Triple therapy trumps dual therapies in lowering COPD exacerbations
A combined triple therapy comprising fluticasone furoate (an ICS*), umeclidinium (a LAMA**), and vilanterol (a LABA***) in a single inhaler significantly lowers the rate of moderate or severe exacerbations compared with dual therapies of either ICS-LABA or LAMA-LABA in patients with symptomatic chronic obstructive pulmonary disease (COPD) and a history of exacerbations, the IMPACT# study shows.
Although experts generally agreed about the role of LAMAs and LABAs in COPD management, the role for ICSs remains debatable in view of their modest effectiveness and safety concerns. According to the 2017 GOLD## guidelines, the addition of an ICS to a dual therapy of LAMA-LABA should be limited to “group D” patients — those with severe loss of lung function and frequent exacerbations despite maximal bronchodilator treatment. [Eur Respir J 2017;49:1700214; N Engl J Med 2018;378:1723-1724]
“However, the evidence supporting the step-up [from a dual bronchodilator regimen] to triple inhaled treatment (ie, LAMA–LABA–inhaled glucocorticoid) is weak; the writers of the GOLD guideline stressed the need for research on this matter,” noted Drs Samy Suissa and Jeffrey Drazen of McGill University, Montreal, Canada, in an accompanying editorial. [N Engl J Med 2018;378:1723-1724]
Triple therapy reduces exacerbations
To address this gap in knowledge, researchers randomized 10,355 patients (mean age 65 years) with COPD in a 2:2:1 ratio to receive once-daily, single-inhaler triple therapy of fluticasone furoate 100 μg + umeclidinium 62.5 μg + vilanterol 25 μg, or dual therapy of fluticasone furoate–vilanterol or umeclidinium–vilanterol in the phase III, double-blind, multicentre IMPACT trial. [N Engl J Med 2018;378:1671-1680]
The primary endpoint of moderate or severe exacerbation rate was significantly lower with triple therapy than with either dual therapy (annual rates, 0.91 vs 1.07 and 1.21; rate ratios [RRs], 0.85; p<0.001 and 0.75; p<0.001 for triple therapy vs fluticasone furoate–vilanterol and umeclidinium–vilanterol, respectively).
The triple-therapy group also had a lower rate of severe exacerbations requiring hospitalization compared with the fluticasone furoate–vilanterol and the umeclidinium–vilanterol groups (0.13 vs 0.15 and 0.19; RRs, 0.87; p=0.06 and 0.66; p<0.001, respectively), although only the difference with umeclidinium–vilanterol was significant.
“These benefits were observed regardless of the patients’ blood eosinophil levels at randomization,” said the researchers. The difference was greater in patients with elevated blood eosinophils of ≥150 cells/µL.
Improvements from baseline in other secondary measures such as lung function (indicated by trough FEV1###) and health-related quality of life (in terms of SGRQ^ score) were greater with triple therapy than with either of the dual therapies (p<0.001 for both comparisons).
There were no new safety signals associated with the use of triple therapy in terms of vital signs, ECG measurements, or clinical laboratory values tested. Adverse-event profile was similar between triple therapy and dual therapies, with similar incidence of adverse events leading to treatment discontinuation or study withdrawal (6 percent vs 8 and 9 percent) and serious adverse events (22 percent vs 21 and 23 percent) among the groups.
However, pneumonia incidence was higher in the triple-therapy group than the umeclidinium–vilanterol group (hazard ratio [HR], 1.53; p<0.001), while the difference was not significant when compared with the fluticasone furoate–vilanterol group (HR, 1.02; p=0.85).
Does this fill the gap in knowledge?
“The IMPACT trial addressed the relevant clinical question of treatment step-up from a dual long-acting bronchodilator regimen to triple therapy, the currently recommended therapeutic route for symptomatic exacerbation-prone patients with GOLD group D COPD,” wrote Suissa and Drazen.
“Nevertheless, the results of the IMPACT trial are challenging to interpret because nearly 40 percent of the patients enrolled in the trial were receiving treatment with triple therapy, more than 70 percent were receiving an inhaled glucocorticoid, and patients with a history of asthma were included.”
This means that many of the patients assigned to the LAMA-LABA group (without ICS) were actually stepping down in their treatment, as ICS was abruptly withdrawn at randomization — potentially leading to COPD exacerbations, explained the editorialists.
“This design peculiarity … the selected trial patients, most of whom were already treated with inhaled glucocorticoids and some of whom had a history of asthma, were not the natural population in which to study this question, potentially artificially inflating the observed effectiveness of the triple-therapy inhaler over dual bronchodilator treatment,” Suissa and Drazen commented.
“As such, we think that the IMPACT trial falls short of providing the awaited robust evidence to better understand the potential for stepping up to single-inhaler triple therapy in clinical practice,” they added, cautioning that extending triple therapy to patients with GOLD groups A, B, and C COPD might do more harm than good.
“Until further evidence is available, we think that clinicians should rely on the updated GOLD 2017 guidelines recommending that escalation to triple therapy occur only after maximized bronchodilator treatment with LAMA–LABA regimens and be limited to patients with more symptomatic GOLD group D COPD with frequent exacerbations,” suggested Suissa and Drazen.