Indacaterol/glycopyrronium or salmeterol/fluticasone for COPD exacerbations
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Published version
Author(s)
Type
Journal Article
Abstract
BACKGROUND
Most guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled
glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the firstchoice
treatment for patients with chronic obstructive pulmonary disease (COPD)
who have a high risk of exacerbations. The role of treatment with a LABA–LAMA
regimen in these patients is unclear.
METHODS
We conducted a 52-week, randomized, double-blind, double-dummy, noninferiority
trial. Patients who had COPD with a history of at least one exacerbation during
the previous year were randomly assigned to receive, by inhalation, either the
LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) once daily or
the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg)
twice daily. The primary outcome was the annual rate of all COPD exacerbations.
RESULTS
A total of 1680 patients were assigned to the indacaterol–glycopyrronium group,
and 1682 to the salmeterol–fluticasone group. Indacaterol–glycopyrronium showed
not only noninferiority but also superiority to salmeterol–fluticasone in reducing the
annual rate of all COPD exacerbations; the rate was 11% lower in the indacaterol–
glycopyrronium group than in the salmeterol–fluticasone group (3.59 vs. 4.03; rate
ratio, 0.89; 95% confidence interval [CI], 0.83 to 0.96; P=0.003). The indacaterol–
glycopyrronium group had a longer time to the first exacerbation than did the
salmeterol–fluticasone group (71 days [95% CI, 60 to 82] vs. 51 days [95% CI, 46 to
57]; hazard ratio, 0.84 [95% CI, 0.78 to 0.91], representing a 16% lower risk; P<0.001).
The annual rate of moderate or severe exacerbations was lower in the indacaterol–glycopyrronium
group than in the salmeterol–fluticasone group (0.98 vs. 1.19; rate
ratio, 0.83; 95% CI, 0.75 to 0.91; P<0.001), and the time to the first moderate or
severe exacerbation was longer in the indacaterol–glycopyrronium group than in
the salmeterol–fluticasone group (hazard ratio, 0.78; 95% CI, 0.70 to 0.86; P<0.001),
as was the time to the first severe exacerbation (hazard ratio, 0.81; 95% CI, 0.66
to 1.00; P=0.046). The effect of indacaterol–glycopyrronium versus salmeterol–
fluticasone on the rate of COPD exacerbations was independent of the baseline
blood eosinophil count. The incidence of adverse events and deaths was similar in
the two groups. The incidence of pneumonia was 3.2% in the indacaterol–glycopyrronium
group and 4.8% in the salmeterol–fluticasone group (P=0.02).
CONCLUSIONS
Indacaterol–glycopyrronium was more effective than salmeterol–fluticasone in preventing
COPD exacerbations in patients with a history of exacerbation during the
previous year. (Funded by Novartis; FLAME ClinicalTrials.gov number, NCT01782326.)
Most guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled
glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the firstchoice
treatment for patients with chronic obstructive pulmonary disease (COPD)
who have a high risk of exacerbations. The role of treatment with a LABA–LAMA
regimen in these patients is unclear.
METHODS
We conducted a 52-week, randomized, double-blind, double-dummy, noninferiority
trial. Patients who had COPD with a history of at least one exacerbation during
the previous year were randomly assigned to receive, by inhalation, either the
LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) once daily or
the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg)
twice daily. The primary outcome was the annual rate of all COPD exacerbations.
RESULTS
A total of 1680 patients were assigned to the indacaterol–glycopyrronium group,
and 1682 to the salmeterol–fluticasone group. Indacaterol–glycopyrronium showed
not only noninferiority but also superiority to salmeterol–fluticasone in reducing the
annual rate of all COPD exacerbations; the rate was 11% lower in the indacaterol–
glycopyrronium group than in the salmeterol–fluticasone group (3.59 vs. 4.03; rate
ratio, 0.89; 95% confidence interval [CI], 0.83 to 0.96; P=0.003). The indacaterol–
glycopyrronium group had a longer time to the first exacerbation than did the
salmeterol–fluticasone group (71 days [95% CI, 60 to 82] vs. 51 days [95% CI, 46 to
57]; hazard ratio, 0.84 [95% CI, 0.78 to 0.91], representing a 16% lower risk; P<0.001).
The annual rate of moderate or severe exacerbations was lower in the indacaterol–glycopyrronium
group than in the salmeterol–fluticasone group (0.98 vs. 1.19; rate
ratio, 0.83; 95% CI, 0.75 to 0.91; P<0.001), and the time to the first moderate or
severe exacerbation was longer in the indacaterol–glycopyrronium group than in
the salmeterol–fluticasone group (hazard ratio, 0.78; 95% CI, 0.70 to 0.86; P<0.001),
as was the time to the first severe exacerbation (hazard ratio, 0.81; 95% CI, 0.66
to 1.00; P=0.046). The effect of indacaterol–glycopyrronium versus salmeterol–
fluticasone on the rate of COPD exacerbations was independent of the baseline
blood eosinophil count. The incidence of adverse events and deaths was similar in
the two groups. The incidence of pneumonia was 3.2% in the indacaterol–glycopyrronium
group and 4.8% in the salmeterol–fluticasone group (P=0.02).
CONCLUSIONS
Indacaterol–glycopyrronium was more effective than salmeterol–fluticasone in preventing
COPD exacerbations in patients with a history of exacerbation during the
previous year. (Funded by Novartis; FLAME ClinicalTrials.gov number, NCT01782326.)
Date Issued
2016-05-15
Date Acceptance
2016-03-28
Citation
New England Journal of Medicine, 2016, 374, pp.2222-2234
ISSN
1533-4406
Publisher
Massachusetts Medical Society
Start Page
2222
End Page
2234
Journal / Book Title
New England Journal of Medicine
Volume
374
Copyright Statement
Copyright © 2016 Massachusetts Medical Society. All rights reserved.
Identifier
https://www.nejm.org/doi/10.1056/NEJMoa1516385
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
OBSTRUCTIVE PULMONARY-DISEASE
TO-SEVERE COPD
INHALED CORTICOSTEROIDS
BLOOD EOSINOPHILS
PARALLEL-GROUP
LUNG-FUNCTION
DOUBLE-BLIND
EXACERBATIONS
EFFICACY
SAFETY
Administration, Inhalation
Adrenergic beta-2 Receptor Agonists
Aged
Double-Blind Method
Drug Combinations
Female
Fluticasone-Salmeterol Drug Combination
Glucocorticoids
Glycopyrrolate
Humans
Indans
Male
Middle Aged
Muscarinic Antagonists
Pulmonary Disease, Chronic Obstructive
Quinolones
FLAME Investigators
Humans
Pulmonary Disease, Chronic Obstructive
Glycopyrrolate
Quinolones
Indans
Muscarinic Antagonists
Drug Combinations
Glucocorticoids
Administration, Inhalation
Double-Blind Method
Aged
Middle Aged
Female
Male
Adrenergic beta-2 Receptor Agonists
Fluticasone-Salmeterol Drug Combination
General & Internal Medicine
11 Medical and Health Sciences
Publication Status
Published
Date Publish Online
2016-06-09