Effectiveness of fluticasone furoate–vilanterol for COPD in clinical practice

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Vestbo J, et al. "Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice". New England Journal of Medicine. 2016. 375(13):1253-1260.
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Clinical Question

In patients with COPD and a history of exacerbations, does fluticasone furoate combined with vilanterol compared to usual care decrease the amount of COPD exacerbations?

Bottom Line

In patients with Chronic Obstructive Pulmonary Disease (COPD) and a history of exacerbations, this study found that a once-daily treatment regimen of combined fluticasone furoate and vilanterol was associated with a lower rate of exacerbations than standard care, without a greater risk of serious adverse events. Biases exist within this study and should be taken into consideration when making clinical decisions.

Major Points

Chronic Obstructive Pulmonary Disease (COPD) is currently the fourth leading cause of death in the world. COPD is characterized by persistent respiratory symptoms and airflow limitations that is due to airway and/or alveolar abnormalities usualardly caused by significant exposure to particles or gases. The treatment for moderate to severe COPD is a long acting muscarinic antagonist (LAMA), long acting beta2 agonist (LABA), inhaler corticosteroid, or a combination of two of the drugs listed above. The 2016 Effectiveness of fluticasone furoate-vilanterol for COPD in Clinical Practice trial was trying to determine if the combination of fluticasone furoate and vilanterol (Breo) was better than standard care (also known as usual care) for COPD.

The trial was a prospective, 12-month, open-label, parallel-group conducted in 75 general practices in Salford and South Manchester, United Kingdom. Patients with COPD, 2799 in total, were randomly assigned to a treatment group, once daily inhaled combination of fluticasone furoate at a dose of 100ug and vilanterol at a dose of 25ug, or to standard care. Data was gathered at general practice visits at months 3, 6, and 9 or they were contacted by telephone by a trial member to assess any serious adverse events or non-serious adverse drug reactions. The trial found that the rate of moderate or severe exacerbation was significantly lowered by 8.4% (95% confidence interval, 1.1 to 15.2), with fluticasone furoate-vilanterol therapy than with standard care. The numbers of serious adverse events were similar in the two groups, there was no significant difference in rates of the first moderate or severe exacerbation and the first severe exacerbation in the time-to-event analysis.

The trial showed that in patient with COPD and a history of exacerbation the treatment with fluticasone furoate and vilanterol was associated with lower rates of exacerbations than usual care without greater risk of serious adverse events. However, this study could have some bias which include, the study being conducted by a pharmaceutical, GSK, that produced the product, patients could switch from the treatment therapy to back to standard care, and the standard care was not defined. In addition the Global initiative for Chronic Obstructive Lung Disease (GOLD) guideline for COPD doesn’t recommend the use of a combination therapy of ICS/LABA over combination therapy of LAMA/LABA due to the increased risk of developing pneumonia.[1]


  • From 2017 report Global initiative for Chronic Obstructive Lung Disease (GOLD) guidelines on COPD general management [2]
    • Long-acting beta-2 agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) significantly improve lung function, dyspnea, health status, and reduce exacerbation rates (Evidence A)
    • LAMAs have a greater effect on exacerbation reduction compared to LABAs (Evidence A) and decrease hospitalizations (Evidence B).
    • Combination treatment with a LABA and LAMA reduces exacerbations compared to monotherapy (Evidence B) or inhaled corticosteroid (ICS)/LABA combination (Evidence B).
    • In patients with exacerbations and moderate to very severe COPD, an ICS/LABA combination is more effective in improving lung function and reducing exacerbations compared to therapy with the individual medications (Evidence A).
    • Regular treatment with an ICS increases the risk of pneumonia especially in those with severe disease (Evidence A)

Evidence A: Requires high quality evidence from at least two well-designed randomized controlled trials involving a substantial amount of patients or a single high quality randomized controlled trial without any bias. Findings in the trials are consistent in the population for which the recommendation is made and the recommendation is made without limitations.

Evidence B: Evidence is from randomized controlled trials that have a limited number of patients included, post hoc or subgroup analyses of randomized controlled trials, or meta analyses of randomized controlled trials. Also, if only a few randomized controlled trials are available or the trials have important limitations such as flaws in the trial or inconsistent results.


  • Trial type: Prospective, open label, parallel group, randomized trial
  • Number of patients randomized: 2802 (after randomization, 3 never took the medication)
  • Experimental group: 1396 patients given fluticasone furoate-vilanterol
  • Standard group: 1403 were given their usual treatment
  • Setting: 75 general practices in Salford and South Manchester, United Kingdom
  • Enrollment: 12 month long trial starting from patient’s first trial visit for recruitment (recruitment was between March 13, 2012 and October 23, 2014)
  • Mean follow-up: Follow up occurred during the trial at months 3, 6, and 9. However, if the patient had no contact with their general practitioner within the 8 weeks leading up to these checkpoints, the patient was contacted by phone by a member of the trial team.
  • Analysis type: intention-to-treat
  • Primary outcome:
    • Mean annual rate of moderate or severe exacerbations, defined as any worsening of respiratory symptoms that led to treatment with antibiotic agents or glucocorticoids or both, to hospital admission, or to scheduled or unscheduled hospital visits
  • Secondary outcomes:
    • Looked at the entire population for secondary outcomes
    • Analyzed the differences in: rate of exacerbations, annual rate of COPD-related contact with primary care, changes in the COPD Assessment Test (CAT) and European Quality of Life-5 Dimensions (EQ-5D) questionnaire, and adverse events (for example: cardiovascular events, pneumonia, and lower respiratory tract infections).


Inclusion Criteria

  • Age >40 years
  • Diagnosis of COPD
  • Had one or more COPD exacerbations in the previous 3 years
  • Patients had to be taking regular maintenance inhaler therapy

Exclusion Criteria

  • Exacerbation within previous 2 weeks
  • Long-term use of oral glucocorticoids

Baseline Characteristics

  • Mean Age: 67
  • Female: 49%
  • BMI: 28
  • Current Smoker: 46%
  • Post bronchodilator FEV1 — liters: 1.62
  • Number of exacerbations during the 12 months before randomization: 2.01


  • Prospective, 12-month, open-label, parallel group, randomized trial conducted in 75 general practices
  • Randomization was performed by means of a centralized randomization service, with stratification according to baseline maintenance therapy and presence or absence of a COPD exacerbation in the past 12 month
  • Patients were randomly assigned to receive one of two treatments, fluticasone furoate plus vilanterol or standard care, in a 1:1 ratio
  • Treatment: combination therapy with 100 μg of fluticasone furoate and 25 μg of vilanterol (Breo) administered once daily as a dry powder through an inhaler
  • Control: continuation of standard care as determined by the general practitioner


Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

The primary outcome was the mean annual rate of moderate or severe exacerbations, defined as any worsening of respiratory symptoms that led to treatment with antibiotic agents or systemic glucocorticoids or both, to hospital admission, or to scheduled or unscheduled hospital visits. The primary outcome was only looked at under a subgroup. The rate of moderate to severe exacerbations were decreased by 8.4% in the patients treated with fluticasone furoate-vilanterol as compared the patient being treated with standard care.

Rate of moderate or severe exacerbations analysis population
1.74/year (Breo) VS 1.90/year (standard care) (p=0.02)
Rate of moderate or severe exacerbations entire trial
1.50/year (Breo) VS 1.64/year (standard care) (p=0.02)

Secondary Outcomes

The secondary outcome was looked at in the entire population; included the rate of first exacerbation, as assessed in a time-to-event analysis, and the annual rates of primary and secondary health care contacts. Other outcomes included the COPD Assessment Test (CAT) score and European Quality of Life–5 Dimensions (EQ-5D) questionnaire results. There was a significant difference in the CAT scores.

A decrease by 2 or more points in CAT score occur in
45% (Breo) vs 36% (standard care)(odds ratio in favor of fluticasone furoate–vilanterol, 1.51; 95% CI, 1.28 to 1.77; P<0.001).

There were no significant difference in the rate of first moderate or severe exacerbation in the time-to-event analysis in the entire population or in the rate of severe exacerbations between the fluticasone furoate-vilanterol group and the standard-care group or the rate of first severe exacerbation in the time-to-event analysis. The annual rate of all primary care contacts was slightly higher in the fluticasone furoate-vilanterol group than in the standard-care group but no significant differences in the secondary health care contacts rates.

Subgroup Analysis

The primary outcome was only looked at under a subgroup. This was the patients in the entire population who had undergone randomization and received a prescription of the trial medication: either fluticasone furoate-vilanterol or, in the standard-care group, a COPD-controller medication.

Adverse Events

Adverse events include:

  • Cardiovascular events
  • Pneumonia
  • Lower respiratory tract infections
  • Decreased bone mineral density/ associated fracture
  • Glucose levels
  • Hypersensitivity
  • Potassium levels
  • Glucocorticoid-associated eye disease
  • Local glucocorticoid effects

There was no notable difference between the two groups to any AE of special interest. There was a trend towards a higher mean number of serious AE of pneumonia in the group receiving treatment without a glucocorticoid at randomization. 1% of patients total had a fatal outcome related to pneumonia. One patient in each group died from an AE related to trial therapy.


  • Patients were selected under strict criteria, so results have limited relevance to everyday clinical practice
  • No statement on what the usual care medications are that fluticasone furoate-vilanterol is being compared to
  • Patients could switch from fluticasone furoate-vilanterol to usual care throughout the study
  • It was an open-label (un-blinded) trial, which could have introduced bias
  • Patients were largely unsupervised over the yearlong period


Funded by GlaxoSmithKline the makers of Breo

Further Reading