + LABA vs ICS + LABA	0.99	(0.68, 1.40)

Notes: A rate ratio smaller (larger) than 1 indicates that the treatment is associated with a reduction (increase) in the rate of exacerbations in COPD relative to the comparator. This reduction (increase) is statistically significant at the 5% level only if the upper end (lower end) of the associated 95% CI is less than (larger than) 1.

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Table 3 Absolute treatment effects corresponding to the 10 treatments for the management of COPD as derived from the primary analysis

Treatment	Absolute treatment effect	95% CI
Placebo	1.21	(1.17, 1.24)
Roflumilast	1.03	(0.87, 1.21)
LABA	1.01	(0.90, 1.11)
LAMA	0.89	(0.80, 0.98)
ICS	0.96	(0.85, 1.08)
Roflumilast + LABA	0.81	(0.58, 1.10)
Roflumilast + LAMA	0.75	(0.53, 1.02)
LABA + LAMA	0.97	(0.67, 1.34)
ICS + LABA	0.83	(0.73, 0.93)
ICS + LAMA + LABA	0.82	(0.57, 1.15)

Note: Absolute treatment effects are expressed as mean exacerbations experienced per patient per patient-year.

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Table 4 Probability each of the 10 treatments for management of COPD is best, obtained on the basis of the random-effects MTC model without covariates

Treatment	P^*1	P2	P3	P4	P5	P6	P7	P8	P9	P10
Placebo	0.000	0.000	0.000	0.000	0.000	0.000	0.001	0.012	0.113	0.875
Roflumilast	0.001	0.004	0.010	0.026	0.052	0.103	0.168	0.238	0.372	0.027
LABA	0.000	0.000	0.002	0.008	0.040	0.117	0.259	0.354	0.218	0.001
LAMA	0.001	0.026	0.110	0.272	0.332	0.199	0.048	0.010	0.002	0.000
ICS	0.001	0.004	0.019	0.060	0.139	0.246	0.308	0.165	0.059	0.000
Roflumilast + LABA	0.244	0.231	0.155	0.114	0.082	0.069	0.042	0.032	0.024	0.007
Roflumilast + LAMA	0.453	0.224	0.130	0.071	0.045	0.032	0.018	0.015	0.010	0.002
LABA + LAMA	0.025	0.066	0.096	0.096	0.104	0.129	0.102	0.124	0.178	0.081
ICS + LABA	0.056	0.218	0.322	0.238	0.121	0.041	0.004	0.000	0.000	0.000
ICS + LAMA + LABA	0.219	0.226	0.157	0.115	0.086	0.065	0.049	0.050	0.026	0.008

Note: P1–P10 refers to probability that each is 1st, 2nd, …, k best.

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Table 5 Estimated rate ratios and 95% CI for the effects of specific pairs of treatment combinations, produced by the additive main effects model considered in our secondary MTC analysis

Treatment vs comparator	Additive main effects model
	Rate ratio	95% CI
LABA plus ICS plus roflumilast vs LABA plus ICS	0.84	(0.74, 0.95)
LABA plus ICS plus LAMA vs LABA plus ICS plus roflumilast	0.89	(0.75, 1.03)
LABA plus ICS plus LAMA plus roflumilast vs LABA plus ICS plus LAMA	0.84	(0.74, 0.95)
LAMA plus LABA plus roflumilast vs LABA plus LAMA	0.84	(0.74, 0.95)
LAMA plus LABA plus roflumilast vs LAMA plus LABA plus ICS	1.00	(0.85, 1.13)

Notes: A rate ratio smaller (larger) than 1 indicates that the treatment is associated with a reduction (increase) in the rate of exacerbations in COPD relative to the comparator. This reduction (increase) is statistically significant at the 5% level only if the upper end (lower end) of the associated 95% CI is less than (larger than) 1.

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Table 6 Absolute treatment effects corresponding to the 15 treatments for the management of COPD (ie, 5 single treatments plus 10 combinations of active treatments), obtained on the basis of the additive main effects model considered in our secondary MTC analysis

Treatment	Absolute treatment effect	95% CI
Placebo	1.20	(1.17, 1.23)
Roflumilast	1.01	(0.89, 1.14)
LABA	1.04	(0.96, 1.12)
LAMA	0.89	(0.81, 0.98)
ICS	0.98	(0.91, 1.06)
Roflumilast + LABA	0.87	(0.75, 1.01)
Roflumilast + LAMA	0.75	(0.64, 0.87)
Roflumilast + ICS	0.82	(0.71, 0.95)
LABA + LAMA	0.77	(0.67, 0.87)
LABA + ICS	0.85	(0.77, 0.94)
LAMA + ICS	0.73	(0.64, 0.82)
Roflumilast + LABA + LAMA	0.65	(0.54, 0.77)
Roflumilast + LABA + ICS	0.71	(0.61, 0.83)
LAMA + LABA + ICS	0.63	(0.54, 0.73)
Roflumilast + LABA + LAMA + ICS	0.53	(0.43, 0.64)

Note: Absolute treatment effects are expressed as mean exacerbations experienced per patient per patient-year.

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Table 7 Probability each of the 15 treatments (ie, 5 single treatments plus 10 combinations of active treatments) for management of COPD is best, obtained on the basis of the additive main effects model considered in our secondary MTC analysis

Treatment	Probability treatment is best
Placebo	0.000
Roflumilast	0.000
LABA	0.000
LAMA	0.000
ICS	0.000
Roflumilast + LABA	0.000
Roflumilast + LAMA	0.000
Roflumilast + ICS	0.000
LABA + LAMA	0.000
LABA + ICS	0.000
LAMA + ICS	0.000
Roflumilast + LABA + LAMA	0.000
Roflumilast + LABA + ICS	0.000
LAMA + LABA + ICS	0.003
Roflumilast + LABA + LAMA + ICS	0.997

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Appendix Table 1 Estimated rate ratios and associated 95% CI for the relative effects of pairs of treatments for the management of COPD, produced by the fixed-effect MTC model without covariates

Treatment vs comparator	Fixed-effect MTC model
	Rate ratio	95% CI
Roflumilast vs placebo	0.85	(0.81, 0.89)
LABA vs placebo	0.83	(0.81, 0.86)
LAMA vs placebo	0.81	(0.79, 0.83)
ICS vs placebo	0.79	(0.77, 0.82)
Roflumilast + LABA vs placebo	0.66	(0.58, 0.76)
Roflumilast + LAMA vs placebo	0.68	(0.58, 0.79)
LABA + LAMA vs placebo	0.87	(0.72, 1.05)
ICS + LABA vs placebo	0.70	(0.68, 0.72)
ICS + LAMA + LABA vs placebo	0.74	(0.60, 0.90)
LABA vs roflumilast	0.98	(0.93, 1.04)
LAMA vs roflumilast	0.96	(0.91, 1.01)
ICS vs roflumilast	0.93	(0.88, 0.99)
Roflumilast + LABA vs roflumilast	0.78	(0.68, 0.90)
Roflumilast + LAMA vs roflumilast	0.80	(0.68, 0.94)
LABA + LAMA vs roflumilast	1.03	(0.85, 1.24)
ICS + LABA vs roflumilast	0.82	(0.78, 0.87)
ICS + LAMA + LABA vs roflumilast	0.88	(0.71, 1.07)
LAMA vs LABA	0.97	(0.94, 1.01)
ICS vs LABA	0.95	(0.92, 0.98)
Roflumilast + LABA vs LABA	0.79	(0.70, 0.90)
Roflumilast + LAMA vs LABA	0.82	(0.70, 0.95)
LABA + LAMA vs LABA	1.05	(0.87, 1.26)
ICS + LABA vs LABA	0.84	(0.81, 0.87)
ICS + LAMA + LABA vs LABA	0.89	(0.73, 1.08)
ICS vs LAMA	0.98	(0.94, 1.01)
Roflumilast + LABA vs LAMA	0.82	(0.71, 0.93)
Roflumilast + LAMA vs LAMA	0.84	(0.72, 0.97)
LABA + LAMA vs LAMA	1.08	(0.89, 1.29)
ICS + LABA vs LAMA	0.86	(0.83, 0.89)
ICS + LAMA + LABA vs LAMA	0.92	(0.75, 1.11)
Roflumilast + LABA vs ICS	0.84	(0.73, 0.96)
Roflumilast + LAMA vs ICS	0.86	(0.73, 1.00)
LABA + LAMA vs ICS	1.11	(0.91, 1.33)
ICS + LABA vs ICS	0.88	(0.85, 0.92)
ICS + LAMA + LABA vs ICS	0.94	(0.76, 1.14)
Roflumilast + LAMA vs roflumilast + LABA	1.03	(0.83, 1.25)
LABA + LAMA vs roflumilast + LABA	1.33	(1.05, 1.66)
ICS + LABA vs roflumilast + LABA	1.06	(0.92, 1.21)
LAMA + ICS + LABA vs roflumilast + LABA	1.13	(0.88, 1.42)
LABA + LAMA vs roflumilast + LAMA	1.29	(1.02, 1.64)
ICS + LABA vs roflumilast + LAMA	1.03	(0.89, 1.21)
ICS + LAMA + LABA vs roflumilast + LAMA	1.10	(0.85, 1.40)
ICS + LABA vs LABA + LAMA	0.81	(0.66, 0.97)
ICS + LAMA + LABA vs LABA + LAMA	0.85	(0.70, 1.03)
ICS + LAMA + LABA vs ICS + LABA	1.06	(0.87, 1.29)

Note: A rate ratio smaller (larger) than 1 indicates that the treatment is associated with a reduction (increase) in the rate of exacerbations in COPD relative to the comparator.

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Appendix Table 3 Probability that each of the 10 treatments for management of COPD is best, obtained on the basis of the fixed-effect MTC model without covariates

Treatment	P1	P2	P3	P4	P5	P6	P7	P8	P9	P10
Placebo	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.001	0.071	0.928
Roflumilast	0.000	0.000	0.000	0.002	0.016	0.061	0.191	0.426	0.304	0.000
LABA	0.000	0.000	0.000	0.001	0.016	0.121	0.409	0.357	0.096	0.000
LAMA	0.000	0.000	0.000	0.019	0.199	0.506	0.240	0.032	0.003	0.000
ICS	0.000	0.000	0.007	0.239	0.531	0.189	0.032	0.002	0.000	0.000
Roflumilast + LABA	0.502	0.279	0.145	0.065	0.008	0.001	0.000	0.000	0.000	0.000
Roflumilast + LAMA	0.335	0.284	0.219	0.130	0.020	0.005	0.003	0.002	0.001	0.000
LABA + LAMA	0.000	0.003	0.009	0.032	0.120	0.066	0.081	0.109	0.508	0.072
ICS + LABA	0.056	0.305	0.473	0.161	0.005	0.000	0.000	0.000	0.000	0.000
ICS + LAMA + LABA	0.106	0.128	0.146	0.352	0.084	0.052	0.044	0.070	0.017	0.001

Note: P1–P10 refers to probability that each is 1st, 2nd, … k best.

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Appendix Table 4 Estimated relative risks and 95% confidence intervals for all pairs of treatments produced by the random-effects MTC model without covariates. Binomial model

Treatment vs comparator	Random-effects MTC model
	Relative risk	95% CI
Roflumilast vs placebo	0.90	(0.79, 0.97)
LABA vs placebo	0.88	(0.79, 0.96)
LAMA vs placebo	0.83	(0.75, 0.90)
ICS vs placebo	0.79	(0.68, 0.89)
Roflumilast + LABA vs placebo	0.74	(0.53, 0.96)
Roflumilast + LAMA vs placebo	0.63	(0.44, 0.85)
LABA + LAMA vs placebo	0.77	(0.56, 1.00)
ICS + LABA vs placebo	0.78	(0.69, 0.87)
ICS + LAMA + LABA vs placebo	0.72	(0.48, 1.00)
LABA vs roflumilast	0.97	(0.82, 1.12)
LAMA vs roflumilast	0.92	(0.77, 1.06)
ICS vs roflumilast	0.88	(0.71, 1.03)
Roflumilast + LABA vs roflumilast	0.82	(0.57, 1.09)
Roflumilast + LAMA vs roflumilast	0.70	(0.47, 0.97)
LABA + LAMA vs roflumilast	0.86	(0.60, 1.14)
ICS + LABA vs roflumilast	0.87	(0.71, 1.02)
ICS + LAMA + LABA vs roflumilast	0.80	(0.52, 1.13)
LAMA vs LABA	0.94	(0.82, 1.07)
ICS vs LABA	0.89	(0.76, 1.02)
Roflumilast + LABA vs LABA	0.83	(0.60, 1.09)
Roflumilast + LAMA vs LABA	0.70	(0.47, 0.99)
LABA + LAMA vs LABA	0.87	(0.61, 1.18)
ICS + LABA vs LABA	0.88	(0.78, 0.98)
ICS + LAMA + LABA vs LAMA	0.81	(0.51, 1.18)
ICS vs LAMA	0.96	(0.84, 1.07)
Roflumilast + LABA vs LAMA	0.90	(0.68, 1.14)
Roflumilast + LAMA vs LAMA	0.79	(0.58, 1.02)
LABA + LAMA vs LAMA	0.94	(0.72, 1.17)
ICS + LABA vs LAMA	0.95	(0.85, 1.05)
ICS + LAMA + LABA vs LAMA	0.89	(0.63, 1.16)
Roflumilast + LABA vs ICS	0.93	(0.62, 1.31)
Roflumilast + LAMA vs ICS	0.77	(0.49, 1.14)
LABA + LAMA vs ICS	0.99	(0.65, 1.40)
ICS + LABA vs ICS	0.99	(0.83, 1.17)
ICS + LAMA + LABA vs ICS	0.91	(0.55, 1.40)
Roflumilast + LAMA vs roflumilast + LABA	0.86	(0.51, 1.31)
LABA + LAMA vs roflumilast + LABA	1.07	(0.66, 1.55)
ICS + LABA vs roflumilast + LABA	1.08	(0.77, 1.42)
LAMA + ICS + LABA vs roflumilast + LABA	1.00	(0.57, 1.53)
LABA + LAMA vs roflumilast + LAMA	1.27	(0.77, 1.88)
ICS + LABA vs roflumilast + LAMA	1.28	(0.87, 1.76)
ICS + LAMA + LABA vs roflumilast + LAMA	1.19	(0.67, 1.84)
ICS + LABA vs LABA + LAMA	1.02	(0.72, 1.36)
ICS + LAMA + LABA vs LABA + LAMA	0.94	(0.62, 1.32)
ICS + LAMA + LABA vs ICS + LABA	0.93	(0.61, 1.30)

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Appendix Table 6 Probability each of the 10 treatments for management of COPD is best, obtained on the basis of the random-effects MTC model without covariates. Binomial model

Treatment	Probability treatment is best
Placebo	0.000
Roflumilast	0.000
LABA	0.000
LAMA	0.000
ICS	0.011
Roflumilast + LABA	0.147
Roflumilast + LAMA	0.562
LABA + LAMA	0.061
ICS + LABA	0.010
ICS + LAMA + LABA	0.207

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Appendix Table 9 Estimated rate ratios and associated 95% CI for the relative effects of pairs of treatments for the management of COPD, produced by random effects MTC involving previously unpublished roflumilast data (M2-111 trial)²⁸

Treatment vs comparator	Rate ratio (95% CI)
	Original MTC analysis
Roflumilast vs placebo	0.83 (0.70, 0.97)
LABA vs placebo	0.84 (0.75, 0.93)
LAMA vs placebo	0.74 (0.66, 0.81)
ICS vs placebo	0.80 (0.71, 0.89)
Roflumilast + LABA vs placebo	0.67 (0.48, 0.91)
Roflumilast + LAMA vs placebo	0.62 (0.45, 0.84)
LABA + LAMA vs placebo	0.80 (0.56, 1.11)
ICS + LABA vs placebo	0.69 (0.61, 0.77)
ICS + LAMA + LABA vs placebo	0.68 (0.47, 0.94)
LABA vs roflumilast	1.01 (0.83, 1.23)
LAMA vs roflumilast	0.89 (0.73, 1.07)
ICS vs roflumilast	0.97 (0.79, 1.18)
Roflumilast + LABA vs roflumilast	0.81 (0.56, 1.14)
Roflumilast + LAMA vs roflumilast	0.75 (0.52, 1.06)
LABA + LAMA vs roflumilast	0.97 (0.65, 1.39)
ICS + LABA vs roflumilast	0.83 (0.68, 1.01)
ICS + LAMA + LABA vs roflumilast	0.82 (0.55, 1.18)
LAMA vs LABA	0.88 (0.77, 1.01)
ICS vs LABA	0.96 (0.84, 1.08)
Roflumilast + LABA vs LABA	0.80 (0.59, 1.07)
Roflumilast + LAMA vs LABA	0.74 (0.53, 1.02)
LABA + LAMA vs LABA	0.96 (0.67, 1.34)
ICS + LABA vs LABA	0.82 (0.74, 0.91)
ICS + LAMA + LABA vs LABA	0.82 (0.56, 1.14)
ICS vs LAMA	1.09 (0.93, 1.26)
Roflumilast + LABA vs LAMA	0.91 (0.65, 1.25)
Roflumilast + LAMA vs LAMA	0.84 (0.62, 1.13)
LABA + LAMA vs LAMA	1.09 (0.78, 1.48)
ICS + LABA vs LAMA	0.94 (0.81, 1.07)
ICS + LAMA + LABA vs LAMA	0.92 (0.65, 1.27)
Roflumilast + LABA vs ICS	0.84 (0.61, 1.15)
Roflumilast + LAMA vs ICS	0.78 (0.55, 1.08)
LABA + LAMA vs ICS	1.00 (0.69, 1.41)
ICS + LABA vs ICS	0.86 (0.76, 0.98)
ICS + LAMA + LABA vs ICS	0.85 (0.59, 1.21)
Roflumilast + LAMA vs roflumilast + LABA	0.95 (0.59, 1.45)
LABA + LAMA vs roflumilast + LABA	1.22 (0.76, 1.89)
ICS + LABA vs roflumilast + LABA	1.05 (0.76, 1.42)
LAMA + ICS + LABA vs roflumilast + LABA	1.04 (0.64, 1.61)
LABA + LAMA vs roflumilast + LAMA	1.32 (0.83, 1.99)
ICS + LABA vs roflumilast + LAMA	1.14 (0.80, 1.55)
ICS + LAMA + LABA vs roflumilast + LAMA	1.12 (0.70, 1.71)
ICS + LABA vs LABA + LAMA	0.88 (0.61, 1.23)
ICS + LAMA + LABA vs LABA + LAMA	0.86 (0.61, 1.18)
ICS + LAMA + LABA vs ICS + LABA	0.99 (0.68, 1.40)

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Appendix Table 12 Estimated rate ratios and 95% CI for the effects of specific pairs of treatment combinations, produced by the additive main effects model considered in our MTC analysis including previously unpublished data (M2-111)²⁸

Treatment vs comparator	Additive main effects model
	Rate ratio	95% CI
LABA plus ICS plus roflumilast vs LABA plus ICS	0.82	0.73–0.93
LABA plus ICS plus LAMA vs LABA plus ICS plus roflumilast	0.90	0.77–1.05
LABA plus ICS plus LAMA plus roflumilast vs LABA plus ICS plus LAMA	0.82	0.73–0.93
LAMA plus LABA plus roflumilast vs LABA plus LAMA	0.82	0.73–0.93
LAMA plus LABA plus ICS vs LAMA plus LABA plus roflumilast	1.00	0.86–1.15

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Appendix Table 2 Absolute treatment effects corresponding to the 10 treatments for the management of COPD, as derived from the fixed-effect MTC model without covariates

Treatment	Absolute treatment effect	95% CI
Placebo	1.17	(1.15, 1.20)
Roflumilast	0.99	(0.94, 1.04)
LABA	0.98	(0.95, 1.02)
LAMA	0.96	(0.93, 0.99)
ICS	0.94	(0.90, 0.97)
Roflumilast + LABA	0.78	(0.68, 0.89)
Roflumilast + LAMA	0.80	(0.69, 0.93)
LABA + LAMA	0.97	(0.81, 1.15)
ICS + LABA	0.82	(0.80, 0.85)
ICS + LAMA + LABA	0.71	(0.60, 0.84)

Note: Absolute treatment effects are expressed as mean exacerbations experienced per patient per patient-year.

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Appendix Table 5 Absolute treatment effects obtained from the random-effects MTC model on binomial model

Treatment	Absolute treatment effect	95% CI
Placebo	0.35	(0.33, 0.36)
Roflumilast	0.31	(0.27, 0.36)
LABA	0.30	(0.27, 0.33)
LAMA	0.28	(0.25, 0.31)
ICS	0.26	(0.23, 0.30)
Roflumilast + LABA	0.25	(0.17, 0.33)
Roflumilast + LAMA	0.21	(0.14, 0.29)
LABA + LAMA	0.26	(0.18, 0.35)
ICS + LABA	0.26	(0.23, 0.29)
ICS + LAMA + LABA	0.24	(0.15, 0.35)

Note: Absolute treatment effects are expressed as mean exacerbations experienced per patient per patient-year.

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Appendix Table 10 Absolute treatment effects obtained from the random-effects MTC model including previously unpublished roflumilast data (M2-111 trial)²⁸

Treatment	Absolute treatment effect (95% CI)
	Original MTC analysis
Placebo	1.18 (1.15, 1.21)
Roflumilast	0.98 (0.83, 1.15)
LABA	0.98 (0.89, 1.09)
LAMA	0.87 (0.78, 0.95)
ICS	0.94 (0.84, 1.05)
Roflumilast + LABA	0.79 (0.57, 1.07)
Roflumilast + LAMA	0.73 (0.53, 1.00)
LABA + LAMA	0.94 (0.66, 1.31)
ICS + LABA	0.81 (0.72, 0.90)
ICS + LAMA + LABA	0.80 (0.56, 1.11)

Note: Absolute treatment effects are expressed as mean exacerbations experienced per patient per patient-year.

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

Appendix Table 11 Probability each of the 15 treatments (ie, 5 single treatments plus 10 combinations of active treatments) for management of COPD is best, obtained on the basis of the additive main effects model considered in our secondary MTC analysis. This table includes previously unpublished roflumilast data (M2-111 trial)²⁸

Treatment	Probability treatment is best
Placebo	0.000
Roflumilast	0.000
LABA	0.000
LAMA	0.000
ICS	0.000
Roflumilast + LABA	0.000
Roflumilast + LAMA	0.000
Roflumilast + ICS	0.000
LABA + LAMA	0.000
LABA + ICS	0.000
LAMA + ICS	0.000
Roflumilast + LABA + LAMA	0.000
Roflumilast + LABA + ICS	0.000
LAMA + LABA + ICS	0.003
Roflumilast + LABA + LAMA + ICS	0.997

Abbreviations: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; LAMA, long-acting antimuscarinic drugs; MTC, mixed-treatment comparison.

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