New England Journal of Medicine JUNE 09, 2016

Indacaterol–Glycopyrronium versus Salmeterol–Fluticasone for COPD

Jadwiga A. Wedzicha, Deepa Banerji, Kenneth R. Chapman, et al.

Bottom Line

In patients with moderate-to-very severe COPD and a history of exacerbations, the once-daily dual bronchodilator indacaterol–glycopyrronium was superior to the twice-daily LABA/ICS combination salmeterol–fluticasone in reducing the rate of all COPD exacerbations.

Key Findings

1. The annual rate of all COPD exacerbations was 11% lower with indacaterol–glycopyrronium compared to salmeterol–fluticasone (rate ratio 0.89; 95% CI, 0.83–0.96; P=0.003).

2. Indacaterol–glycopyrronium significantly reduced the rate of moderate or severe COPD exacerbations by 17% compared to salmeterol–fluticasone (rate ratio 0.83; 95% CI, 0.75–0.91; P<0.001).

3. Time to the first COPD exacerbation was significantly longer in the indacaterol–glycopyrronium group compared to the salmeterol–fluticasone group (hazard ratio 0.84; P<0.001).

4. Incidence of pneumonia was significantly lower in the indacaterol–glycopyrronium group (3.2%) compared with the salmeterol–fluticasone group (4.8%).

5. No statistically significant difference was observed in rates of death or serious adverse events between the two study arms.

Study Design

Design

RCT

Double-Blind

Sample

3,362

Patients

Duration

52 wk

Median

Setting

Multicenter, International

Population Patients aged 40 or older with moderate-to-very severe COPD and a history of at least one exacerbation in the previous year.

Intervention Indacaterol (110 μg) and glycopyrronium (50 μg) once daily.

Comparator Salmeterol (50 μg) and fluticasone (500 μg) twice daily.

Outcome Annual rate of all (mild, moderate, and severe) COPD exacerbations.

Study Limitations

• The study employed a per-protocol analysis for the primary outcome, which may introduce potential bias.

• Patient self-reporting of symptoms and rescue medication use is subject to potential recall bias.

• The trial was industry-funded, which may influence the design, reporting, or interpretation of outcomes.

• Participants with severe comorbidities, such as those necessitating high-risk management, were generally excluded from the study population.

Clinical Significance

The FLAME trial challenged the long-standing clinical paradigm favoring LABA/ICS as the primary maintenance therapy for patients with COPD at high risk of exacerbations. The results demonstrated that dual bronchodilator therapy (LABA/LAMA) is a more effective and safer alternative for preventing exacerbations while reducing the risk of pneumonia associated with chronic inhaled corticosteroid use.

Historical Context

Prior to the FLAME trial, international guidelines predominantly recommended the combination of a Long-Acting Beta-Agonist (LABA) and an Inhaled Corticosteroid (ICS) for patients with severe COPD and high exacerbation risk. The FLAME trial provided landmark evidence shifting the therapeutic focus toward dual bronchodilation (LABA/LAMA) and reducing reliance on ICS in this patient population.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Compare the mechanisms of action between a Long-Acting Muscarinic Antagonist (LAMA) like glycopyrronium and an Inhaled Corticosteroid (ICS) like fluticasone in the context of COPD pathophysiology. Why might a dual bronchodilator be more effective than an anti-inflammatory in this specific disease?

Key Response

COPD is characterized by fixed airflow obstruction and cholinergic-mediated bronchoconstriction rather than the eosinophilic inflammation typical of asthma. LAMAs reduce vagal tone and LABAs increase cAMP to relax smooth muscle; together, they maximize lung volume reduction and decrease hyperinflation more effectively than ICS, which has limited efficacy against the neutrophilic inflammation predominant in most COPD patients.

Resident

Based on the FLAME trial results, how should a clinician choose between LAMA/LABA and LABA/ICS for a patient with moderate-to-severe COPD and one exacerbation in the past year, and how does this align with current GOLD guidelines?

Key Response

The FLAME trial demonstrated that LAMA/LABA (indacaterol–glycopyrronium) was superior to LABA/ICS (salmeterol–fluticasone) in reducing the annual rate of all exacerbations. Following these findings, GOLD guidelines transitioned to recommending LAMA/LABA as the preferred maintenance therapy for most symptomatic patients with exacerbations, reserving ICS specifically for those with blood eosinophils ≥300 cells/µL or a concomitant diagnosis of asthma.

Fellow

The FLAME trial found LAMA/LABA superiority across all subgroups, including those with blood eosinophil counts ≥2% or ≥300 cells/µL. How do you reconcile these findings with subsequent trials like IMPACT or TRIBUTE which suggest an ICS benefit in high-eosinophil populations?

Key Response

Differences may stem from the study populations; FLAME excluded patients with asthma and included those with fewer prior hospitalizations compared to IMPACT. Furthermore, FLAME compared dual therapy to dual therapy, whereas IMPACT compared triple therapy to dual therapy. A fellow must recognize that while LAMA/LABA is robustly superior as a baseline, the 'added value' of ICS becomes more apparent as exacerbation risk and eosinophil counts escalate beyond the FLAME inclusion criteria.

Attending

Given the 17% reduction in exacerbations and the significantly lower pneumonia risk observed in the LAMA/LABA arm of the FLAME trial, what is the clinical justification for continuing a patient on LABA/ICS in the absence of a high blood eosinophil count or asthmatic features?

Key Response

There is little clinical justification for LABA/ICS as a primary strategy in non-eosinophilic COPD. The FLAME trial confirms that LAMA/LABA provides better exacerbation protection with fewer side effects (specifically pneumonia). For attendings, this represents a practice-changing paradigm shift: 'de-escalating' or 'switching' from ICS-containing regimens to dual bronchodilation can improve outcomes while reducing the long-term morbidity associated with inhaled steroids.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The FLAME trial utilized a non-inferiority design with a pre-specified hierarchical transition to a superiority analysis. Critique the choice of a non-inferiority margin of 1.10 and the use of the negative binomial regression model for the primary endpoint of exacerbation rates.

Key Response

A margin of 1.10 (10% leeway) is conservative in COPD trials, ensuring that the non-inferiority result is statistically meaningful. The negative binomial model is the appropriate choice for count data like exacerbations because it accounts for 'overdispersion' (the variance exceeding the mean), which is common in clinical populations where a small number of 'frequent exacerbators' can skew the data.

Journal Editor

As a reviewer, how would you address the potential for 'withdrawal bias' in the FLAME trial, given that many patients were transitioned from ICS-containing triple therapy to a LAMA/LABA regimen at the start of the study?

Key Response

A tough reviewer would flag that if the LABA/ICS arm's performance was degraded by 'steroid withdrawal' symptoms masquerading as exacerbations early in the study, it might artificially favor the LAMA/LABA arm. However, the FLAME authors addressed this by showing that the benefit of LAMA/LABA was sustained throughout the 52-week period and was not just a transient effect seen in the first few weeks, strengthening the validity of the superiority claim.

Guideline Committee

The FLAME trial is a cornerstone for the GOLD 'LABA/LAMA over LABA/ICS' recommendation. Should the committee further restrict ICS use to only 'Triple Therapy' (LAMA/LABA/ICS) for those who fail dual bronchodilation, or is there still a role for LABA/ICS as a standalone maintenance option?

Key Response

The FLAME evidence, supported by the risk of pneumonia with ICS (4.8% vs 3.2% in FLAME), suggests that LABA/ICS should no longer be a preferred starting point. Current GOLD recommendations (Group E) now prioritize LAMA/LABA. The committee must decide if LABA/ICS remains an 'alternative' or if it should be entirely replaced by LAMA/LABA + ICS (triple therapy) when an anti-inflammatory effect is required, effectively making LABA/ICS obsolete for COPD.

Clinical Landscape

Noteworthy Related Trials

2007

TORCH Trial

n = 6,112 · NEJM

Tested

Salmeterol–fluticasone propionate

Population

Patients with moderate-to-severe COPD

Comparator

Placebo

Endpoint

All-cause mortality

Key result: The study failed to show a statistically significant reduction in all-cause mortality, though it demonstrated improvements in lung function and exacerbation rates.

2014

WISDOM Trial

n = 2,485 · NEJM

Tested

Stepwise withdrawal of inhaled glucocorticoids

Population

Patients with severe COPD and a history of exacerbations

Comparator

Continued treatment with inhaled glucocorticoids plus long-acting bronchodilators

Endpoint

Time to the first moderate or severe COPD exacerbation

Key result: Withdrawal of inhaled glucocorticoids did not increase the risk of exacerbations in patients already receiving dual long-acting bronchodilators.

2018

SUNSET Trial

n = 1,053 · ERJ

Tested

Direct switch from triple therapy to dual bronchodilation

Population

Patients with moderate-to-very severe COPD

Comparator

Continued triple therapy (ICS/LABA/LAMA)

Endpoint

Change in trough FEV1

Key result: Switching from triple therapy to dual bronchodilation did not result in a significant decrease in lung function, suggesting many patients are over-treated with ICS.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis