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Reference - FLAME trial (N Engl J Med 2016 May 15 early online) (level 1 [likely reliable] evidence)
- Dual bronchodilator therapy with a long-acting inhaled beta-2 agonist (LABA) plus a long-acting anticholinergic agent may be an option for preventing COPD exacerbations, but its efficacy compared to the standard therapy of a LABA plus an inhaled corticosteroid is unknown.
- Compared to salmeterol/fluticasone, dual bronchodilator therapy with indacaterol/glycopyrronium significantly reduced COPD exacerbations and increased the time to COPD exacerbations in a randomized trial including 3,362 patients with moderate-to-severe COPD and at least 1 exacerbation in the previous year.
- Indacaterol/glycopyrronium also decreased the risk of pneumonia and did not increase the risk of other adverse events, suggesting it is a safe and effective alternative to current first-line COPD therapies.
COPD exacerbations are associated with an increased risk of hospitalization, reduced lung function, reduced quality of life, and increased mortality (GOLD 2016). Current recommendations suggest a long-acting inhaled beta-2 agonist (LABA) plus an inhaled corticosteroid, a long-acting anticholinergic agent, or a combination of all three for patients at a high risk for COPD exacerbations (GOLD 2016 PDF, Ann Intern Med 2011 Aug 2;155(3):179). Long-term use of an inhaled corticosteroid is associated with an increased risk of pneumonia and other serious adverse events, however, and dual bronchodilator regimens including a LABA plus an anticholinergic may provide an alternative option. Current evidence suggests dual bronchodilator therapy is more effective than LABA or anticholinergic monotherapy (Am J Respir Crit Care Med 2015 Nov 1;192(9):1068, Chest 2014 May;145(5):981), but the effectiveness of these regimens compared to a LABA plus an inhaled corticosteroid is unknown. To further assess the efficacy of dual bronchodilator therapy, the FLAME trial randomized 3,362 patients (mean age 65 years, 76% male) with moderate-to-severe COPD and ≥ 1 exacerbation in the previous year to indacaterol 110 mcg/glycopyrronium 50 mcg once daily vs. salmeterol 50 mcg/fluticasone 500 mcg twice daily for 52 weeks.
Treatment was discontinued before 52 weeks in 16.6% of patients randomized to indacaterol/glycopyrronium and 19% randomized to salmeterol/fluticasone (no p value reported), but 99.8% were included in the intention-to-treat analysis. This trial was designed to test the noninferiority indacaterol/glycopyrronium, but superiority statistics were performed after the noninferiority criterion was met. The annual rate of all COPD exacerbations was 3.59 with indacaterol/glycopyrronium vs. 4.09 with salmeterol/fluticasone (p< 0.001). The decreased rate of exacerbations with indacaterol/glycopyrronium was consistent in analyses of moderate-to-severe and severe exacerbations as well as in subgroup analyses by baseline eosinophil count and prior therapy. Indacaterol/glycopyrronium was also associated with significantly increased median time to the first exacerbation, reduced use of rescue medication, increased lung function, and improved health status. While there was a similar rate of adverse events overall with the two therapies, pneumonia was reported in 3.2% with indacaterol/glycopyrronium vs. 4.8% with salmeterol/fluticasone (p = 0.02).
The results of this trial suggest that the dual bronchodilator therapy is more effective at preventing COPD exacerbations than the currently recommended combination of a LABA plus an inhaled corticosteroid. The consistency of these results regardless of exacerbation severity and across subgroup analyses further strengthens the case for the use of dual bronchodilator therapy in patients at increased risk of COPD exacerbations. The once daily dose of indacaterol/glycopyrronium used in this trial is not currently approved in the United States, but a lower twice daily dose of this combination medication is approved and available. While some evidence suggests the once and twice daily regimens may have similar effectiveness, no direct comparisons have been performed to date. Overall, the results of the FLAME trial suggest that combination therapy with a LABA plus a long-acting anticholinergic should be considered as a first line option for patients with COPD.
For more information, see the Bronchodilators for COPD topic in DynaMed.