Triple Therapy for COPD More Effective Than Dual Inhalers?

Pam Harrison

April 24, 2018

Triple therapy delivered in a single inhaler reduces moderate to severe exacerbations in chronic obstructive pulmonary disease (COPD) to a greater extent than dual-inhaler therapy in patients at high risk for exacerbations, according to results from the Informing the Pathway of COPD Treatment (IMPACT) trial.

The data also show that the triple therapy, a combination of the inhaled glucocorticoid fluticasone furoate, the long-acting muscarinic antagonist (LAMA) umeclidinium, and the long-acting β2-agonist (LABA) vilanterol (Trelegy Ellipta, GlaxoSmithKline), reduces the need for hospitalization from COPD compared with the dual inhaler containing umeclidinium plus vilanterol, but not compared with the inhaler containing fluticasone furoate plus vilanterol. The study was published online April 18 in the New England Journal of Medicine.

On the basis of these new data, the US Food and Drug Administration approved the triple therapy for approval for long-term, once-daily, maintenance therapy in patients with COPD, including chronic bronchitis and/or emphysema.

However, in an accompanying editorial, Samy Suissa, PhD, from McGill University, Montreal, Quebec, Canada, and Jeffrey Drazen, MD, the editor-in-chief of the New England Journal of Medicine, caution that a "peculiarity" of the study design, as well as the type of patients enrolled, may have skewed findings from the study, "falsely exaggerating the benefit of triple therapy in comparison to the LAMA–LABA comparator group."

Until more robust evidence provides a strong rationale to step up to single-inhaler triple therapy, the editorialists advise physicians to follow the updated 2017 Global Initiative for Chronic Obstructive Lung Disease guidelines, which recommend that physicians limit the addition of an inhaled glucocorticoid to patients with more symptomatic Global Initiative for Chronic Obstructive Lung Disease–defined COPD with frequent exacerbations.

Large, Double-Blind Trial

IMPACT was a large, phase 3, double-blind trial initially involving 10,355 patients (mean age, 65.3 years) who were randomly assigned to 52 weeks of once-daily triple therapy (100 μg fluticasone furoate, 62.5 μg umeclidinium, 25 μg vilanterol) or to one of two dual-inhaler therapies consisting of either 100 μg fluticasone furoate plus 25 μg vilanterol or 62.5 μg umeclidinium plus 25 μg vilanterol. "Each regimen was administered in a single dry-powder inhaler (Ellipta, GlaxoSmithKline)," write David Lipson, MD, an employee of GlaxoSmithKline in Collegeville, Pennsylvania, and colleagues.

Patients were 40 years of age or older and had a score of at least 10 or more on the COPD Assessment Test. They also had to have either a forced expiratory volume in 1 second (FEV1) less than 50% of the predicted normal value and at least one moderate to severe COPD exacerbation in the previous year, or an FEV1 between 50% and 80% of normal and at least 2 moderate exacerbations or one severe exacerbation in the previous year.

A total of 7991 patients, almost two-thirds of whom were men, completed the study while receiving an investigational treatment.

At the end of the 52-week trial, the rate of moderate or severe exacerbations, which was the primary endpoint of the trial, was significantly lower at 0.91 exacerbations per year among those in the triple-therapy group vs 1.07 exacerbations per year for patients in the fluticasone furoate-vilanterol group (95% confidence interval [CI], 0.80 to 0.90; P < .001) and 1.21 exacerbations per year for those in the umeclidinium-vilanterol group (95% CI, 0.70 to 0.81; P < .001).

"The annual rate of moderate or severe exacerbations was lower with triple therapy than with either dual-therapy combination, regardless of eosinophil level, although a greater reduction in the exacerbation rate was observed in patients with eosinophil levels of at least 150 cells per microliter," investigators note. Elevated blood eosinophil levels are considered a good marker by which to judge the effectiveness of using inhaled glucocorticoids in COPD.

In this group, the annual exacerbation rate was 0.95 for those receiving triple therapy (95% CI, 0.09 - 1.01) vs 1.08 (95% CI, 1.02 - 1.14) with fluticasone furoate-vilanterol and 1.39 (95% CI, 1.29 - 1.51) with umeclidinium-vilanterol.

The investigators also measured the mean change in trough FEV1 from baseline to study endpoint. Here again, the difference was significantly in favor of the triple therapy, as was the mean change from baseline to study endpoint in the St George's Respiratory Questionnaire total score in the intention-to-treat population. The St George's Respiratory Questionnaire helps assess health-related quality of life, with lower scores indicating an improvement.

Table. Trough FEV1 and St George's Respiratory Questionnaire Total Score at Week 52

  Triple Therapy Fluticasone Furoate-Vilanterol Umeclidinium-Vilanterol
Mean trough FEV1 at week 52 1274 mL 1177 mL 1220 mL
Mean change from baseline 94 mL −3 mL 40 mL
St George's Respiratory Questionnaire score: mean at 52 weeks 45.0 46.8 46.8
Mean change from baseline −5.5 −3.7 −3.7

Adverse Event Profile

"Overall, the adverse-event profile of triple therapy was similar to that of the dual-therapy comparators, and there were no new safety findings associated with the use of an inhaled glucocorticoid, a LAMA, or a LABA in combination," the researchers note. Adverse event rates leading to discontinuation of the study drug were 6% for triple therapy, 8% for fluticasone furoate-vilanterol, and 9% for umeclidinium-vilanterol.

In contrast, the incidence of pneumonia was significantly higher in the triple therapy group than in the umeclidinium-vilanterol group. Expressed as a time-to-first event analysis, the risk for pneumonia was 53% higher among the triple therapy group than it was for patients receiving umeclidinium-vilanterol, at a hazard ratio (HR) of 1.53 (95% CI, 1.22 - 1.92; P < 0.001). In contrast, the difference in the risk for pneumonia between those receiving triple therapy and those receiving fluticasone furoate-vilanterol was not significantly different, with a HR of 1.02 (95% CI, 0.87 - 1.19; P = 0.85).

"[T]he results of the IMPACT trial show that a once-daily combination of fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations and better lung function and health-related quality of life than dual therapy with fluticasone furoate–vilanterol or umeclidinium–vilanterol," the authors conclude.

The editorialists Suissa and Drazen agree with the IMPACT investigators that one of the strengths of the study was that the same drugs and doses of a LAMA and a LABA were used in both the triple-therapy group and the 2 comparator groups. They also applaud the fact that investigators included information on exacerbations that occurred in patients who discontinued the study drug during follow-up, which lessens any bias in their findings.

"Nevertheless, the results of the IMPACT trial are challenging to interpret because nearly 40% of the patients enrolled in the trial were receiving treatment with triple therapy, more than 70% were receiving an inhaled glucocorticoid, and patients with a history of asthma were included [in the study]," Suissa and Drazen write.

This means that many of the patients assigned to the dual-inhaler groups were actually randomly assigned to "step-down" treatment on study enrolment, as inhaled glucocorticoids were "abruptly withdrawn" on randomization, they stress. "[T]his could lead to COPD exacerbations," the editorialists say, an observation that appears to be supported by the "rapid surge" in exacerbations seen in the first month after enrolment in the LAMA-LABA group.

Moreover, the incidence of exacerbations during the ensuing 11 months of follow-up in those receiving the LAMA-LABA combination was actually "practically identical" to the incidence seen in the triple-therapy group, they add.

That said, Suissa and Drazen agree that it is important to know whether the shift from two drugs to three improves patient outcomes, which IMPACT was designed to address. "However, 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," the editorialists suggest.

"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," Suissa and Drazen conclude.

The study was funded by GlaxoSmithKline. Multiple coauthors report receiving personal fees or other support from GlaxoSmithKline; many coauthors report additional multiple conflicts of interest. Suissa reports receiving personal fees from Astra Zeneca and grants and personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, and Novartis.

N Engl J Med. Published online April 18, 2018. Full text, Editorial full text

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