COPD Study Finds Benefits, Risks in Comparison of Triple, Dual Therapies

Allison Inserro

A new study comparing triple therapy for chronic obstructive pulmonary disease (COPD) against dual therapy resulted in a lower rate of moderate or severe COPD exacerbations and a lower rate of hospitalizations. However, triple therapy had a much higher incidence of pneumonia, which the researchers said was to be expected.

Triple inhaled therapy for COPD consists of a combined inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA) and a long-acting muscarinic antagonist (LAMA). Triple therapy is recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) for patients who experience recurrent exacerbations despite treatment with either a dual bronchodilator or LABA/ICS combination. The GOLD guidelines do not recommend ICS as a monotherapy given the pneumonia risks.

Results of the study—The Informing the Pathway of COPD Treatment (IMPACT) trial—were published in The New England Journal of Medicine Wednesday.1 The 1-year randomized trial involved 10,355 patients with COPD.

It compared a once-daily combination of fluticasone furoate, an ICS, at a dose of 100 μg, umeclidinium (a LAMA) at a dose of 62.5 μg, and vilanterol (a LABA) at a dose of 25 μg (triple therapy) with fluticasone furoate–vilanterol (at doses of 100 μg and 25 μg, respectively) and umeclidinium–vilanterol (at doses of 62.5 μg and 25 μg, respectively).

Each regimen was administered in a single Ellipta inhaler. Ellipta is sold by GlaxoSmithKline, which also sponsored the study. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment.

The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate–vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P <.001) and 1.21 per year in the umeclidinium–vilanterol group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P <.001).

The annual rate of severe exacerbations resulting in hospitalization in the triple-therapy group was 0.13, as compared with 0.19 in the umeclidinium–vilanterol group (rate ratio, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P <.001).

The incidence of pneumonia in the ICS groups were higher than in the umeclidinium–vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium–vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P <.001).

The rate of pneumonia was more than 50% higher with triple therapy than with the umeclidinium–vilanterol combination (9.6 vs 6.1 per 100 patient-years).

In an accompanying editorial, the authors recommended that the GOLD guidelines stay unchanged for now and that triple therapy be reserved only for patients with severe loss of lung function and frequent exacerbations (called “group D” in the guidelines).2

“Although single-inhaler triple therapy offers simplicity in treating COPD, any potential benefit could be lost and potential undue harm induced if triple therapy is expanded to patients with GOLD groups A, B, and C,” the authors wrote.

The editorial said the trial has several strengths. It addressed the key question posed by GOLD guidelines, about when to move from a dual bronchodilator regimen to triple therapy. The trial used the same agents and doses of LAMA and LABA in the triple-therapy and comparison groups. Moreover, data on exacerbations in many of the patients who discontinued trial treatment during follow-up were included in the data analysis, which helped to lessen bias.

However, they called the results challenging to interpret. The authors wrote that the results may have been affected by who was included in the study. Since many of the trial patients were already treated with ICS and may have also had asthma, they were not the natural population to study in order to answer the question as to whether or not patients should step up from dual therapy to triple therapy. That may have inflated the final results of the study, the editorial's authors wrote. They recommended that until more evidence is available, clinicians should rely on the updated GOLD 2017 guidelines.


1. Lipson DA, Barnhart, F, Brealey, N, et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD [published online April 18, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1713901.
2. Suissa S, Drazen JM. Making sense of triple inhaled therapy for COPD [published online April 18, 2018]. N Engl J Med. doi:10.1056/NEJMe1716802.

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