Once-daily triple therapy with fluticasone furoate/umeclidinium/vilanterol improves health-related quality of life and reduces COPD exacerbations compared to twice-daily budesonide/formoterol in patients with advanced COPD
EBM Focus - Volume 12, Issue 37
- The recent randomized FULFIL trial compared the efficacy of triple therapy with fluticasone furoate/umeclidinium/vilanterol once-daily vs. dual therapy with budesonide/formoterol twice-daily in 1,810 patients with advanced symptomatic chronic obstructive pulmonary disease (COPD).
- Compared to dual therapy, triple therapy was associated with a reduced rate of severe-to-moderate exacerbations occurring in 10% vs. 14% with dual therapy (p < 0.05, NNT 25) and improved health-related quality of life and trough FEV1.
- Improved clinical outcomes with a triple therapy using other medications in the same classes as the FULFIL trial were also observed in the TRILOGY trial, indicating that the benefits of triple therapy may not be medication specific but rather reflect a class effect.
Escalation to triple therapy with an inhaled corticosteroid (ICS) plus a long-acting muscarinic antagonist (LAMA) plus a long-acting beta-2 agonist (LABA) is currently recommended for patients classified as Global Initiative for Chronic Obstructive Lung Disease (GOLD) Group D who develop exacerbations despite dual therapy with a LAMA/LABA or ICS/LABA (GOLD 2017). Recommendations for the use of triple therapy are based on three trials that evaluated outcomes at 12 weeks or less (Thorax 2008, Thorax 2015, COPD 2016) and the 52-week long TRILOGY trial (Lancet 2016). To further evaluate the efficacy of triple therapy with ICS/LAMA/LABA compared to dual therapy with ICS/LABA, 1,810 patients (mean age 64 years, 74% male) with advanced symptomatic COPD were randomized in the FULFIL trial to fluticasone furoate/umeclidinium/vilanterol 100 mcg/62.5 mcg/25 mcg once daily via single ELLIPTA inhaler plus placebo vs. budesonide/formoterol 400 mcg/12 mcg twice daily via Turbuhaler plus placebo for 24 weeks. The first 430 patients continued blinded treatment up to 52 weeks. All patients had a normal electrocardiogram and a COPD Assessment test score ≥ 10. Patients also had a forced expiratory volume in 1 second (FEV1) < 50% predicted or FEV1 from 50% to less than 80% predicted plus one of the following in the previous year: ≥ 2 moderate exacerbations or ≥ 1 severe exacerbations. Moderate exacerbations were defined as requiring treatment with systemic corticosteroids or antibiotics and severe exacerbations as requiring hospitalization. A clinically important improvement in quality of life was defined as a ≥ 4 point decrease on the St. George’s Respiratory Questionnaire (SGRQ) (range 0-100 with higher score indicating worse quality of life).
At 24 weeks, a clinically important improvement in quality of life was observed in 50% with triple therapy vs. 41% with dual therapy (p < 0.001, NNT 12). Triple therapy was also associated with a reduced rate of severe-to-moderate exacerbations occurring in 10% vs. 14% with dual therapy (p < 0.05, NNT 25). In addition, a clinically important improvement in trough FEV1 (defined as ≥ 100 mL increase from baseline) was observed in 50% with triple therapy vs. 21% with dual therapy (p < 0.001, NNT 4). Consistent findings for these outcomes were observed in the 52-week extension phase. Major cardiovascular events up to 24 weeks occurred in 0.4% with triple therapy vs. 0.8% with dual therapy and in 2.4% vs. 0.9% up to 52 weeks. Over 52 weeks, on-treatment severe adverse events occurred in 10% with triple therapy vs. 12.7% with dual therapy (no statistical comparisons for adverse events were reported).
The FULFIL trial demonstrated that fluticasone furoate/umeclidinium/vilanterol once daily reduced the rate of moderate-to-severe COPD exacerbations and improved health-related quality of life and lung function as assessed by trough FEV1 compared to budesonide/formoterol twice daily. The findings of the FULFIL trial are consistent with those of the TRILOGY trial (Lancet 2016) which compared triple therapy with beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide vs. dual therapy with beclometasone dipropionate/formoterol fumarate. Together, these trials provide evidence that the improved outcomes with ICS/LAMA/LABA triple therapy vs. ICS/LABA dual therapy may not be medication specific but rather reflect a class effect. Moreover, the improvements in clinically relevant outcomes observed with triple therapy with ICS/LAMA/LABA vs. dual therapy with ICS/LABA in both trials may suggest a role for triple therapy as an earlier rather than a later step-up therapy. However, further studies with a head-to-head comparison of ICS/ LAMA/LABA vs. LAMA/LABA are first needed to better clarify the role of the ICS component in the benefits of triple therapy compared to dual therapy for patients with advanced symptomatic COPD. Finally, it should be noted that the rate of major cardiovascular events continued to increase in the extension period after the first 6 months of triple therapy suggesting that close monitoring of these patients over time may be warranted.