Triple Therapy Lessens Severe COPD Exacerbations & All-Cause Mortality

Among patients with COPD, the triple therapy of single-inhaler fluticasone furoate (FF)/ umeclidinium (
UMEC)/ vilanterol (VI) significantly reduced severe exacerbation rates and all-cause mortality (ACM) risk
versus the dual therapy of UMEC/VI, according to results from the InforMing the PAthway of COPD Treatment
(IMPACT) trial.

“Exacerbations contribute to the overall disease burden experienced by patients with COPD, with patients
with frequent or prolonged exacerbations shown to have worse health status and faster disease progression
compared with patients with infrequent exacerbations,” J. Michael Wells, MD, and colleagues wrote. In
addition, patients with COPD have a considerable risk for mortality during severe exacerbations as well as
an underlying risk for cardiovascular (CV) disease.

Dr. Wells and colleagues conducted the 52-week, double-blind IMPACT trial, which included randomized patients
with symptomatic COPD and one or more exacerbations in the prior year 2:2:1 to once-daily FF/UMEC/VI
100/62.5/25mcg, FF/VI 100/25mcg, or UMEC/VI 62.5/25mcg. Post hoc endpoints included the risk for ACM
during days 1-90 and 91-365 after a moderate or severe exacerbation and time-to-first cardiopulmonary
composite event. Results of the study were published in Chronic Obstructive Pulmonary Disease.

Using a Cox proportional hazards model with covariates of sex, treatment group, exacerbation history
(≤1, ≥2 moderate/severe), smoking status at screening, geographical region, and post-bronchodilator
percent predicted FEV1 at screening, the re- searchers assessed the time-to-first cardiopulmonary composite
event. The time to event was the date of the first event, and subsequent events were not used in the analyses
for patients who experienced more than one of the prespecified events. For patients who experienced none
of the prespecified events, they were cut from the analysis at their last known on-treatment time.

Nearly One-Half of Patients Experienced Moderate/Severe Exacerbations

With this post hoc analysis, researchers sought to define the risk for ACM during and after a moderate/severe
exacerbation and examine the benefits and risks of FF/UMEC/VI versus FF/VI and UMEC/VI using a cardiopulmonary
composite adverse event endpoint.

Among 10,355 patients included in the trial, nearly half (49%) presented with moderate or severe exacerbations.
During a severe exacerbation event, risk for ACM was significantly increased compared with baseline (HR, 41.22
[95% CI, 26.49–64.15]; P<0.001) but not considerable different at 1-90 days post-severe exacerbation (HR, 2.13
[95% CI, 0.86–5.29]).

Compared with the exacerbation-free period, the study team observed a 41-fold increased risk for mortality
during a severe COPD exacerbation, and a two-fold increased risk during days 1 to 90 after resolution
(Figure). However, the difference noted between the risk for ACM at days 1 to 90 after resolution and 91
to 365 days post resolution was not significant, compared with the baseline period. This was “likely due
to the low number of events,” Dr. Wells and colleagues noted. “These results are consistent with previous
studies, which have also linked severe COPD exacerbations with increased risk [for mortality].” Additionally,
previous research revealed that risk for death was increased around 14-fold with at least one severe
exacerbation in the previous year.

The risk for ACM did not significantly increase due to moderate exacerbations. Of patients receiving
FF/UMEC/VI, FF/VI, and UMEC/VI, cardiopulmonary composite events occurred in 16%, 65%, and 17%,
respectively. FF/UMEC/VI considerably decreased cardiopulmonary composite event risk versus UMEC/VI by
16.5%(95% CI, 5.0-26.7; P=0.006).

Results from the IMPACT trial “emphasize the substantial mortality risk associated with severe COPD
exacerbations, the importance of preventing exacerbations as a treatment goal, and the need to optimize
treatment in patients at risk for exacerbations,” Dr. Wells and colleagues noted.

The study team added that this research underscores “the importance of the underlying CV risk in this
population and that treatment with [FF/UMED/VI] triple therapy confers a favorable benefit-risk profile
compared with dual therapy in patients with symptomatic COPD and a history of exacerbations.”