The New England Journal of Medicine June 09, 2016

Indacaterol–Glycopyrronium versus Salmeterol–Fluticasone for COPD (FLAME)

Wedzicha JA, Banerji D, Chapman KR, et al.

Bottom Line

In patients with COPD and a history of exacerbations, once-daily dual bronchodilation with indacaterol-glycopyrronium was superior to twice-daily salmeterol-fluticasone in reducing the annual rate of all COPD exacerbations.

Key Findings

1. Indacaterol-glycopyrronium demonstrated a significantly lower annual rate of all COPD exacerbations compared to salmeterol-fluticasone (3.59 vs. 4.03; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.003).

2. The LABA/LAMA combination significantly prolonged the median time to the first exacerbation of any severity (71 days vs. 51 days; hazard ratio, 0.84; 95% CI, 0.78 to 0.91; P<0.001).

3. The annual rate of moderate or severe exacerbations was significantly lower in the indacaterol-glycopyrronium group (0.98 vs. 1.19; rate ratio, 0.83; 95% CI, 0.75 to 0.91; P<0.001).

4. The incidence of pneumonia was significantly lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (3.2% vs. 4.8%; P=0.02).

Study Design

Design

Randomized Controlled Trial

Double-Blind

Sample

3,362

Patients

Duration

52 wk

Median

Setting

Multicenter, global

Population Patients aged ≥40 years with symptomatic COPD (FEV1 25-60% of predicted, modified Medical Research Council dyspnea scale score ≥2) and a history of at least 1 exacerbation in the previous year.

Intervention Indacaterol 110 μg plus glycopyrronium 50 μg once daily

Comparator Salmeterol 50 μg plus fluticasone 500 μg twice daily

Outcome Annual rate of all COPD exacerbations (mild, moderate, or severe) over 52 weeks of treatment.

Study Limitations

• The study specifically excluded patients with a history of asthma, meaning the findings cannot be generalized to patients with asthma-COPD overlap, a group known to benefit from inhaled corticosteroids.

• The comparator arm utilized a high dose of inhaled corticosteroid (fluticasone 500 μg twice daily), which may have contributed to the relatively higher incidence of pneumonia observed in that group.

• Only about 20% of the enrolled population had a history of ≥2 exacerbations in the preceding year; the results are primarily driven by patients who had exactly 1 exacerbation, limiting power to draw firm conclusions for the most frequent exacerbators.

Clinical Significance

The FLAME trial reshaped COPD treatment algorithms by demonstrating that maximizing bronchodilation with a LABA/LAMA combination provides superior exacerbation prevention compared to LABA/ICS therapy, without the elevated risk of pneumonia. This catalyzed a major shift in the GOLD guidelines, establishing LABA/LAMA as a preferred initial maintenance therapy for high-risk patients and reserving ICS primarily for those with concomitant asthma or elevated blood eosinophils.

Historical Context

Prior to FLAME, combination therapy with a long-acting beta-agonist and an inhaled corticosteroid (LABA/ICS) was the standard of care for COPD patients at high risk of exacerbations, largely influenced by findings from trials like TORCH. However, long-term ICS use in COPD was increasingly linked to adverse effects, most notably an increased risk of pneumonia. FLAME was a landmark head-to-head non-inferiority (and subsequently superiority) trial designed to challenge the supremacy of LABA/ICS by testing it against a dual bronchodilator (LABA/LAMA) strategy. Its definitive results drove a paradigm shift away from empirical ICS use in COPD management.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What are the differing mechanisms of action between a LAMA, a LABA, and an ICS, and based on the pathophysiology of COPD compared to asthma, why might dual bronchodilation (LAMA/LABA) be more effective than an ICS-containing regimen for preventing exacerbations?

Key Response

LAMAs block muscarinic receptors (M3) preventing bronchoconstriction, LABAs stimulate beta-2 receptors causing bronchodilation, and ICS reduce eosinophilic inflammation. Unlike asthma, COPD inflammation is predominantly neutrophilic and steroid-resistant. Therefore, maximizing bronchodilation (LABA/LAMA) targets the primary pathophysiologic derangement in COPD (airflow limitation and hyperinflation) more effectively than broad immunosuppression.

Resident

A patient with COPD experiences two exacerbations in the past year despite monotherapy with a LAMA. Based on the FLAME trial, you consider switching to a LABA/LAMA combination instead of a LABA/ICS. Are there any specific laboratory markers or clinical phenotypes where you might still prefer to prescribe the LABA/ICS regimen despite the FLAME trial results?

Key Response

While FLAME showed superiority of LABA/LAMA for general exacerbation reduction, patients with a significant asthma-COPD overlap or high blood eosinophil counts (e.g., greater than 300 cells per microliter) derive substantial benefit from ICS. For typical non-eosinophilic COPD exacerbators, LABA/LAMA is preferred to avoid ICS-related pneumonia risks.

Fellow

The FLAME trial was initially designed to demonstrate non-inferiority of indacaterol-glycopyrronium compared to salmeterol-fluticasone, but it ultimately demonstrated superiority. How does the choice of the primary endpoint (annual rate of all exacerbations) versus secondary endpoints (time to first exacerbation) impact the clinical interpretation of dual bronchodilation efficacy in the frequent exacerbator phenotype?

Key Response

Time-to-first-event analysis can be skewed by a single early event and ignores subsequent exacerbations, whereas the annual rate captures the cumulative burden of disease over time. Proving superiority in the annual rate of all exacerbations (mild, moderate, and severe) provides more robust evidence that LABA/LAMA fundamentally alters the disease trajectory in frequent exacerbators, rather than just delaying an initial flare.

Attending

Given that the FLAME trial demonstrates the superiority of LABA/LAMA over LABA/ICS in reducing exacerbations, how should we approach the large population of stable COPD patients currently well-controlled on historical LABA/ICS regimens? Does this data mandate an active de-escalation of ICS in clinical practice?

Key Response

FLAME shifts the paradigm away from reflexive ICS use in COPD. For patients stable on LABA/ICS without an asthma component or high eosinophils, attendings must weigh the risk of continued ICS (pneumonia, bone loss, mycobacterial infections) against the risk of withdrawal. Studies like WISDOM show ICS can often be safely withdrawn if patients are on dual bronchodilators, making proactive ICS de-escalation a key quality improvement metric in modern COPD care.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The FLAME trial utilized a 4-week run-in period where all patients received tiotropium monotherapy before randomization. How might this specific run-in design, combined with the abrupt discontinuation of prior inhaled corticosteroids for patients previously on them, introduce a withdrawal bias that could theoretically skew the exacerbation rates in either arm?

Key Response

Patients randomized to LABA/LAMA who were previously on ICS experienced abrupt ICS withdrawal after the run-in, which in some populations can trigger a short-term increase in exacerbations. Conversely, patients randomized to LABA/ICS lost LAMA coverage. Methodologists must evaluate if the transition period disproportionately punished one arm. However, the FLAME trials demonstration of LABA/LAMA superiority despite potential ICS withdrawal effects actually strengthens the conclusion, though it complicates the pure estimation of effect size.

Journal Editor

Indacaterol-glycopyrronium is administered once daily via a single inhaler, whereas salmeterol-fluticasone is administered twice daily. As a reviewer evaluating the internal validity of the FLAME trial, how does this discrepancy in dosing frequency and potential inhaler device differences threaten the ability to isolate the pharmacological efficacy of the drug classes versus the adherence benefits of a once-daily regimen?

Key Response

A rigorous peer reviewer would flag that comparing a once-daily regimen to a twice-daily regimen in a clinical trial inherently bundles the pharmacological effect of the drugs with the behavioral effect of improved adherence. Double-dummy designs (where patients take placebo inhalers to match dosing frequency) are required to isolate pure pharmacological efficacy. Without this, the superiority of LABA/LAMA in FLAME might partially reflect better compliance with a once-daily device rather than just superior receptor-level pharmacology.

Guideline Committee

Following the publication of the FLAME trial, how should the GOLD guideline recommendations for initial pharmacological treatment in patients with a high risk of exacerbations (formerly Group D, now Group E) be restructured regarding the positioning of LABA/LAMA versus LABA/ICS, and what specific biomarker thresholds should dictate deviations from this new standard?

Key Response

Prior to FLAME, LABA/ICS was heavily favored for frequent exacerbators. Post-FLAME, GOLD guidelines were updated to strongly recommend LABA/LAMA combinations as initial therapy for highly symptomatic patients with exacerbation history (Group E). The guidelines now specifically relegate LABA/ICS (or triple therapy) to a secondary role, explicitly requiring a blood eosinophil count threshold (e.g., greater than 300 cells per microliter) or a history of asthma to justify the initial inclusion of an ICS due to the pneumonia risk and inferior generalized exacerbation prevention demonstrated in FLAME.

Clinical Landscape

Noteworthy Related Trials

2007

TORCH Trial

n = 6,112 · NEJM

Tested

Salmeterol-Fluticasone

Population

Patients with moderate-to-severe COPD

Comparator

Placebo, salmeterol alone, or fluticasone alone

Endpoint

All-cause mortality at 3 years

Key result: Salmeterol-fluticasone did not significantly reduce all-cause mortality compared to placebo but improved lung function and reduced exacerbations.

2014

WISDOM Trial

n = 2,485 · NEJM

Tested

Stepwise withdrawal of inhaled glucocorticoids

Population

Patients with severe COPD receiving tiotropium, salmeterol, and fluticasone

Comparator

Continued triple therapy

Endpoint

Time to first moderate or severe COPD exacerbation

Key result: Withdrawal of ICS was non-inferior to continuation in terms of exacerbation risk, though lung function slightly decreased.

2018

IMPACT Trial

n = 10,355 · NEJM

Tested

Fluticasone furoate-umeclidinium-vilanterol (Triple therapy)

Population

Patients with symptomatic COPD and a history of exacerbations

Comparator

Fluticasone-vilanterol (ICS/LABA) or umeclidinium-vilanterol (LAMA/LABA)

Endpoint

Annual rate of moderate or severe COPD exacerbations

Key result: Triple therapy significantly resulted in a lower rate of moderate or severe COPD exacerbations than either dual therapy.

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