Rationale for Earlier Treatment in COPD: A Systematic Review of Published Literature in Mild-to-Moderate COPD

Figures & data

Figure 1.  The flow of published articles through the systematic review process.

Table 1.  Articles meeting the inclusion criteria for the systematic review, which reported baseline data and outcomes with no treatment.

Citation	Interventions, follow-up	Outcome measures	Patients and baseline characteristics	Main findings
PBO/control arm analysis only
Double-blind PBO-controlled parallel-group; analysis of EUROSCOP study data (Watson et al., ref. 59)	PBO arm only, 3 y	FEV1 and predictors	n = 642 COPD (72% male), current smokers (46% quit during study), median 38.3 (interquartile range 28.5–51.3) pack-years for men, 29.5 (21.0–40.0) pack-years for women, median age: men 54 years (48–58 years); women 52 years (46–58 years). Post-bronchodilator (2) FEV1% pred 79.2 (69–88) FEV1 2.8 L (2.3–3.2 L) for men, FEV1% pred 81.5 L (71–89 L) FEV1 2.1 L (1.7–2.4 L) for women; FEV1/FVC% pred 63.7 (58–68) (men) 65.5 (60–70) (women); FEV1/IVC% 63.3 (57.1–66.9) for men 64.5 (59.1–67.9) for women. Median reversibility% pred 2.7 (0–5.1) for men and 2.9 (0–5.7) for women. Wheezing anytime: 54.1% men; 60.5% women. Dyspnea after activity: 34.6% men 39.9% women. Dyspnea at rest: 6.9% men; 6.2% women. Cough in winter: 48.7% men; 58.4% women. Median BMI: 24.7 (22.7–27.1) male; 22.9 (20.5–25.3) female kg/m2	Rate of FEV1 decline reported graphically. Symptoms associated with lower baseline FEV1 in men but not women. Annual decline in FEV1 not associated with symptoms; less in obese men, more with greater smoking. In women, more severe airway obstruction associated with accelerated decline in FEV1.
Open-label, crossover (Magnussen et al., ref. 58)	Inhaler A versus inhaler B versus inhaler C; all containing PBO powder, no follow-up	PIF	n = 48 COPD: n = 24 moderate (75% male, 63% current smokers, mean 61.5 ± 25.7 pack-years, age 63 ± 8 y, post-bronchodilator FEV1% pred 59.5 ± 6.9, FVC 3.78 ± 1.23 L, FEV1/FVC 47.8 ± 9.5%, reversibility 19.3 ± 15.1%, BMI 28.0 ± 5.2 kg/m2), n = 24 severe	For moderate patients, highest PIF approximately 50–100 L/min
Pharmacologic intervention only—PBO controlled
Double-blind, PBO-controlled, parallel-group (DIMCA study) (van Grunsven et al., ref. 32)	Fluticasone propionate 250 μg bid versus PBO, 2 y	Pulmonary function, symptoms, functional status (COOP/ WONCA), exacerbations	n = 48 early COPD, 3 months’ symptoms, previous FEV1 decline 109 ± 46 ml/year (fluticasone) 124 ± 66 ml/year (PBO). Mean age 46 ± 10 years and 47 ± 11 years, 50% and 54% male, current smokers 42%, pack-years 11.9 ± 9.5 and 5.8 ± 8.4. Mean baseline post-bronchodilator FEV1% pred 98 ± 15 and 99 ± 18 FEV1 3.16 ± 0.68 L and 3.19 ± 0.79 L; pre-bronchodilator (3) FEV1% pred 95 ± 18 and 98 ± 17 FEV1 3.05 ± 0.7 L and 3.17 ± 0.76 L; pre-bronchodilator FEV1/FVC 75 ± 10% and 77 ± 6%; FEV1 reversibility% pred 4.0 ± 5.1 and 3.0 ± 4.0; symptom score 1.7 ± 1.5 and 1.3 ± 1.3. COOP/WONCA scores varied from not impaired (1.2 ± 0.6 for social activities) to slightly impaired (2.4 ± 1.2 for general health)	For PBO, annual decline in FEV1 –14 ± 17 ml post-bronchodilator and –38 ± 19 ml pre-bronchodilator; 4 exacerbations in 3 patients, no change in COOP/WONCA over study, 57 episodes of increased respiratory symptoms in 17 patients
Double-blind PBO-controlled parallel-group (DIMCA 3a study) (van Grunsven et al., ref. 40)	Fluticasone propionate 250 μg versus PBO, 2 years	Compliance, patient opinion	n = 48 COPD. Mean FEV1% pred 96 ± 17, FEV1 reversibility 3 ± 5% pred, age 47 years (range 29–71 y), 42% smokers, mean pack-years 9 (0–29), 52% male, number of symptoms in past 3 months 1.5 ± 1.4	Only outcomes are compliance
Double-blind PBO-controlled parallel-group, post-hoc analysis of EUROSCOP study (Löfdahl et al., ref. 34)	Budesonide 800 μg/day versus PBO, 3 years	Ischemic events, and baseline predictors	n = 1277 COPD, current smokers, pack-yrs median 36 (range 0–171), 73% male, mean age 52.5 years (range 25–66 y), BMI 24.8 (15–44) kg/m2, FEV1 2.5 (1.0–4.7) L, FEV1% pred 76.9 (42–103), IVC 4.1 (1.9–7.8) L.	5.3% (31/582) PBO patients had 38 ischemic events. Estimated yearly severe exacerbation rate (oral steroids) 0.07 for PBO.
Double-blind PBO-controlled parallel-group, prespecified subgroup analysis of UPLIFT® trial (Decramer et al., ref. 30)	Tiotropium 18 μg od versus PBO, 4 years	Yearly rates of decline in pre-bronchodilator FEV1 and in post-bronchodilator FEV1, other pulmonary function outcomes, SGRQ, time to first exacerbation, numbers of exacerbations	n = 2739 COPD GOLD stage II, 72% male, mean age 65 ± 9 years (tiotropium) 64 ± 9 years (PBO), BMI 27 ± 5 kg/m2 (both groups), current smokers 31% (tiotropium), and 35% (PBO), pack-years 48 ± 28 (tiotropium) 47 ± 27 (PBO), pre-bronchodilator FEV1% pred 49 ± 8 (both groups) 1.36 ± 0.4 L (both groups), post-bronchodilator FEV1% pred 59 ± 6 (both groups) 1.63 ± 0.4 L (both groups), SGRQ total score 41 ± 17 units (tiotropium) and 42 ± 17 units (PBO)	For PBO, mean annual rate of decline of post-bronchodilator FEV1 –49 ± 2 ml; pre-bronchodilator FEV1 –37 ± 2 ml; pre-bronchodilator FVC –43 ± 4 ml; pre-bronchodilator SVC –43 ± 4 ml; post-bronchodilator FVC –58 ± 4 ml; post-bronchodilator SVC –60 ± 4 ml. Deterioration in SGRQ total score 0.99 ± 0.13 units per year. Exacerbations: 1 or more in 65%, mean number per patient per year 0.70 (95% CI, 0.65–0.75), median time to first 17.5 (95% CI, 15.9–19.7) months. Hospitalized exacerbations: 1 or more in 19%, mean number per patient per year 0.10 (95% CI, 0.08–0.12). Mortality 10%
Double-blind PBO-controlled, parallel-group (Pauwels et al., ref. 38)	Budesonide 400 μg bid versus PBO, 3 years	FEV1	n = 1227 COPD, mean age 52.4 ± 7.7 years (PBO) and 52.5 ± 7.5 years (budesonide), 72.2% and 73.5% male, current smokers, pack-years 39.2 ± 20.1 and 39.4 ± 20.1, about 10% quit during study. Pre-bronchodilator FEV1% pred 76.9 ± 13.2 versus 76.8 ± 12.4, FEV1 2.54 ± 0.64 L and 2.53 ± 0.64 L, FEV1/SVC 61.7 ± 7.0, and 62.2 ± 6.8. Reversibility of FEV1 2.8 ± 3.6 and 2.9 ± 3.8% pred	For PBO, median decline in post-bronchodilator FEV1 –65 ml per year. Mortality n = 10
Double-blind PBO-controlled, parallel-group, post-hoc analysis of TORCH study (Jenkins et al., ref. 31)	Salmeterol 50 μg versus fluticasone propionate 500 μg versus SFC 50/500 μg versus PBO; 3 years	Pulmonary function, exacerbations, SGRQ	n = 6112 COPD: GOLD stage II (n = 2156, 72% male, 47% current smokers, mean age 64.9 ± 8.7 y, BMI 26.6 ± 5.2 kg/m2, post-bronchodilator FEV1% pred 58.8 ± 7.4, FEV1 1616 ± 399 ml, reversibility FEV1 4.3 ± 4.0% pred, SGRQ total score 45.4 ± 17.7 [for PBO group, 43.9], exacerbations requiring steroids/antibiotics in last year 0.9 ± 1.2, exacerbations requiring hospitalization in last year 0.2 ± 0.5), GOLD stage III (n = 3019), GOLD stage IV (n = 937)	For GOLD stage II PBO patients, 10.6% probability of pneumonia, adjusted mean FEV1 over 3 years 1522 ml, adjusted rate of decline in FEV1 –60 ml/y, change in SGRQ total score –1.3, annual rate of moderate/severe exacerbations 0.82. Mortality 11.4%
Double-blind, PBO-controlled, parallel-group (Rennard et al., ref. 39)	Infliximab 3 mg/kg versus infliximab 5 mg/kg versus PBO, 44 weeks	CRQ, pre-bronchodilator FEV1, 6MWD, SF-36®, TDI, exacerbations	n = 234 COPD: GOLD stage I (n = 7), GOLD stage II (n = 98), GOLD stage III (n = 93), GOLD stage IV (n = 36). Baseline data not stratified for severity	GOLD stage I patients not analyzed. For GOLD stage II PBO patients, at Week 24, mean change from baseline in CRQ total score 12.1, 6MWD 2.4 meters; the SF-36® score, the TDI score, cough symptoms, and sputum production improved. Few 44-week data reported
PBO-controlled, parallel-group (Dal Negro et al., ref. 35)	Erdosteine 300 mg bid versus N-acetylcysteine 600 mg bid versus PBO, 10 days	FEV1 reversibility to salbutamol	n = 30 COPD GOLD stage I or II, 67% male, mean BMI 24.6 ± 2.1 kg/m2, mean pre-bronchodilator FEV1% pred 63.3 ± 8.4 (erdosteine) 58.8 ± 7 (N-acetylcysteine) 60.1 ± 7.8 (PBO); post-bronchodilator FEV1% pred 64.7 ± 8.8, 59.8 ± 9.8, 62.5 ± 7.4; FEV1/FVC% 61.4 ± 6.2, 54.6 ± 11.1, 61.5 ± 8.5, FEV1% pred reversibility 1.38 ± 4.4, 1.02 ± 3.6, 2.38 ± 1.9, age 60.8 ± 12.1 years, 63.6 ± 11.3 years, 60.2 ± 13.4 years, current smokers, pack-years 25.4 ± 3.5, 26.3 ± 3.1, 28.1 ± 2.3. For PBO, FEV1 0.061 ± 0.05 L	FEV1 reversibility with PBO: 1.03 ± 2.35% at Day 4 (–1.35 versus baseline) and 1.5 ± 1.62% at Day 10 (–0.88 versus baseline). FEV1 0.031 ± 0.05 L at Day 4 (–0.03 versus baseline) and 0.035 ± 0.04 L at Day 10 (–0.026 versus baseline)
Double-blind PBO-controlled crossover (O'Donnell et al., ref. 37)	Ipratropium bromide 500 μg versus PBO; 2 days each arm, 7 days between visits (1 month)	Pulmonary function, dyspnea, ventilatory parameters, exercise test	n = 16 COPD GOLD stage I, 63% male, mean age 63 ± 8 years, BMI 27.8 ± 4.6 kg/m2, BDI focal score 8.3 ± 2, MRC dyspnea scale 1.8 ± 0.7, symptom-limited peak work rate 72% pred, post-bronchodilator FEV1% pred 90 (2.5 ± 0.58 L), FVC 108% pred (4.25 ± 1.08 L), FEV1/FVC 84% (59 ± 7), RV (2.83 ± 0.48, 129% pred), TLC (7.11 ± 1.50, 113%) IC (3.01 ± 0.97, 103%), FRC (4.10 ± 0.91, 122%); smoking history 44 ± 16 pack-years, n = 4 current smokers	After PBO, change in FEV1 +3%, FVC +1%, FEV1/FVC +2%, TLC –1%, RV –6%, FRC –2%, IC +1%. At peak of exercise (80–85% Wmax) exercise time was 8.2 ± 5.3 minutes, dyspnea BORG 7.8 ± 2.9, during constant-load exercise dyspnea BORG was 7.4 ± 2.4
Double-blind PBO-controlled, crossover (Kryger et al., ref. 33)	Ramelteon 8 mg versus PBO, single dose, 1 night each arm	Polysomno-graphy, blood gases, respiratory effort	n = 25 COPD moderate or severe; n = 9 GOLD stage II, n = 16 GOLD stage III. Baseline data not stratified for severity	Only oxygen saturation data are stratified by severity
Double-blind, crossover (Kryger et al., ref. 36)	Ramelteon 16 mg versus PBO, 1 night each arm	FEV1 and FEV1/FVC at baseline	n = 26 COPD. Mean FEV1% pred of eligible patients (n = 14) 60.6. Mean baseline FEV1/FVC of eligible patients (n = 14) 59.9%. Baseline characteristics not stratified by severity	Outcomes not stratified by spirographic severity
Non-pharmacologic intervention only, with suitable control arm
Double-blind PBO-controlled, parallel-group (Soler et al., ref. 48)	OM-85 (bacterial extracts: test) versus PBO, for 30 days then 10-day course for Months 3, 4, 5; total 6 months	Exacerbation rate	n = 273 COPD GOLD stage I or 2, 28–33% smokers, with current exacerbation. Mean age 57.3 years (95% CI, 55.7 to 58.9) (test) and 57.9 years (56.2–59.6) (PBO), 54.9% and 43.5% male, BMI 26.3 (25.4–27.2) and 26.5 (25.7–27.3) kg/m2. Mean exacerbations in last year 2.96 ± 1.69 and 3.32 ± 1.64. Mean FEV1% pred 85 (81.7–88.3) and 82.6 (79.9–86.1). Mean baseline FVC 91 (88.2–93.8)% and 89.7 (86.7–93.3)%.	0.86 exacerbations per PBO patient over 6 months.
Parallel-group (Clark et al., ref. 49)	Weight training versus control (usual activities, no weight training), 12 weeks	Isokinetic and isotonic muscle function, whole body endurance, maximal exercise capacity, and lung function	n = 43 COPD (58% male, mean age 49 ± 11 years, BMI 26 ± 4 kg/m2, FEV1 2.29 ± < 0.88 L (training) and 2.38 ± 0.86 L (control), FEV1% pred 76 < ± 23 and 79 ± 23, RV 2.22 ± < 0.91 L and 2.41 ± < 0.88 L, RV% pred 113 < ± 48 and 125 ± 41, BORG score peak exercise 3.5 ± 1.9 and 2.4 ± 1.7) versus n = 52 healthy controls	Exercise performance for control patients: V02maxml·min–1·kg–1 19.1 ± < 6.1 (baseline) 16.6 < ± 4.0 (end); HRmaxbeats·min–1 133 < ± 21 versus 129 < ± 21; VEmaxL·min–1 44.8 < ± 16.7 versus 40.4 < ± 14.3; VTmax L 1.69 ± < 0.45 versus 1.55 ± < 0.47; resp rate breaths·min–1 28 ± < 4 versus 28 ± < 4
Double-blind crossover (Fujimoto et al., ref. 52)	Compressed air versus O2 during exercise test	6MWD, lung hemodynamics	n = 75 COPD: mild (n = 16, age 71 ± 2 years, baseline FEV1% pred 62.7 ± 2.9, FEV1 1.39 ± 0.06 L, FEV1/FVC% 47.0 ± 1.8, air trapping 0.23 ± 0.06 L, VC% pred 100.0 ± 3.0, RV% 211.3 ± 13.4, RV/TLC 54.2 ± 1.2, ex-smokers with > 30 pack-years), moderate (n = 25), severe (n = 34)	In mild patients, 6MWD 475 ± 20 meters (92.9 ± 5.0% pred) on air
Double-blind PBO-controlled, parallel-group (Haider et al., ref. 50)	Hypoxic breathing intervals versus PBO (normoxic breathing), 3 weeks	Blood gases, CV data, respiratory control	n = 18 COPD GOLD stage 0–II with mild symptoms (56% male, mean age 51.7 ± 2.4 y, mean FEV1% pred 78.2 ± 3.6 [training] 72.9 ± 1.9 [PBO], FEV1 2.54 ± 0.2 L and 2.32 ± 0.18 L, FVC 3.53 ± 0.3 L and 3.50 ± 0.26 L, FEV1/FVC 72.3 ± 1.9% and 66.2 ± 1.5%, n = 8 current smokers, n = 3 former smokers, BMI 26.4 ± 1.9 and 25.4 ± 0.9 kg/m2) versus n = 14 healthy controls	Mild COPD patients showed CV autonomic abnormalities at baseline (higher heart rate, depressed baroreflex sensitivity)
Open label, crossover (Faager et al., ref. 51)	Pursed lips breathing versus not pursed lips breathing, follow-up time unknown	Lung function and exercise capacity	n = 32 COPD: GOLD stage I (n = 1 female, FEV1% pred 89, PEF 390 L/min, endurance shuttle walking test 1, age 76 years), GOLD stage II (n = 6 [1 male], mean baseline FEV1% pred 61 ± 9, PEF 305 ± 107 L/min, endurance shuttle walking test 4, age 69 ± 4 years), GOLD stage III (n = 11), GOLD stage IV (n = 14)	Outcomes not stratified by severity
Studies with baseline data only, no PBO outcome data
Parallel-group (Spencer et al., ref. 47)	Weekly supervised exercise + home exercise versus control (unsupervised home exercise), follow-up 12 months	6MWD, SGRQ, lung function, shuttle walk tests (ISWT, ESWT), HAD Score, hospitalization, exacerbations	n = 48 COPD moderate GOLD stage II, 46% male, n = 11 current smokers (test group mean age 65 ± 8 y, BMI 25 ± 5 kg/m2, FEV1/FVC% 51 ± 11, FEV1% pred 57 ± 21, 6MWD 523 ± 107 meters; control group age 67 ± 7 y, BMI 27 ± 7 kg/m2, FEV1/FVC% 54 ± 11, FEV1% pred 60 ± 16, 6MWD 530 ± 86 meters)	No PBO or suitable control arm.
Parallel-group, Lung Health Study (Scanlon et al., ref. 29)	Smoking cessation intervention + ipratropium versus smoking cessation intervention + PBO versus advice to quit, 5-year follow-up	Smoking cessation rates, lung function	n = 3926 COPD, mean post-bronchodilator FEV1% pred (79.4 ± 9.1 [sustained quitters], 78.4 ± 9.2 [intermittent quitters], 78.1 ± 8.9 [continuing smokers]), FEV1 (2.82 ± 0.64 L, 2.74 ± 0.64 L, 2.75 ± 0.61 L) FEV1/FVC (63.1 ± 5.6, 62.9 ± 5.5, 63.0 ± 5.4). Wheezing in 74.4%, 76.8%, 76.9%, chronic cough in 39.7%, 40.6%, 44.3%, dyspnea in 39%, 41.3%, 44.1%. Age 49.1 ± 6.8 years, 48.6 ± 6.9 years, 48.3 ± 6.8 years, men 67.1%, 61.9%, 63.9%, pack-years 40.1 ± 18.8, 39.4 ± 18.2, 40.8 ± 19.0, BMI 26.0 ± 3.9, 25.9 ± 3.9, 25.4 ± 3.9 kg/m2, bronchodilator response% 4.5 ± 4.9, 4.6 ± 4.8, 4.1 ± 5.1	No PBO or suitable control arm
Parallel-group, Lung Health Study (Harber et al., ref. 53)	Smoking cessation intervention + ipratropium versus smoking cessation intervention + PBO versus advice to quit, 5-year follow-up	Effect of air pollution on lung function, lung function	n = 5724 COPD, mean age 48.4 years (range 34–66 years) (men) and 48.5 years (35–67 years) (women), pack-years 42.8 ± 20.1 (men) and 36.2 ± 16.5 (women). Mean FEV1% pred for men 75.2 ± 8.8 (pre-bronchodilator) 78.4 ± 9.2 (post-bronchodilator); for women 75.1 ± 8.8 (pre-bronchodilator) 78.2 ± 9 (post-bronchodilator). Mean FVC% pred for men 96.6 ± 10.6 (pre-bronchodilator) 97.6 ± 10.6 (post-bronchodilator); for women 97.3 ± 10.3 (pre-bronchodilator) 98.1 ± 10.4 (post-bronchodilator). Mean FEV1/FVC for men 62.7 ± 5.7 (pre-bronchodilator) 64.6 ± 6.2 (post-bronchodilator); for women 63.3 ± 5.3 (pre-bronchodilator) 65.5 ± 5.9 (post-bronchodilator)	No PBO or suitable control arm
Parallel-group, Lung Health Study (Kanner et al., ref. 54)	Smoking cessation intervention + ipratropium versus smoking cessation intervention + PBO versus advice to quit, 5-year follow-up	Quit rate, lower respiratory illness, physician visits, change in FEV1	n = 5887 COPD, mean age 48.5 ± 6.8 years (intervention) 48.4 ± 6.8 years (usual care), men 62% and 64%, pack-years 40.4 ± 19.2 and 40.5 ± 18.9, FEV1% pred 78.3 ± 9.1 and 78.2 ± 9.1, bronchodilator response 4.3 ± 5.1 and 4.2 ± 5.1%, doctor visits for lower respiratory illness 13 ± 33 and 11 ± 32 per year. Chronic bronchitis 35%	No PBO or suitable control arm
Parallel-group, Lung Health Study (Kanner et al., ref. 55)	Smoking cessation intervention + ipratropium versus smoking cessation intervention + PBO versus advice to quit, 5-year follow-up	Gender effects in airway hyper-responsiveness	n = 5662 COPD, mean age 48.4 ± 7 years (men) 48.5 ± 6.6 years (women), pack-years 42.7 ± 20 and 36.4 ± 16.8, FEV1% pred 74.9 ± 9.6 and 75.1 ± 8.8, FEV1 2.94 ± 0.48 L and 2.08 ± 0.35 L, FEV1/FVC% 62.7 ± 6.2 and 63.5 ± 5.7. Chronic cough in 42.9% and 40.4%, wheezing history in 78.3% and 74%, no shortness of breath in 63.4% men and 46.7% women	No PBO or suitable control arm
Parallel-group, Lung Health Study (Kanner et al., ref. 56)	Smoking cessation intervention + ipratropium versus smoking cessation intervention + PBO versus advice to quit, 5-year follow-up	Symptoms	n = 5887 COPD. 49–51% had cough ≥ 3 months per year: mean pre-bronchodilator FEV1% pred 74.3 ± 9 versus 76 ± 8.6 for asymptomatic (p < 0.001), FEV1/FVC% 62.6 ± 5.7 versus 63.3 ± 5.3 (p < 0.001), age 48.2 ± 6.7 versus 48.7 ± 6.9 y, pack-years 42.2 ± 18.9 versus 38.5 ± 19.1, men 63.2% and 62.4%, BMI 25.6 ± 4 and 25.5 ± 3.9 kg/m2. Baseline data also provided for phlegm, wheeze, and dyspnea (same patients, stratified by symptom presence/absence)	No PBO or suitable control arm
Parallel-group, Lung Health Study (Tashkin et al., ref. 57)	Smoking cessation intervention + ipratropium versus smoking cessation intervention + PBO versus advice to quit, 5-year follow-up	Relationship between baseline metacholine reactivity and change in lung function	n = 5733 COPD, mean age 48.4–48.6 years, men 61–64%. FEV1% pred 78.2 ± 9.1 (ipratropium), 78.4 ± 9.0 (PBO), 78.3 ± 9.1 (usual care). FEV1/FVC% 64.9 ± 6.3, 65 ± 6, 65 ± 6. FEV1 2.73 ± 0.64 L, 2.75 ± 0.62 L, 2.76 ± 0.62 L. Pack-years 40.3 ± 19.6, 40.2 ± 18.8, 40.5 ± 18.9. Bronchodilator response 4.2 ± 5.1, 4.4 ± 5.0, 4.3 ± 5.1%. LMCR for men (0.386 ± 0.365, 0.356 ± 0.355, 0.358 ± 0.360%/mg/ml and women (0.591 ± 0.392, 0.592 ± 0.387, 0.616 ± 0.365)	No PBO or suitable control arm
Open-label, parallel-group (DiLorenzo et al., ref. 41)	Theophylline SR bid versus salmeterol 50 μg bid, 12 months	Peak flow, symptoms, rescue medication, blood theophylline, lung function, assessment of efficacy, SF-36®	n = 178 COPD (ATS), symptomatic, mean age 56 ± 12.9 years, 69% male, n = 12 smokers, n = 81 ex-smokers. Mean baseline FEV1 2.0 ± 0.6 L (salmeterol) 1.9 ± 0.5 L (theophylline). FVC 2.9 ± 0.9 L and 2.8 ± 0.7 L. PEFR morning 324.0 ± 99.7 L/min and 298.8 ± 88.7 L/min. PEFR evening 340.9 ± 104.7 L/min and 314.0 ± 89.2 L/min	No PBO or suitable control arm
Double-blind parallel-group (Rabe et al., ref. 42)	Tiotropium 18 μg od + formoterol 12 μg bid versus salmeterol 50 μg bid + fluticasone 500 μg bid, 6 weeks	Lung function	n = 399 GOLD stage II (mean FEV1 1.48 L, FVC 2.86 L) and n = 193 GOLD stage III–IV. Baseline data not stratified	No PBO or suitable control arm
Open-label, crossover (Kanehara et al., ref. 43)	Theophylline 400 mg versus tulobuterol 2 mg, 8 weeks each arm	Pulmonary function, SGRQ	n = 26 COPD: GOLD stage I (n = 15) or GOLD II (n = 11), 77% male. Combined GOLD stage I and II baseline FEV1% pred 83.8 ± 16.3, FVC 2.37 ± 0.56 L, FEV1 1.50 ± 0.39 L, FEV1/FVC 63.2 ± 4.41%, age 77.3 ± 3.3 y, SGRQ total score 35.7 ± 17.9 (tulobuterol) to 34.0 ± 15.9 (theophylline). n = 8 were never-smokers, n = 4 current smokers (pack-years 23.7 ± 8.69), n = 14 former smokers (pack-years 47.9 ± 35.2)	No PBO or suitable control arm
Open-label, parallel-group (D'Elia et al., ref. 44)	Neltenexine versus carbocysteine, 12 days	Symptoms, lung function	n = 30 COPD (BTS or ERS criteria) with current exacerbation. Mean age 65.43 ± 15.19, 50% male, pack-years 28 ± 13.77, n = 2 were non-smokers, n = 15 current smokers, mean exacerbations 1.23 ± 0.5 per year, FEV1 1.87 ± 0.54 L (neltenexine) to 1.9 ± 0.51 L (carbocysteine), VC 2.46 ± 0.69 L and 2.46 ± 0.52 L, PEF 3.74 ± 1.3 L and 3.95 ± 1.45 L. Symptoms (scale 0 = absent, 4 = very severe): cough 2.53 ± 0.64/2.47 ± 0.52, dyspnea 2.60 ± 1.06/2.07 ± 0.7. Sputum characteristics (1 = serous, 5 = purulent) 2.53 ± 1.25/1.80 ± 1.61	No PBO or suitable control arm
Open-label, parallel-group (Santra et al., ref. 45)	Doxofylline 400 mg bid versus SR theophylline 400 mg od, 4 weeks	Lung function, salbutamol use	n = 75 moderate COPD, 60% male, aged 40–70 years. For doxofylline group FEV1% pred 58.19 ± 5.13, PEFR 49.26 ± 5.32% pred, FEV1/FVC 59.06 ± 4.95. For theophylline group FEV1% pred 57.9 ± 4.88, PEFR 49.76 ± 5.38% pred, FEV1/FVC 61.7 ± 4.27. No smoking information	No PBO or suitable control arm
Double-blind, crossover (AkkocaYildiz et al., ref. 46)	Formoterol 12 μg bid versus ipratropium bromide 40 μg qid, 2 weeks each arm	Exercise capacity, lung function, functional parameters	n = 10 COPD GOLD stage I or II, 90% male, all heavy smokers, pack-years 47.75 ± 26.50, mean age 51.1 ± 5.45 years. Mean FEV1% 68.95 ± 10.64, FVC% 82.65 ± 10.85, FEV1/FVC% 68.00 ± 6.60, FEF25–75% 41.40 ± 11.25, TLC% 93.53 ± 12.72, FRC% 95.71 ± 19.45, RV% 121.12 ± 39.19, RV/TLC% 41.59 ± 9.10, IC 2.80 ± 0.62 L, DLCO% 77.89 ± 17.76, exercise time (min) 7.03 ± 0.73, work rate (Watt) 121.50 ± 15.52	No PBO or suitable control arm

6MWD: 6-min walk distance test; ATS: American Thoracic Society; BDI: baseline dyspnea index; bid: twice daily; BMI: body mass index; BTS: British Thoracic Society; CI: confidence interval; COOP/WONCA: Dartmouth COOP Functional Health Assessment Charts/World Organization of General Practice/Family Physicians; COPD: chronic obstructive pulmonary disease; CRQ: Chronic Respiratory Questionnaire; CV: cardiovascular; DIMCA: Detection, Intervention, and Monitoring Program of COPD and Asthma; DLCO: diffusing capacity of the lung for carbon monoxide; ERS: European Respiratory Society; ESWT: endurance shuttle walk test; EUROSCOP: European Respiratory Society Study on Chronic Obstructive Pulmonary Disease; FEF: forced expiratory flow; FEV1: forced expiratory volume in 1 sec; FRC: functional residual capacity; FVC: forced vital capacity; GOLD: Global Initiative for Chronic Obstructive Lung Disease; HAD: hospital anxiety and depression; HRmax: maximum heart rate; IC: inspiratory capacity; ISWT: incremental shuttle walking test; IVC: inferior vena cava; LMCR: light meal combat ration; od: once daily; MRC: Medical Research Council; PBO: placebo; PEF: peak expiratory flow; PEFR: peak expiratory flow rate; PIF: peak inspiratory flow; RV: right ventricle; SF-36®: Short Form (36) Health Survey; SFC: salmeterol/fluticasone propionate combination; SGRQ: St George's Respiratory Questionnaire; SR: sustained release; SVC: slow vital capacity; TDI: transition dyspnea index; TLC: total lung capacity; TORCH: Towards a Revolution in COPD Health; UPLIFT®: Understanding Potential Long-term Impacts on Function with Tiotropium; VC: vital capacity; VEmax: maximal ventilatory reserve; V02max: maximum oxygen consumption; V02max: maximum oxygen consumption; VTmax: maximum tidal volume; Wmax: maximum workload.

Table 2.  COPD disease progression: summary of available outcomes data (baseline and over study period) in mild and moderate COPD patients in control groups.

Outcome	Mild COPD (GOLD stage I)	Moderate COPD (GOLD stage II)
Lung function: rate of decline in FEV1	• –14 ml/year (32)	• –49 to –60 ml/year (30, 31)
Rate of exacerbations	• Severe exacerbations: 0.07/year (34)	• Moderate or severe exacerbations: 0.70 to 0.82/year (29, 30)
• Severe exacerbations: 0.10/year (30)
Symptoms (dyspnea)	• Baseline BDI = 8.3; baseline MRC score = 1.8 (chronic exercise-related dyspnea) (37)
• 57 symptom episodes in 17/24 (71%) patients over 2 years (32)	• Dyspnea present in ∼40% patients at baseline (29, 59)
SGRQ total score (QoL)	• 36 units at baseline (61)	• 39–42 units at baseline (30, 31, 47)
• Change over time: 1.3 unit improvement (3 y) (31) to worsening of 0.99 units (4 years) (30)
Exercise capacity	• Baseline exercise capacity 72–75% of pred (37, 61)
• Power output > 20% lower than normal individuals (62)
• Muscle strength reduced (49)	• Baseline (after PR) 6MWD 523–530 meters (47)
Functional status	• Baseline COOP/WONCA score range: 1.2 for social activities (not impaired) to 2.4 for general health (slightly impaired) (32)	NR
Mortality	NR	• Rates of 1.6 to 11.4% over 3–4 years (30, 31, 38)

COPD: chronic obstructive pulmonary disease; GOLD: Global Initiative for Chronic Obstructive Lung Disease; FEV1: forced expiratory volume in 1 sec; SGRQ: St George's Respiratory Questionnaire; QoL: quality of life; COOP/WONCA: Dartmouth COOP Functional Health Assessment Charts/World Organization of General Practice/Family Physicians; PR: pulmonary rehabilitation; 6MWD: 6-minute walk distance test; NR: not reported.

Table 3.  Articles meeting the inclusion criteria for the systematic review and which reported outcomes with intervention (the effect of treatment on mild-to-moderate COPD).

Citation	Interventions, follow up	Outcome measures	Patients and baseline characteristics	Main findings
Pharmacologic intervention only—PBO-controlled
Double-blind, PBO-controlled, parallel-group (DIMCA study) (van Grunsven 2003) (32)	Fluticasone propionate 250 μg bid versus PBO, 2 years	Pulmonary function, symptoms, functional status (COOP/WONCA), exacerbations	n = 48 early COPD, 3 months’ symptoms, previous FEV1 decline 109 ± 46 ml/year (fluticasone) 124 ± 66 ml/year (PBO). Mean age 46 ± 10 years and 47 ± 11 years, 50% and 54% male, current smokers 50% and 33%, pack-years 11.9 ± 9.5 and 5.8 ± 8.4. Mean baseline post-BD FEV1% pred 98 ± 15 and 99 ± 18 FEV1 3.16 ± 0.68 L and 3.19 ± 0.79 L; pre-BD FEV1% pred 95 ± 18 and 98 ± 17; FEV1 3.05 ± 0.7 L and 3.17 ± 0.76 L; pre-BD FEV1/FVC 75 ± 10% and 77 ± 6%; FEV1 reversibility% pred 4.0 ± 5.1 and 3.0 ± 4.0; symptom score 1.7 ± 1.5 and 1.3 ± 1.3. COOP/WONCA scores varied from not impaired (1.2 ± 0.6 for social activities) to slightly impaired (2.4 ± 1.2 for general health)	Over 2-year study, annual rate of post-BD FEV1 decline –93 ± 30 ml (fluticasone, n = 24) versus –14 ± 17 (PBO, n = 24; p = 0.001); for pre-BD FEV1 decline, –85 ± 32 mL (fluticasone) versus –38 ± 19 ml (PBO, p = 0.078). At 2 years, difference between groups was 47 ± 63 ml for post-bronchodilator FEV1 (favoring PBO, p = 0.458) and 60 ± 70 ml for pre-bronchodilator (favoring fluticasone, p = 0.394). No difference between groups in PC20 at any time point. Exacerbations: 6 in 5 fluticasone patients versus 4 in 3 PBO patients. No difference between groups for COOP/WONCA scores. 57 episodes of increased respiratory symptoms in 17 patients (PBO) versus 127 episodes in 18 patients (fluticasone)
Double-blind PBO-controlled parallel-group (DIMCA 3a study) (van Grunsven 2000) (40)	Fluticasone propionate 250 μg versus PBO, 2 years	Compliance, patient opinion	n = 48 COPD. Mean FEV1% pred 96 ± 17, FEV1 reversibility 3 ± 5% pred, age 47 years (range 29–71 years), 42% smokers, mean pack-years 9 (0–29), 52% male, number of symptoms in past 3 months 1.5 ± 1.4	Only outcomes are compliance
Double-blind PBO-controlled, parallel-group, post-hoc analysis of EUROSCOP study (Lofdahl 2007) (34)	Budesonide 800 μg/day versus PBO, 3 years	Ischemic events, and baseline predictors	n = 1277 COPD, current smokers, pack-years median 36 (range 0–171), 73% male, mean age 52.5 years (range 25–66 y), BMI 24.8 (15–44) kg/m2, FEV1 2.5 (1.0–4.7) L, FEV1% pred76.9 (42–103), IVC 4.1 (1.9–7.8) L	Estimated annual severe exacerbation rate (oral steroids) reduced by 37% for budesonide (n = 593) versus PBO (n = 582) (0.05 versus 0.07; p = 0.002); yearly exacerbation rate ratio of 0.63 (95% CI, 0.47–0.85). Ischemic events significantly lower for budesonide (3%) versus PBO (5.3%; p = 0.048)
Double-blind, PBO-controlled, parallel-group, pre-specified subgroup analysis of UPLIFT® trial (Decramer et al., ref. 30)	Tiotropium 18 μg od versus PBO, 4 years	Yearly rates of decline in pre-bronchodilator FEV1 and in post-bronchodilator FEV1, other pulmonary function outcomes, SGRQ, time to first exacerbation, numbers of exacerbations	n = 2739 COPD GOLD stage II, 72% male, mean age 65 ± 9 years (tiotropium) 64 ± 9 years (PBO), BMI 27 ± 5 kg/m2 (both groups), current smokers 31% (tiotropium), and 35% (PBO), pack-years 48 ± 28 (tiotropium) 47 ± 27 (PBO), pre-BD FEV1% pred 49 ± 8 (both groups) 1.36 ± 0.4 L (both groups), post-BD FEV1% pred 59 ± 6 (both groups) 1.63 ± 0.4 L (both groups), SGRQ total score 41 ± 17 units (tiotropium) and 42 ± 17 units (PBO)	Lower rate of decline of post-bronchodilator FEV1 for tiotropium (n = 1384) versus PBO (n = 1355) (43 ± 2 ml/year versus 49 ± 2 ml/year; p = 0.024); no difference for FVC and SVC and no difference for pre-bronchodilator values. Mean values of pre-bronchodilator and post-bronchodilator FEV1 were higher in the tiotropium group than in the control group at all time points during the trial (p < 0.0001 for all time points—between-group differences 101–119 ml and 52–82 ml, respectively). Mean pre-bronchodilator FVC was 164–194 ml higher and mean pre-bronchodilator SVC was 44–175 ml higher in the tiotropium group (p < 0.001 at all time points). Differences for post-bronchodilator FVC and SVC were 42–68 ml (p < 0.01 at all time points) and 15–35 ml (p > 0.05 at all time points), respectively. SGRQ total score deteriorated in both groups (tiotropium 0.89 units/year [SE 0.13]; control 0.99 units/year [SE 0.13]; p = 0.58), but better at all time points for tiotropium versus PBO (p ≤ 0.006 for all time points). Differences in SGRQ scores between groups ranged from 2.7–4.0 units (total score) and 2.3–3.9 units (impact), 2.7–4.1 units (symptom) and 3.1–4.4 units (activity). One or more exacerbations in 60% tiotropium and 65% PBO patients; mean number per patient per year significantly less for tiotropium (HR 0.80; 95% CI, 0.72–0.88; p < 0.0001). One or more hospitalized exacerbations in 15% tiotropium and 19% PBO patients. Time to first exacerbation (HR 0.82; 95% CI; 0.75–0.90; p < 0.0001) and time to hospitalized exacerbation (0.74; 95% CI, 0.62–0.88; p = 0.001) longer for tiotropium versus PBO. Risks of mortality during trial from lower respiratory tract conditions and all causes lower for tiotropium versus PBO; but no significant effect on mortality
Double-blind PBO-controlled, parallel-group (Pauwels et al., ref. 38)	Budesonide 400 μg bid versus PBO, 3 years	FEV1	n = 1227 COPD, mean age 52.4 ± 7.7 (PBO) and 52.5 ± 7.5 years (budesonide), 72.2% and 73.5% male, current smokers, pack-years 39.2 ± 20.1 and 39.4 ± 20.1, about 10% quit during study. Pre-bronchodilator FEV1% pred 76.9 ± 13.2 versus 76.8 ± 12.4, FEV1 2.54 ± 0.64 L and 2.53 ± 0.64 L, FEV1/SVC 61.7 ± 7.0 and 62.2 ± 6.8. Reversibility of FEV1 2.8 ± 3.6 and 2.9 ± 3.8% pred	Median decline in post-bronchodilator FEV1 over 3-year period 140 ml (budesonide, n = 634) versus 180 ml (PBO, n = 643; p = 0.05), or 4.3% and 5.3% pred value, respectively. FEV1 improved with treatment over first 6 months, then declined at similar rate to PBO from 9 months to end of treatment. Similar mortality both groups
Double-blind PBO-controlled, parallel-group, post-hoc analysis of TORCH study (Jenkins et al., ref. 31)	Salmeterol 50 μg versus fluticasone propionate 500 μg versus SFC 50/500 μg versus PBO; 3 years	Pulmonary function, exacerbations, SGRQ	n = 6112 COPD: GOLD stage II (n = 2156, 72% male, 47% current smokers, mean age 64.9 ± 8.7 years, BMI 26.6 ± 5.2 kg/m2, post-BD FEV1% pred 58.8 ± 7.4, FEV1 1,616 ± 399 ml, reversibility FEV1 4.3 ± 4.0% pred, SGRQ total score 45.4 ± 17.7, exacerbations requiring steroids/antibiotics in last year 0.9 ± 1.2, exacerbations requiring hospitalization in last year 0.2 ± 0.5), GOLD stage III (n = 3019), GOLD stage IV (n = 937)	For GOLD stage II patients, SFC (n = 562) versus PBO (n = 535) resulted in improvements in FEV1 (101 ml; 95% CI, 71–132), reduction in rate of decline in FEV1 by 16 ml/year (95% CI, 0–32), 31% (19–40) reduction in annual rate of moderate/severe exacerbations (mean 0.57/year for SFC versus 0.82/year for PBO) and reduced mortality (by 33% [HR 0.67; 95% CI, 0.45–0.98; absolute risk reduction 3.6%]. Difference in adjusted mean change in SGRQ for SFC versus PBO was –2.3 (–4.0 to –0.7)
Double-blind, PBO-controlled, parallel-group (Rennard et al., ref. 39)	Infliximab 3 mg/kg versus infliximab 5 mg/kg versus PBO, 44 weeks	CRQ, pre-BD FEV1, 6MWD, SF-36®, TDI, exacerbations	n = 234 COPD: GOLD stage I (n = 7), GOLD stage II (n = 98), GOLD stage III (n = 93), GOLD stage IV (n = 36). Baseline data not stratified for severity	GOLD stage I patients not analyzed. For GOLD stage II patients, no effect of infliximab (versus PBO) on any outcome. At Week 24, for GOLD stage II, mean change from baseline in CRQ total score 12.1 for PBO versus 10.8 for infliximab (p = 0.74), 6MWD 2.4 meters for PBO versus 17.6 for infliximab (p = 0.39); the SF-36® score, the TDI score, cough symptoms, and sputum production improved, with no significant differences between groups. Few 44-week data reported; no difference between groups in CRQ.
PBO-controlled, parallel-group (Dal Negro et al., ref. 35)	Erdosteine 300 mg bid versus N-acetylcysteine 600 mg bid versus PBO, 10 days	FEV1 reversibility to salbutamol	n = 30 COPD GOLD stage I or II, 67% male, mean BMI 24.6 ± 2.1 kg/m2, mean pre-bronchodilator FEV1% pred 63.3 ± 8.4 (erdosteine) 58.8 ± 7 (N-acetylcysteine) 60.1 ± 7.8 (PBO); post-BD FEV1% pred 64.7 ± 8.8, 59.8 ± 9.8, 62.5 ± 7.4; FEV1/FVC% 61.4 ± 6.2, 54.6 ± 11.1, 61.5 ± 8.5, FEV1% pred reversibility 1.38 ± 4.4, 1.02 ± 3.6, 2.38 ± 1.9, age 60.8 ± 12.1 years, 63.6 ± 11.3 years, 60.2 ± 13.4 years, current smokers, pack-years 25.4 ± 3.5, 26.3 ± 3.1, 28.1 ± 2.3. For PBO, FEV1 0.061 ± 0.05 L	FEV1 response to salbutamol significantly enhanced after erdosteine (6.45 ± 4.3% at Day 4 [p = 0.0038 versus PBO] and 6.42 ± 4.2% Day 10 [p = 0.0047]; absolute changes of +0.1461 [95% CI, –0.002–0.294], and +0.1411 [95% CI, 0.065–0.217], respectively); no change with PBO or N-acetylcysteine. Slight increase in FVC with erdosteine (–0.002 L at baseline to 0.147 L at Day 10) only
Double-blind PBO-controlled crossover (O'Donnell et al., ref. 37)	Ipratropium bromide 500 μg versus PBO; 2 days each arm, 7 days between visits (total 1 month)	Pulmonary function, dyspnea, ventilatory parameters, exercise test	n = 16 COPD GOLD stage I, 63% male, mean age 63 ± 8 y, BMI 27.8 ± 4.6 kg/ m2, BDI focal score 8.3 ± 2, MRC dyspnea scale 1.8 ± 0.7, symptom-limited peak work rate 72% pred, post-BD FEV1% pred 90 (2.5 ± 0.58 L), FVC 108% pred (4.25 ± 1.08 L), FEV1/FVC 84% (59 ± 7), RV (2.83 ± 0.48, 129% pred), TLC (7.11 ± 1.50, 113%) IC (3.01 ± 0.97, 103%), FRC (4.10 ± 0.91, 122%); smoking history 44 ± 16 pack-years, n = 4 current smokers	Ipratropium increased FEV1 by 5 ± 9% pred, decreased RV 12 ± 20% pred and specific airway resistance 81 ± 93% pred (all p < 0.05). During exercise, dynamic IC and VT significantly increased (p < 0.05), dyspnea decreased (p = 0.07) and dyspnea/ventilation ratios decreased (p < 0.05). At peak of exercise (80–85% Wmax) exercise time was 8.2 ± 4.8 min, dyspnea BORG 7.7 ± 2.5; at constant-load exercise dyspnea BORG was 6.6 ± 2.4 (p < 0.07 versus PBO)
Double-blind, crossover (Kryger et al., ref. 36)	Ramelteon 16 mg versus PBO, 1 night each arm	FEV1 and FEV1/FVC at baseline	n = 26 COPD. Mean FEV1% pred of eligible patients (n = 14) 60.6. Mean baseline FEV1/FVC of eligible patients (n = 14) 59.9%. Baseline characteristics not stratified by severity	Outcomes not stratified by spirographic severity
Double-blind PBO-controlled crossover (Kryger et al., ref. 33)	Ramelteon 8 mg versus PBO, single dose, 1 night each arm	Polysomnography, blood gases, respiratory effort	n = 25 COPD moderate or severe; n = 9 GOLD stage II, n = 16 GOLD stage III. Baseline data not stratified for severity	Only oxygen saturation data are stratified by severity
Pharmacologic intervention only—non-PBO controlled
Open-label, parallel-group (DiLorenzo et al., ref. 41)	Theophylline SR bid versus salmeterol 50 μg bid, 12 months	Peak flow, symptoms, rescue medication, blood theophylline, lung function, assessment of efficacy, SF-36®	n = 178 COPD (ATS), symptomatic, mean age 56 ± 12.9 y, 69% male, n = 12 smokers, n = 81 ex-smokers. Mean baseline FEV1 2.0 ± 0.6 L (salmeterol) 1.9 ± 0.5 L (theophylline). FVC 2.9 ± 0.9 L and 2.8 ± 0.7 L. PEFR morning 324.0 ± 99.7 L/min and 298.8 ± 88.7 L/min. PEFR evening 340.9 ± 104.7 L/min and 314.0 ± 89.2 L/min	At 3 months, salmeterol (n = 91) improved PEFR morning significantly more than theophylline (n = 87) (difference between groups 16.56 L/min, p = 0.02), and increased number of symptom-free nights (from baseline 23.4–67.2% for salmeterol, 18.4–49.3% for theophylline; p < 0.01) and days (14.6–59.7% for salmeterol, 13.7–46.1% for theophylline; p < 0.01) and amount of rescue medication (p < 0.001). FEV1 and FVC improved in both groups (significant difference in max FEV1 at 1, 2, and 3 months); improvements in FEV1 with salmeterol persisted over 12 months, while those with theophylline were not maintained at 9 and 12 months. Significantly higher mean FVC for salmeterol versus theophylline at 2 months (p = 0.03), and higher mean increases over baseline for salmeterol: 0.24 L (1 month), 0.26 L (2 months) and 0.29 L (3 months), compared with theophylline (0.13 L, 0.12 L, 0.16 L). Salmeterol improved 3 SF-36® domains more than theophylline (physical functioning at 3 months [adjusted mean changes 10.34 versus 3.79, p = 0.02], change in health perception at 9 months [24.25 versus 14.41, p = 0.03] and social functioning at 12 months [15.13 versus 6.84, p = 0.04])
Double-blind, parallel-group (Rabe et al., ref. 42)	Tiotropium 18 mg qd + formoterol 12 μg bid versus salmeterol 50 μg bid + fluticasone 500 μg bid, 6 wks	Lung function	n = 399 GOLD stage II (mean FEV1 1.48 L, FVC 2.86 L) and n = 193 GOLD stage III/IV. Baseline data not stratified	For GOLD stage II patients, significant benefit for tiotropium/formoterol versus SFC at 6 weeks (FEV1 AUC0–12 [1.84 ± 0.02 versus 1.77 ± 0.02 L], peak FEV1 [1.98 ± 0.02 versus 1.89 ± 0.03 L], FVC AUC0–12 [3.33 ± 0.03 versus 3.18 ± 0.04 L], peak FVC [3.55 ± 0.04 versus 3.38 ± 0.04]; all p < 0.05. No difference between treatments for pre-dose FEV1 or FVC). Other data not stratified by severity
Open-label, crossover (Kanehara et al., ref. 43)	Theophylline 400 mg versus tulobuterol 2 mg, 8 weeks each arm	Pulmonary function, SGRQ	n = 26 COPD: GOLD stage I (n = 15) or GOLD stage II (n = 11), 77% male. Combined GOLD stage I/II baseline FEV1% pred 83.8 ± 16.3, FVC 2.37 ± 0.56 L, FEV1 1.50 ± 0.39 L, FEV1/FVC 63.2 ± 4.41%, age 77.3 ± 3.3 y, SGRQ total score 35.7 ± 17.9 (tulobuterol) to 34.0 ± 15.9 (theophylline). n = 8 were never-smokers, n = 4 current smokers (pack-years 23.7 ± 8.69), n = 14 former smokers (pack-years 47.9 ± 35.2)	For GOLD stage I/II patients (not stratified), no significant change from baseline in SGRQ total for either treatment (activity domain worsened p < 0.05 versus baseline in both treatment groups, other domains no change). Theophylline increased pulmonary function significantly versus baseline: FEV1% pred 80.49 ± 14.3 to 86.0 ± 11.6 (p < 0.05); FVC 2.30 ± 0.5 to 2.4 ± 0.47 L (p < 0.05); FEV1 1.46 ± 0.34 to 1.56 ± 0.32 L (p < 0.05); PEF 3.93 ± 1.57 to 4.56 ± 1.64 L/sec (p < 0.05); MEF50 1.22 ± 0.44 to 1.36 ± 0.44 L/s (p < 0.05); MEF25 0.39 ± 0.14 to 0.43 ± 0.14 L/s (p < 0.05). Tulobuterol no effect
Open-label, parallel-group (D'Elia and Sechi, ref. 44)	Neltenexine versus carbocysteine, 12 days	Symptoms, lung function	n = 30 COPD (BTS or ERS) with current exacerbation. Mean age 65.43 ± 15.19, 50% male, pack-yrs 28 ± 13.77, n = 2 were nonsmokers, n = 15 current smokers, mean exacerbations 1.23 ± 0.5 per year, FEV1 1.87 ± 0.54 L (neltenexine) to 1.9 ± 0.51 L (carbocysteine), VC 2.46 ± 0.69 L and 2.46 ± 0.52 L, PEF 3.74 ± 1.3 L and 3.95 ± 1.45 L. Symptoms (scale 0 = absent, 4 = very severe): cough 2.53 ± 0.64 and 2.47 ± 0.52, dyspnea 2.60 ± 1.06 and 2.07 ± 0.7. Sputum characteristics (1 = serous, 5 = purulent) 2.53 ± 1.25 and 1.80 ± 1.61	Neltenexine improved cough (0.40 ± 0.63 neltenexine, 1.13 ± 0.52 carbocysteine) and sputum characteristics (1.40 ± 0.51 and 2.13 ± 0.64) significantly better (p < 0.05 for both) at Day 12 than did carbocysteine; and significantly faster improvement in expectoration, cough and sputum characteristics. Neither drug had any effect on change from baseline in FEV1, PEF, or VC
Open-label, parallel-group (Santra, ref. 45)	Doxofylline 400 mg bid versus theophylline 400 mg od, 4 weeks	Lung function, salbutamol use	n = 75 moderate COPD, 60% male, aged 40–70 years. For doxofylline group FEV1% pred 58.19 ± 5.13, PEFR 49.26 ± 5.32% pred, FEV1/FVC 59.06 ± 4.95. For theophylline group FEV1% pred 57.9 ± 4.88, PEFR 49.76 ± 5.38% pred, FEV1/FVC 61.7 ± 4.27. No smoking information	Compared with baseline, both drugs resulted in significant increase in FEV1, FEV 125–75, and PEFR, but not FEV1/FVC. At Day 28 for doxofylline FEV1% pred 63.36 ± 4.77, PEFR 57.20 ± 6.22% pred, FEV1/FVC 61.46 ± 4.94; for theophylline FEV1% pred 61.8 ± 4.84, PEFR 56.33 ± 5.20% pred, FEV1/FVC 64.03 ± 4.20 (no difference between groups). Both drugs significantly reduced salbutamol use.
Double-blind, crossover (AkkocaYildiz et al., ref. 46)	Formoterol 12 μg bid versus ipratropium bromide 40 μg qid, 2 weeks each arm	Exercise capacity, lung function, functional parameters	n = 10 COPD GOLD stage I or II, 90% male, all heavy smokers, pack-years 47.75 ± 26.50, mean age 51.1 ± 5.45 years. Mean FEV1% 68.95 ± 10.64, FVC% 82.65 ± 10.85, FEV1/FVC% 68.00 ± 6.60, FEF25–75% 41.40 ± 11.25, TLC% 93.53 ± 12.72, FRC% 95.71 ± 19.45, RV% 121.12 ± 39.19, RV/TLC% 41.59 ± 9.10, IC 2.80 ± 0.62 L, DLCO% 77.89 ± 17.76%, exercise time (min) 7.03 ± 0.73, work rate (Watt) 121.50 ± 15.52	Formoterol significantly improved FEV1% (76.60 ± 9.05, p < 0.05) and FEV1/FVC% (71.50 ± 6.24 p < 0.05) at 90 min post-dose, and FEV1/FVC% (71.20 ± 6.19 p < 0.05) at Day 14. Ipratropium significantly improved FEV1% (75.00 ± 8.98 p < 0.05) and FEF25–75 (48.20 ± 16.92 p < 0.05) at 90 min post-dose and peak oxygen uptake and minute ventilation at 90 min. Both treatments increased exercise time (8.10 ± 1.17 [formoterol] 8.00 ± 0.94 [ipratropium] both p < 0.05 versus baseline at Day 14). No difference between treatments on exercise capacity and functional parameters. Improvement in exercise capacity also correlated with increase in FEV1
Nonpharmacologic intervention only
Parallel-group (Spencer et al., ref. 47)	Weekly supervised exercise + home exercise versus control (unsupervised home exercise), follow-up 12 months	6MWD, SGRQ, lung function, shuttle walk tests (ISWT, ESWT), HAD Score, hospitalization, exacerbations	n = 48 COPD moderate GOLD stage II, 46% male, n = 11 current smokers (test group mean age 65 ± 8 y, BMI 25 ± 5 kg/m2, FEV1/FVC% 51 ± 11, FEV1% pred 57 ± 21, 6MWD 523 ± 107 meters; control group age 67 ± 7 y, BMI 27 ± 7 kg/m2, FEV1/FVC% 54 ± 11, FEV1% pred 60 ± 16, 6MWD 530 ± 86 meters)	At 12 months, mean difference (n = 24/group) showed no significant change from baseline in 6MWD (test −11 meters, 95% CI, –21 to 10 meters; control –6 meters, 95% CI, –34 to 11 meters) or total SGRQ score (test 3, 95% CI, –0.8 to 7; control –3; 95% CI, –7 to 3). At 12 months, no significant change from baseline, nor difference between groups, for lung function, ISWT, ESWT, HAD Score, hospital admissions, or length of hospital stay in either group. No difference in number of exacerbations between groups: exacerbation rate 2.3 ± 3 (test) 1.4 ± 1.8 (control) in 12 months. Prior to the study, 8-wk pulmonary rehabilitation significantly improved 6MWD and SGRQ
Double-blind, PBO-controlled, parallel-group (Soler et al., ref. 48)	OM-85 (bacterial extracts: test) versus PBO, for 30 days then 10-day course for Months 3, 4, 5; total 6 months	Exacerbation rate	n = 273 COPD GOLD stage I or II, 28–33% smokers, with current exacerbation. Mean age 57.3 (95% CI, 55.7–58.9) years (test) and 57.9 years (56.2–59.6) (PBO), 54.9% and 43.5% male, BMI 26.3 (25.4–27.2), and 26.5 (25.7–27.3) kg/m2. Mean exacerbations in last year 2.96 ± 1.69 and 3.32 ± 1.64. Mean FEV1% pred 85 (81.7–88.3) and 82.6 (79.9–86.1). Mean baseline FVC% 91 (88.2–93.8) and 89.7 (86.7–93.3)	29% fewer exacerbations over 6 months for test (n = 142) (0.61 per patient) versus PBO (n = 131) (0.86, p = 0.03)
Parallel-group (Clark et al., ref. 49)	Weight training versus control (usual activities, no weight training), 12 weeks	Isokinetic and isotonic muscle function, whole body endurance, maximal exercise capacity and lung function	n = 43 COPD (58% male, mean age 49 ± 11 years, BMI 26 ± 4 kg/m2, FEV1 2.29 ± < 0.88 L (training) and 2.38 ± < 0.86 L (control), FEV1% pred 76 < ± 23 and 79 < ± 23, RV 2.22 ± < 0.91 L and 2.41 ± < 0.88 L, RV% pred 113 < ± 48 and 125 < ± 41, BORG score peak exercise 3.5 < ± 1.9 and 2.4 < ± 1.7) versus n = 52 healthy controls	At baseline, COPD patients had reduced isokinetic muscle function (with the exception of sustained upper limb strength) versus healthy controls. Muscle function and whole body endurance during treadmill walking improved after 12 weeks’ training. Mean improvement on treadmill (joules) was 344 (95% CI, 109–579) for control and 4205 (95% CI, 1404–5650) for training (p < 0.001). No effect on lung function
Double-blind PBO-controlled, parallel-group (Haider et al., ref. 50)	Hypoxic breathing intervals versus PBO (normoxic breathing), 3 weeks	Blood gases, CV data, respiratory control	n = 18 COPD GOLD stages 0–II with mild symptoms (56% male, mean age 51.7 ± 2.4 years, mean FEV1% pred 78.2 ± 3.6 [training] 72.9 ± 1.9 [PBO], FEV1 2.54 ± 0.2 L and 2.32 ± 0.18 L, FVC 3.53 ± 0.3 L and 3.50 ± 0.26 L, FEV1/FVC 72.3 ± 1.9% and 66.2 ± 1.5%, n = 8 current smokers, n = 3 former smokers, BMI 26.4 ± 1.9 and 25.4 ± 0.9 kg/m2) versus n = 14 healthy controls	The CV autonomic abnormalities seen at baseline (higher heart rate, depressed baroreflex sensitivity) normalized with hypoxic training
Open-label, crossover (Faager et al., ref. 51)	Pursed lips breathing versus not pursed lips breathing, same-day follow-up?	Lung function and exercise capacity	n = 32 COPD: GOLD stage I (n = 1 female, FEV1% pred 89, PEF 390 L/min, ESWT 1, age 76 years), GOLD stage II (n = 6 [1 male], mean baseline FEV1% pred 61 ± 9, PEF 305 ± 107 L/min, ESWT 4, age 69 ± 4 years), GOLD stage III (n = 11), GOLD stage IV (n = 14)	Outcomes not stratified by severity
Double-blind crossover (Fujimoto et al., ref. 52)	Compressed air versus O2 during exercise test	6MWD, lung hemodynamics	n = 75 COPD: mild (n = 16, age 71 ± 2 years, baseline FEV1% pred 62.7 ± 2.9, FEV1 1.39 ± 0.06 L, FEV1/FVC% 47.0 ± 1.8, air trapping 0.23 ± 0.06 L, VC% pred 100.0 ± 3.0, RV% 211.3 ± 13.4, RV/TLC 54.2 ± 1.2, ex-smokers with > 30 pack-years), moderate (n = 25), severe (n = 34)	In mild patients, 6MWD 475 ± 20 meters (92.9 ± 5.0% pred) on air and 487 ± 20 meters (95.4 ± 5.4% pred) on O2 (a 2.6 ± 0.8% increase, p < 0.05 versus air). No effect of supplemental oxygen on 6MWD in mild patients with mild desaturation
Mixed interventions (pharmacologic plus non-pharmacologic)
Parallel-group, Lung Health Study (Scanlon et al., ref. 29)	Smoking cessation intervention + ipratropium versus smoking cessation intervention + PBO versus advice to quit, 5-year follow up	Smoking cessation rates, lung function	n = 3926 COPD, mean post-BD FEV1% pred (79.4 ± 9.1 [sustained quitters], 78.4 ± 9.2 [intermittent quitters], 78.1 ± 8.9 [continuing smokers]), FEV1 (2.82 ± 0.64 L, 2.74 ± 0.64 L, 2.75 ± 0.61 L) FEV1/FVC (63.1 ± 5.6, 62.9 ± 5.5, 63.0 ± 5.4). Wheezing in 74.4%, 76.8%, 76.9%, chronic cough in 39.7%, 40.6%, 44.3%, dyspnea in 39%, 41.3%, 44.1%. Aged 49.1 ± 6.8 years, 48.6 ± 6.9 years, 48.3 ± 6.8 years, men 67.1%, 61.9%, 63.9%, pack-years 40.1 ± 18.8, 39.4 ± 18.2, 40.8 ± 19.0, BMI 26.0 ± 3.9, 25.9 ± 3.9, 25.4 ± 3.9 kg/m2, bronchodilator response% 4.5 ± 4.9, 4.6 ± 4.8, 4.1 ± 5.1	Rate of FEV1 decline for sustained quitters with usual care –30 ± 54 ml/year and with smoking cessation intervention –32 ± 46 ml/year; –62 ± 55 ml/year for continuing smokers, –43 ± 57 ml/year for intermittent smokers and –52 ± 56 for all smokers combined. Smoking cessation improved FEV1 and reduced the rate of decline. Predictors of change in lung function included responsiveness to β-agonist, baseline FEV1, methacholine reactivity, age, sex, race, and baseline smoking rate; but not respiratory symptoms
Parallel-group, Lung Health Study (Harber et al., ref. 53)	Smoking cessation intervention + ipratropium versus smoking cessation intervention + PBO versus advice to quit, 5-year follow up	Effect of air pollution on lung function, lung function	n = 5724 COPD, mean age 48.4 years (range 34–66 years) (men) and 48.5 years (35–67 years) (women), pack-years 42.8 ± 20.1 (men) and 36.2 ± 16.5 (women). Mean FEV1% pred for men 75.2 ± 8.8 (pre-bronchodilator) 78.4 ± 9.2 (post-bronchodilator); for women 75.1 ± 8.8 (pre-bronchodilator) 78.2 ± 9 (post-bronchodilator). Mean FVC% pred for men 96.6 ± 10.6 (pre-bronchodilator) 97.6 ± 10.6 (post-bronchodilator); for women 97.3 ± 10.3 (pre-bronchodilator) 98.1 ± 10.4 (post-bronchodilator). Mean FEV1/FVC for men 62.7 ± 5.7 (pre-bronchodilator) 64.6 ± 6.2 (post-bronchodilator); for women 63.3 ± 5.3 (pre-bronchodilator) 65.5 ± 5.9 (post-bronchodilator)	Reduction in FEV1 was related to fume exposure in men (not significant), and continued smoking and airway hyper-responsiveness (men and women). At 5 years (not stratified by intervention): mean FEV1% pred for men 71.1 ± 12.3 (pre-bronchodilator) 75.0 ± 12.0 (post-bronchodilator); for women 70.6 ± 12.7 (pre-bronchodilator) 74.8 ± 12.3 (post-bronchodilator). Mean FVC% pred for men 93.3 ± 12.0 (pre-bronchodilator) 95.9 ± 11.7 (post-bronchodilator); for women 93.3 ± 12.6 (pre-bronchodilator) 96.3 ± 11.8 (post-bronchodilator). Mean FEV1/FVC for men 60.7 ± 7.8 (pre-bronchodilator) 62.4 ± 8.0 (post-bronchodilator); for women 61.0 ± 7.4 (pre-bronchodilator) 62.8 ± 7.9 (post-bronchodilator)
Parallel-group, Lung Health Study (Kanner et al., ref. 54)	Smoking cessation intervention + ipratropium versus smoking cessation intervention + PBO versus advice to quit, 5-year follow up	Quit rate, lower respiratory illness, physician visits, change in FEV1	n = 5887 COPD, mean age 48.5 ± 6.8 years (intervention) 48.4 ± 6.8 years (usual care), men 62% and 64%, pack-years 40.4 ± 19.2 and 40.5 ± 18.9, FEV1% pred 78.3 ± 9.1 and 78.2 ± 9.1, BD response 4.3 ± 5.1 and 4.2 ± 5.1%, doctor visits for lower respiratory illness 13 ± 33 and 11 ± 32 per year. Chronic bronchitis 35%	At 5 y, 21.8% sustained quitters with intervention versus 5.2% usual care. Quitting smoking associated with fewer lower respiratory illnesses. Decline of FEV1 was associated with lower respiratory illness in smokers; mean 0.24 doctor visits per year
Parallel-group, Lung Health Study (Kanner et al., ref. 55)	Smoking cessation intervention + ipratropium versus smoking cessation intervention + PBO versus advice to quit, 5-year follow up	Gender effects in airway hyper-responsiveness	n = 5662 COPD, mean age 48.4 ± 7 years (men) 48.5 ± 6.6 years (women), pack-years 42.7 ± 20 and 36.4 ± 16.8, FEV1% pred 74.9 ± 9.6 and 75.1 ± 8.8, FEV1 2.94 ± 0.48 L and 2.08 ± 0.35 L, FEV1/FVC% 62.7 ± 6.2 and 63.5 ± 5.7. Chronic cough in 42.9% and 40.4%, wheezing history in 78.3% and 74%, no shortness of breath in 63.4% men and 46.7% women	High prevalence of airway hyper-responsiveness, associated with decrease in airway caliber. 87% women and 62.5% men had positive response to methacholine. Seen especially in women due to smaller caliber
Parallel-group, Lung Health Study (Kanner et al., ref. 56)	Smoking cessation intervention + ipratropium versus smoking cessation intervention + PBO versus advice to quit, 5-year follow up	Symptoms	n = 5887 COPD. 49–51% had cough ≥ 3 months per year: mean pre-bronchodilator FEV1% pred 74.3 ± 9 versus 76 ± 8.6 for asymptomatic (p < 0.001), FEV1/FVC% 62.6 ± 5.7 versus 63.3 ± 5.3 (p < 0.001), age 48.2 ± 6.7 versus 48.7 ± 6.9 years, pack-years 42.2 ± 18.9 versus 38.5 ± 19.1, men 63.2% and 62.4%, BMI 25.6 ± 4 and 25.5 ± 3.9 kg/m2. Baseline data also provided for phlegm, wheeze, and dyspnea (same patients, stratified by symptom presence/absence)	Prevalence of symptoms (cough, phlegm, wheezing, shortness of breath) higher with usual care than with interventions (p < 0.0001). Smoking associated with symptoms. Symptoms associated with greater decline in FEV1 during study (p < 0.001). Ipratropium had no effect on symptoms
Parallel-group, Lung Health Study (Tashkin et al., ref. 57)	Smoking cessation intervention + ipratropium versus smoking cessation intervention + PBO versus advice to quit, 5-year follow up	Relationship between baseline metacholine reactivity and change in lung function	n = 5733 COPD, mean age 48.4–48.6 years, men 61–64%. FEV1% pred 78.2 ± 9.1 (ipratropium), 78.4 ± 9.0 (PBO), 78.3 ± 9.1 (usual care). FEV1/FVC% 64.9 ± 6.3, 65 ± 6, 65 ± 6. FEV1 2.73 ± 0.64 L, 2.75 ± 0.62 L, 2.76 ± 0.62 L. Pack-years 40.3 ± 19.6, 40.2 ± 18.8, 40.5 ± 18.9. Bronchodilator response 4.2 ± 5.1, 4.4 ± 5.0, 4.3 ± 5.1%. LMCR for men (0.386 ± 0.365, 0.356 ± 0.355, 0.358 ± 0.360%/mg/ml and women (0.591 ± 0.392, 0.592 ± 0.387, 0.616 ± 0.365)	Methacholine reactivity is a predictor of decline in FEV1 in smokers

6MWD: 6-min walk distance test; ATS: American Thoracic Society; AUC: area under the curve; BD: bronchodilator; BDI: baseline dyspnea index; bid: twice daily; BMI: body mass index; BTS: British Thoracic Society; CI: confidence interval; COOP/WONCA: Darthmouth COOP Functional Health Assessment Charts/World Organization of General Practice/Family Physicians; COPD: chronic obstructive pulmonary disease; CRQ: Chronic Respiratory Questionnaire; CV: cardiovascular; DIMCA: Detection, Intervention, and Monitoring Program of COPD and Asthma; DLCO: diffusing capacity of the lung for carbon monoxide; ERS: European Respiratory Society; ESWT: endurance shuttle walk test; EUROSCOP: European Respiratory Society Study on Chronic Obstructive Pulmonary Disease; FEF: forced expiratory flow; FEV1: forced expiratory volume in 1 sec; FRC: functional residual capacity; FVC: forced vital capacity; GOLD: Global Initiative for Chronic Obstructive Lung Disease; HAD: hospital anxiety and depression; HR: hazard ratio; IC: inspiratory capacity; ISWT: incremental shuttle walking test; IV: intravenous; IVC: inferior vena cava; LMCR: light meal combat ration; MEF: mid-expiratory flow; MRC: Medical Research Council; od: once daily; PBO: placebo; PEF: peak expiratory flow; PEFR: peak expiratory flow rate; qid: 4 times daily; RV: right ventricle; SE: standard error; SF-36®: Short Form (36) Health Survey; SFC: salmeterol/fluticasone propionate combination; SGRQ: St George's Respiratory Questionnaire; SR: sustained release; SVC: slow vital capacity; TDI: transition dyspnea index; TLC: total lung capacity; TORCH: Towards a Revolution in COPD Health; UPLIFT®: Understanding Potential Long-term Impacts on Function with Tiotropium; VC: vital capacity; VT: tidal volume.

Table 4.  Top-line summary of the effects of different interventions on selected efficacy outcomes in studies of patients with mild-to-moderate COPD.

Interventions, follow-up	Citation	Outcome measures*
		Lung function	Rate of exacerbations	Quality of life/symptoms/rescue medication use	Exercise capacity
Pharmacologic intervention only—PBO-controlled
Budesonide 800 μg/day versus PBO, 3 years	Double-blind PBO-controlled, parallel-group, post-hoc analysis of EUROSCOP study (Löfdahl et al., ref. 34)	NR	Significant reduction in annual severe exacerbation rate with budesonide versus PBO	NR	NR
Budesonide 400 μg bid versus PBO, 3 years	Double-blind PBO-controlled, parallel-group (Pauwels et al., ref. 38)	Mean decline in post-bronchodilator FEV1 significantly reduced with budesonide versus PBO over 3-year period
FEV1 improved with budesonide over first 6 months then declined at similar rate to PBO (9 months to end of treatment)	NR	NR	NR
Fluticasone propionate 250 μg bid versus PBO, 2 years	Double-blind, PBO-controlled, parallel-group (DIMCA study) (van Grunsven et al., ref. 32)	Significantly higher decline in post-bronchodilator FEV1 with fluticasone versus PBO; no between-groups difference in pre-bronchodilator FEV1 decline	Similar between groups	Higher number of episodes of increased respiratory symptoms in fluticasone group versus PBO	NR
Salmeterol 50 μg versus fluticasone propionate 500 μg versus SFC 50/500 μg versus PBO; 3 years	Double-blind PBO-controlled, parallel-group, post-hoc analysis of TORCH study (Jenkins et al., ref. 31)	In GOLD stage II patients, SFC improved FEV1 and reduced rate of decline in FEV1 versus placebo	In GOLD stage II patients, SFC reduced annual rate of moderate/severe exacerbations versus PBO	In GOLD stage II patients, SFC improved SGRQ score versus placebo	NR
Tiotropium 18 μg od versus PBO, 4 years	Double-blind, PBO-controlled, parallel-group, pre-specified sub-group analysis of UPLIFT® trial (Decramer et al., ref. 30)	Significantly higher pre-and post-bronchodilator FEV1, pre-bronchodilator FVC and pre-bronchodilator SVC versus PBO at all time points. Significantly lower rate of decline in post-bronchodilator FEV1 with tiotropium versus PBO	Mean number per patient year significantly lower for tiotropium versus PBO. Time to first exacerbation and first hospitalized exacerbation significantly longer for tiotropium versus. PBO	SGRQ total score deteriorated in both groups but to lesser extent in the tiotropium group	NR
Ipratropium bromide 500 μg versus PBO; 2 days each arm, 7 days between visits (total 1 month)	Double-blind PBO-controlled crossover (O'Donnell et al., ref. 37)	Ipratropium increased FEV1, decreased RV, and specific airway resistance versus PBO	NR	NR	During exercise, ipratropium significantly increased dynamic IC and VT, and decreased dyspnea and dyspnea/ ventilation ratios
Erdosteine 300 mg bid versus N-acetylcysteine 600 mg bid versus PBO, 10 days	PBO-controlled, parallel-group (Dal Negro et al., ref. 35)	FEV1 response to salbutamol significantly enhanced after erdosteine. Slight increase in FVC with erdosteine versus PBO	NR	NR	NR
Infliximab 3 mg/kg versus infliximab 5 mg/kg versus PBO, 44 weeks	Double-blind, PBO-controlled, parallel-group (Rennard et al., ref. 39)	In GOLD stage II patients, no effect of infliximab versus PBO	In GOLD II patients, no effect of infliximab versus PBO	In GOLD stage II patients, no effect of infliximab versus PBO	NR
Pharmacologic intervention only—non-PBO controlled
Tiotropium 18 mg qd + formoterol 12 μg bid versus salmeterol 50 μg bid + fluticasone 500 μg bid, 6 weeks	Double-blind, parallel-group (Rabe et al., ref. 42)	In GOLD stage II patients, tiotropium/formoterol significantly improved FEV1 AUC0–12, peak FEV1, FVC AUC0–12, and peak FVC versus SFC	NR	NR	NR
Formoterol 12 μg bid versus ipratropium bromide 40 μg qid, 2 weeks each arm	Double-blind, crossover (AkkocaYildiz et al., ref. 46)	Formoterol significantly improved FEV1 (90 min post-dose) and FEV1/FVC at Day 14
Ipratropium improved FEV1% pred and FEF25−75 at 90 min post-dose	NR	NR	No difference between groups on exercise capacity or functional parameters
Theophylline SR bid versus salmeterol 50 μg bid, 12 months	Open-label, parallel-group (DiLorenzo et al., ref. 41)	Salmeterol improved morning PEFR versus theophylline
FEV1 and FVC improved in both groups and FEV1 improvement persisted over 12 months with salmeterol
Significantly higher FVC with salmeterol at 2 months with higher mean increases over baseline at 1, 2, and 3 months versus theophylline	NR	Salmeterol increased number of symptom-free nights and amount of rescue medication versus theophylline. Salmeterol improved SF-36® domains of physical functioning, change in health perception and social functioning versus theophylline	NR
Theophylline 400 mg versus tulobuterol 2 mg, 8 weeks each arm	Open-label, crossover (Kanehara et al., ref. 43)	In GOLD stage I/II patients, theophylline increased FEV1% pred, FVC, FEV1, PEF, MEF50 and MEF25 versus baseline. Tulobuterol had no effect on lung function	NR	No significant change from baseline in SGRQ total score in either treatment group (activity domain worsened)	NR
Doxofylline 400 mg bid versus theophylline 400 mg od, 4 weeks	Open-label, parallel-group (Santra et al., ref. 45)	Both drugs significantly increased FEV1, FEV 125−75 and PEFR, but not FEV1/FVC	NR	Both drugs significantly reduced salbutamol use	NR
Neltenexine versus carbocysteine, 12 days	Open-label, parallel-group (D'Elia and Sechi, ref. 44)	No change from baseline in FEV1, PEF or VC with either drug	NR	Neltenexine improved cough and sputum characteristics versus carbocysteine and improved expectoration, cough, and sputum characteristics faster than carbocysteine	NR
Non-pharmacologic intervention only
Weekly supervised exercise + home exercise versus control (unsupervised home exercise), follow-up 12 months	Parallel-group (Spencer et al., ref. 47)	No significant change from baseline or difference between groups	No difference in number of exacerbations between groups	No change from baseline in SGRQ score	No change from baseline in 6MWD test
Weight training versus control (usual activities, no weight training), 12 weeks	Parallel-group (Clark et al., ref. 49)	No effect of intervention on lung function	NR	NR	Weight training improved muscle function and whole body endurance during treadmill walking versus control
Compressed air versus O2 during exercise test	Double-blind crossover (Fujimoto et al., ref. 52)	NR	NR	NR	In patients with mild COPD, increased 6MWD on oxygen versus air
OM-85 (bacterial extracts: test) versus PBO, for 30 days then 10-day course for Months 3, 4, 5; total 6 months	Double-blind, PBO-controlled, parallel-group (Soler et al., ref. 48)	NR	Fewer exacerbations for test versus PBO	NR	NR
Mixed interventions (pharmacologic plus non-pharmacologic)
Smoking cessation intervention + ipratropium versus smoking cessation intervention + PBO versus advice to quit, 5-year follow-up	Parallel-group, Lung Health Study (Scanlon et al., ref. 29)**
(Harber et al., ref. 53)†
(Kanner et al., ref. 56)‡	Smoking cessation improved FEV1 and reduced rate of decline.** Increase in pre- and post-bronchodilator FEV1% pred, FEV% pred and FEV1/FVC in both men and women at 5 years (not stratified by intervention)†	NR	Prevalence of symptoms (cough, phlegm, wheezing, and shortness of breath) significantly lower with interventions than with usual care; ipratropium had no effect on symptoms‡	NR
Interventions, follow-up	Citation	Lung function	Rate of exacerbations	Quality of life/symptoms/rescue medication use	Exercise capacity
Interventions, follow-up	Citation	Lung function	Rate of exacerbations	Quality of life/symptoms/rescue medication use	Exercise capacity

*Studies selected for the review but not reporting data on these outcomes are excluded from the table. **N = 3818. †N = 5724. ‡N = 5887.

6MWD: 6-min walk distance test; AUC0–12: area under the curve from 0 to 12 hours; bid: twice daily; COPD: chronic obstructive pulmonary disease; DIMCA: Detection, Intervention, and Monitoring Program of COPD and Asthma; EUROSCOP: European Respiratory Society Study on Chronic Obstructive Pulmonary Disease; FEF: forced expiratory flow; FEV1: forced expiratory volume in 1 sec; FVC: forced vital capacity; GOLD: Global Initiative for Chronic Obstructive Lung Disease; IC: inspiratory capacity; MEF: mid-expiratory flow; od: once daily; NR: not reported; PBO: placebo; PEF: peak expiratory flow; PEFR: peak expiratory flow rate; qid: 4 times daily; RV, residual volume; SF-36®: Short Form (36) Health Survey; SFC: salmeterol/fluticasone propionate combination; SGRQ: St George's Respiratory Questionnaire; SR: sustained release; SVC: slow vital capacity; TORCH: Towards a Revolution in COPD Health; UPLIFT®: Understanding Potential Long-term Impacts on Function with Tiotropium; VC: vital capacity; VT: tidal volume.