LABA + ICS + LAMA vs LABA + LAMA (DRUG 6C)

Ref ID: 19542
ReferenceStudy type/ Evidence levelNumber of patientsPatient characteristicsInterventionComparisonLength of follow-upOutcome measuresSource of funding
Aaron SD, Vandemheen KL, Fergusson D et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007; 146(8):545-555. Ref ID: 19542RCT
Double blinded; allocation concealment; ITT; powered (80%)

High loss to follow-up 47% tio + placebo

43% tio + salmeterol

Versus

25% tio + salmeterol/fluticasone (possible attrition bias)

Multicentre- Canada
N = 449Inclusion: people > 35 years old with COPD who had ≥ 1 exacerbation of COPD requiring antibiotic or systemic steroids within previous 12 months; history of ≥ 10 pack years; documented chronic airflow obstruction with an FEV1-FVC ratio < 0.70 and post bronchodilator FEV1 < 65% predicted value

Exclusion: asthma before 40 years of age; history of CHF with persistent LV dysfunction; those receiving oral prednisone; hypersensitivity/intolerance to tiotropium, salmeterol, or fluticasone-salmeterol; severe glaucoma or severe UT obstruction, previous lung transplantation or lung volume reduction surgery, diffuse bilateral bronchiectasis; pregnancy or breastfeeding. Pts with a recent COPD exacerbation requiring oral or intravenous antibiotics or steroids were required to wait until treatment with these agents had been discontinued for 28 days before entering the study.

Baseline characteristics: similar between groups
Tiotropium (18 microgram once daily) + salmeterol (25 microgram /puff, 2 puffs twice daily)
N= 148
Tiotropium (18 microgram once daily) + placebo (2 puffs twice daily)
N=156
1 yearPrimary outcome: proportion who had ≥ 1 acute exacerbation of COPD (defined as physician-directed short-term use of oral or IV steroids or oral or IV antibiotics or both)

Secondary outcomes:

Mean number exacerbations/patient year

Number hospitalisations for COPD

Change in SGRQ

Change in TDI

All cause mortality

Pneumonia

MI or arrhythmia

Change in mean FEV1

Change in mean prebronchodilator FEV1
CIHR and Ontario Thoracic Society
Tiotropium (18 microgram once daily) + fluticasone/salmeterol (250/25 microgram /puff, 2 puffs twice daily)
N=145

[Three arms received albuterol for symptom relief. Oxygen, antileukotrienes, methylxanthines permitted in all groups]
Tiotropium (18 microgram once daily) + placebo (2 puffs twice daily)
N=156

Procedure: Any ICS, LABA, LAMA discontinued at entry. Patients with moderate/severe COPD randomised to one of 3 arms. Patients monitored for exacerbations monthly and had clinic visits at baseline, 4, 20, 36, and 52 weeks.
Tio + placeboTio + SalmeterolTio + Salmeterol
Mean age68.1 (8.9)67.6 (8.2)67.5 (8.9)
% ipratropium34.444.542.9
% tiotropium57.855.546.4
% SABA77.982.280.0
% LABA11.719.217.9
% ICS + LABA51.943.945.7
% ICS25.334.927.1
Mean post bronchodilator FEV1 - Litres1.08 (0.40)1.08 (0.43)1.12 (0.41)
Mean % predicted FEV142.1 (13.5)41.2 (13.0)42.2 (12.2)
Mean TDI6.3 (1.8)6.5 (1.9)6.5 (2.0)
Effect Size

Comparison: Tiotropium + salmeterol vs Tiotropium + placebo (Drug 5b)
ARR = absolute risk reduction
IRR= incidence rate ratio
RR = relative risk
MD = mean difference
OUTCOMETiotropium + salmeterol N= 148Tiotropium + placebo N=156Effect Size (95% CI) reported in paper (compared with tio + placebo)Effect size calculated by NCC
Primary analysis - – assuming all pts lost to follow up did not have an exacerbation
Patients with ≥ 1 acute exacerbation of COPD (this includes people who were hospitalised - personal communication with S. Aaron) n, (%)
96 (64.8)98 (62.8)ARR -2.0% (-12.8%, 8.8%) NSRR: 1.03 (0.87 – 1.22)
Sensitivity analysis 1 – assuming all pts lost to follow up had an exacerbation
Patients with ≥ 1 acute exacerbation of COPD (this includes people who were hospitalised - personal communication with S. Aaron) n, (%)
107 (72.3)117 (75)ARR 2.7% (-7.2% to 12.6%)RR: 0.96 (0.84 – 1.1)
Sensitivity analysis 2 – assuming all pts lost to follow up had exacerbations at the same rate as those who stayed in the study
Patients with ≥ 1 acute exacerbation of COPD (this includes people who were hospitalised - personal communication with S. Aaron) n, (%)
104 (70.3)112 (71.8)ARR 1.5% (-8.7% to 11.7%)RR: 0.93 (0.57 – 1.52)
Mean exacerbations/patient-year, (this includes people who were hospitalised - personal communication with S. Aaron) n1.751.61IRR 1.09 (0.84, 1.40)-
Mean Hospitalisations for acute COPD exacerbation per patient year38/129.4 = 0.29449/138 = 0.355IRR 0.83 (0.54, 1.27)-
Change from baseline in SGRQ (at 1 year)- 6.3 points- 4.5 pointsP=0.02MD = -1.8 points
Change from baseline in mean pre bronchodilator FEV1 (at 1 year, litres)Approx + 0.06 L (estimated from graph)+ 0.027 LP=0.87MD = 0.033 L
Mean difference in TDI at 1 year (SD)1.40 (3.96)1.78 (4.08)P=0.35MD -0.38 (-1.28, 0.52)
All-cause mortality at 1 year (n)6 (4.1%)4 (2.6%)-RR 1.58 (0.46, 5.49)
Adverse event: number of patients with Pneumonia leading to mechanical ventilation or death (n)10-RR 3.16 (0.13, 76.99)
Adverse event: Number of patients with MI or acute arrhythmia (n)22-RR 1.05 (0.15, 7.39)
Comparison: Tiotropium + fluticasone/salmeterol vs Tiotropium + placebo (Drug 6b)
ARR = absolute risk reduction
IRR= incidence rate ratio
RR = relative risk
MD = mean difference
OutcomeTiotropium + fluticasone/salmeterol N=145Tiotropium + placebo N=156Effect Size (95% CI) compared with tio + placebo reported in paperEffect size calculated by NCC (triple vs tio + placebo)
Primary analysis - – assuming all pts lost to follow up did not have an exacerbation
People with ≥ 1 acute exacerbation of COPD (this includes people who were hospitalised - personal communication with S. Aaron) n, (%)
87 (60.0)98 (62.8)ARR: 2.8% (-8.2%, 13.8%)RR 0.96 (0.80, 1.14)
Sensitivity analysis 1 – assuming all pts lost to follow up had an exacerbation
People with ≥ 1 acute exacerbation of COPD (this includes people who were hospitalised - personal communication with S. Aaron) n, (%)
96 (66.2)117 (75)ARR: 8.8% (-1.5%, 19.0%)RR 0.88 (0.76, 1.02)
Sensitivity analysis 2 – assuming all pts lost to follow up had exacerbations at the same rate as those who stayed in the study
People with ≥ 1 acute exacerbation of COPD (this includes people who were hospitalised - personal communication with S. Aaron) n, (%)
93 (64.1)112 (71.8)ARR: 7.6% (-2.9%, 18.1%)RR 0.89 (0.76, 1.04)
Mean exacerbations/patient-year (this includes people who were hospitalised - personal communication with S. Aaron), n1.371.61IRR 0.85 (0.65, 1.11)-
Mean Hospitalisation for acute exacerbation (per patient year)26/137.1 = 0.19049/138.0 = 0.355IRR 0.53 (0.33, 0.86)-
Change from baseline in SGRQ (at 1 year)- 8.6 points- 4.5 pointsP=0.01-
Change from baseline in mean pre bronchodilator FEV1 (at 1 year, litres)+ 0.086 L+ 0.027 LP=0.049MD 0.059
mean difference in TDI score at 1 year (SD)1.84 (3.86)1.78 (4.08)P=0.38MD 0.06 (-0.84, 0.96)
All-cause mortality at 1 year (n)6 (4.1%)4 (2.6%)-RR 1.61 (0.46, 5.60)
Adverse event: Pneumonia leading to mechanical ventilation or death (n)1 (0.7%)0 (0%)-RR 3.23 (0.13, 78.56)
Adverse event: MI or acute arrhythmia (n)2 (1.4%)2 (1.3%)-RR 1.08 (0.15, 7.54)
Comparison: Tiotropium + fluticasone/salmeterol versus Tiotropium + salmeterol (Drug 6c)
NB: The study was not designed or powered to compare the differences between the tiotropium plus salmeterol group versus tiotropium plus fluticasone-salmeterol group.

RR = relative risk
MD = mean difference
outcomeTiotropium + fluticasone/salmeterol N=145Tiotropium + salmeterol N= 148Effect size (95% CI) reported in paperEffect size calculated by NCC
Primary analysis - – assuming all pts lost to follow up did not have an exacerbation
≥ 1 acute exacerbation of COPD (this includes people who were hospitalised - personal communication with S. Aaron) n, (%)
87 (60.0)96 (64.8)-RR 0.93 (0.77, 1.11)
Sensitivity analysis 1 – assuming all pts lost to follow up had an exacerbation
≥ 1 acute exacerbation of COPD (this includes people who were hospitalised - personal communication with S. Aaron) n, (%)
96 (66.2)107 (72.3)-RR 0.92 (0.79, 1.07)
Sensitivity analysis 2 – assuming all pts lost to follow up had exacerbations at the same rate as those who stayed in the study
≥ 1 acute exacerbation of COPD (this includes people who were hospitalised - personal communication with S. Aaron) n, (%)
93 (64.1)104 (70.3)-RR 0.91 (0.78, 1.07)
Mean exacerbations/patient-year (this includes people who were hospitalised - personal communication with S. Aaron), n1.371.75--
Mean Hospitalisation for acute exacerbation/patient year, n26/137.1 =0.19038/129.4 = 0.294--
Change from baseline in total SGRQ score (at 1 year)- 8.6 points- 6.3 points--
Change in mean pre bronchodilator FEV1 (at 1 year, litres)+ 0.086 LApprox + 0.06 L (estimated from graph)--
mean difference in TDI score at 1 year (SD)1.84 (3.86)1.40 (3.96)-MD 0.44 (-0.46, 1.34)
All-cause mortality at 1 year (n)6 (4.1%)6 (4.1%)-RR 1.02 (0.34, 3.09)
Adverse event: Pneumonia leading to mechanical ventilation or death (n)1 (0.7%)1 (0.7%)-RR 1.02 (0.06, 16.16)
Adverse event: MI or acute arrhythmia (n)2 (1.4%)2 (1.4%)-RR 1.02 (0.15, 7.15)

From: Appendix F, Evidence tables

Cover of Chronic Obstructive Pulmonary Disease
Chronic Obstructive Pulmonary Disease: Management of Chronic Obstructive Pulmonary Disease in Adults in Primary and Secondary Care [Internet].
NICE Clinical Guidelines, No. 101.
National Clinical Guideline Centre (UK).
Copyright © 2010, National Clinical Guideline Centre - Acute and Chronic Conditions.

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