FLAME (COPD)

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Wedzicha JA, et al. "Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD". The New England Journal of Medicine. 2016. 374(23):2222-2234.
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Clinical Question

Among patients with COPD and mMRC dyspnea grade ≥2 symptoms, does indacaterol+glycopyrronium (LABA+LAMA) reduce rates of annual COPD exacerbations when compared to salmeterol+fluticasone (LABA+ICS)?

Bottom Line

Among patient with COPD and mMRC dyspnea grade ≥2 symptoms, indacaterol+glycopyrronium (LABA+LAMA) is associated with a reduction in the rate of annual COPD exacerbations when compared to salmeterol+fluticasone (LABA+ICS).

Major Points

COPD is a leading cause of morbidity and mortality worldwide and 80-90% of its prevalence is attributable to cigarette smoking.[1] While high-quality evidence supports smoking cessation for prevention of COPD progression[2] and reduction in mortality,[3], the search for the ideal medication to reduce COPD exacerbations is ongoing. One popular intervention, ICS therapy, has been associated with increased risk of pneumonia.[4] Further, combined LABA+ICS therapy (salmeterol+fluticasone) had a similar COPD exacerbation rate as LAMA monotherapy (tiotropium) in INSPIRE (2008).[5] Whether LABA+LAMA therapy provides benefit over LABA+ICS was unknown.

Published in 2016, the Effect of Indacaterol Glycopyronium Vs. Fluticasone Salmeterol on COPD Exacerbations (FLAME) trial randomized 3,362 patients in 43 countries with COPD and mMRC dyspnea grade ≥2 symptoms (slow walking on a flat surface 2/2 breathlessness) to indacaterol+glycopyrronium (LABA+LAMA) or salmeterol+fluticasone (LABA+ICS). At 52 weeks, indacaterol+glycopyrronium was associated with a significant reduction in the annual rate of exacerbation when compared to salmeterol+fluticasone (RR 0.88; 95% CI 0.82-0.94; P<0.001). [Note: while the primary outcome was powered for non-inferiority, it achieved superiority]. While the two arms experienced similar rates of serious adverse events overall, indacaterol+glycopyrronium had fewer incident pneumonia events.

Many of the primary outcome events were from mild COPD exacerbations, which are of low clinical significance.[6]

Guidelines

GOLD COPD (2017, adapted)[7]

  • Lung function, dyspnea, overall health, and COPD exacerbation rates are significantly improve with either LABA or LAMA therapy (evidence A)
  • LAMA outperforms LABA therapy for reduction of COPD exacerbations (evidence A) and hospitalizations (evidence B)
  • Combination LABA+LAMA increases FEV1 and reduces symptoms compared to monotherapy (evidence A), reduces exacerbations compared to monotherapy with either agent (evidence B) or ICS+LABA (evidence B)

Design

  • Randomized, double-blind, double-dummy, noninferiority trial (note: a superiority analysis was a secondary outcome)
  • N=3362
    • Indacaterol+glycopyrronium (n=1680)
    • Salmeterol+fluticasone (n=1682)
  • Setting: 356 centers in 43 countries
  • Enrollment: 2013-2015
  • Treatment period: 52 weeks
  • Analysis: Modified intention-to-treat
  • Primary outcome: Annual rate of all COPD exacerbations

Population

Inclusion Criteria

  • Age ≥40 years who are current or former smokers with ≥10 PYH
  • Stable COPD per GOLD 2011 criteria on a stable medication
  • Post-bronchodilator FEV1 25-60% of predicted and FEV1 <0.70 (after administration of ipratropum 84 ug+salbutamol 400 ug)
  • ≥1 COPD exacerbation requiring systemic corticosteroids and/or antibiotics in the prior year
  • mMRC symptom grade ≥2 ("On level ground, I walk slower than people of the same age because of breathlessness, or have to stop for breath when walking at my own pace.")[8]

Exclusion Criteria

  • T1DM or T2DM
  • Long QT syndrome or QTc >450 ms
  • "Clinically-significant EKG abnormalities"
  • Significant renal disease, CVD (i.e., NYHA class ≥III symptoms, MI, unstable CAD), arrhythmia (including paroxysmal AF though continuous AF on stable medications were not excluded), neurological, endocrine, immunological, psychiatric, GI, hepatic, oncologic, or hematologic abnormalities that could interfered with study efficacy or safety
  • Pregnancy, lactating, childbearing-potential not on an effective contraception
  • Hypersensitivity to study medications
  • COPD exacerbation between screening and initiation of treatment
  • Respiratory tract infection in prior month
  • Requiring oxygen therapy >12 hours/day
  • Prior asthma
  • Onset of symptoms <40 years
  • Other pulmonary disease, including clinically-significant bronchiectasis
  • Intermittent use of antihistamine or nasal corticosteroids for allergic rhinitis
  • Alpha-1 antitrypsin deficiency
  • In pulmonary rehab
  • Use of various medications in tables 5-1, 5-2, and 5-3 of the protocol[9] or who are on other investigational therapies
  • Unable to use study medications

Baseline Characteristics

Among all study patients.

  • Demographics: Age 65 years, male sex 76%
  • COPD duration: 7 years
  • ICS use: 56%
  • Current smoker: 40%
  • COPD severity by 2015 GOLD criteria
    • Group A (low risk and low symptom burden): <1%
    • Group B (low risk and high symptom burden): 24%
    • Group C (high risk and low symptom burden): <1%
    • Group D (high risk and high symptom burden): 75%
  • Post-bronchodilator FEV1 (% predicted): 1.2 L (44%)
  • Post bronchodilator FEV1:FVC: 0.42
  • Total SGRQ-C score: 47 (out of 100, higher scores indicating worse health status)

Interventions

  • After a 1 week screening period, participants were treated with tiotropium 18 ug/day for 4 weeks then were randomized to a group:
    • Indacaterol+glycopyrronium 100 ug+50 ug inh qday
    • Salmeterol+fluticasone 50 ug+500 ug inh BID
  • Treatments were continued for 52 weeks
  • Salbutamol 100 ug was the designated rescue medication

Outcomes

Only modified intention-to-treat analyses are presented.

Primary Outcomes

Annual rate of COPD exacerbations

The true primary outcome was non-inferiority. Here we present superiority outcomes.

Lower for indacaterol+glycopyrronium (RR 0.88; 95% CI 0.82-0.94; P<0.001)

Secondary Outcomes

The following are via modified intention-to-treat analyses.

Time to first exacerbation
Longer for indacaterol+glycopyrronium (71 vs. 51 days; HR 0.84; 95% CI 0.78-0.91; P<0.001)
First moderate or severe exacerbation: Longer for indacaterol+glycopyrronium 127 vs. 87 days (HR 0.78; 95% CI 0.70-0.86; P<0.001)
Annual rate of moderate or severe exacerbations
Lower for indacaterol+glycopyrronium (RR 0.83; 95% CI 0.75-0.91; P<0.001)
Difference in change of FEV1 from baseline to week 52
Greater increase in indacaterol+glycopyrronium (between group difference 62 mL; P<0.001)
Decrease in SGRQ-C score
Greater decrease (better improvement in indacaterol+glycopyrronium group (P<0.01)
Details are in figure S7C on page 34 of the supplementary appendix.[10]
Rescue medication use
Lower use with indicaterol+glycopyrronium group (decrease of 1.01 vs. 0.76 puff/day; P<0.001)

Subgroup Analysis

There were no significant differences in the primary outcome when analyzed by eosinophil level, sex, race, smoking status, airflow obstruction severity, COPD severity, number of exacerbations in the prior year, or by type of inhaled medications at baseline.

Adverse Events

The incidence of adverse events, including serious adverse events, was similar in the two treatment groups.
  • A total of 24 participants in each group (1.4%) died
    • The most common causes of death were (IND/GP and SFC groups, respectively)
      • Respiratory (11 (0.7%) and 8 (0.5%))
      • Cardiovascular (9 (0.5%) and 11 (0.7%)
Pneumonia
3.2% in indacaterol+glycopyrronium and 4.8% in salmeterol+fluticasone (P=0.02)

Criticisms

  • This trial required an unconventional 1 week washout of relevant COPD medications. After this time, 49% of the 1,580 patients excluded had an FEV1 out of the eligibility range.[6]
  • Few participants were included based upon frequent exacerbations. These participants may have benefited from ICS therapy.[6]
  • Most of the events of interest were mild and are of questionable clinical relevance.[6]

Funding

  • Novartis, manufacturers of Utibron Neohaler, the brand name of indacaterol+glycopyrronium
  • Authors with multiple financial disclosures

Further Reading

  1. Littner MR & In the clinic. Chronic obstructive pulmonary disease. Ann. Intern. Med. 2011. 154:ITC4-1-ITC4-15; quiz ITC4-16.
  2. Anthonisen NR et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994. 272:1497-505.
  3. Anthonisen NR et al. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann. Intern. Med. 2005. 142:233-9.
  4. Lee MC et al. Inhaled Corticosteroids Increase the Risk of Pneumonia in Patients With Chronic Obstructive Pulmonary Disease: A Nationwide Cohort Study. Medicine (Baltimore) 2015. 94:e1723.
  5. Wedzicha JA et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am. J. Respir. Crit. Care Med. 2008. 177:19-26.
  6. 6.0 6.1 6.2 6.3 Multiple authors. Letters to the editor for FLAME. The New England Journal of Medicine. 2016;375:897-900.
  7. Agusti A, et al. "Global initiative for chronic obstructive lung disease: 2017 report." goldcopd.org. Published 2016-12. Accessed 2017-01-31.
  8. FLETCHER CM et al. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. Br Med J 1959. 2:257-66.
  9. Supplementary appendix of FLAME
  10. Supplementary appendix