Single-inhaler triple therapy ups survival in COPD

A once-daily triple therapy of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI; ICS/LAMA/LABA*) in a single inhaler significantly reduces the risk of all-cause mortality compared with a dual therapy of UMEC/VI (LAMA/LABA) in chronic obstructive pulmonary disease (COPD) patients with a history of moderate or severe exacerbations, confirm the latest results of the IMPACT** study. 

Previously published data from the primary analyses have shown significant benefits with the triple therapy, including reductions in moderate/severe exacerbations, COPD hospitalization, death risk, and improved lung function and HRQoL***. However, data from 5.5 percent of the patients were censored from the previous analysis due to lack of vital status information for all-cause mortality. [N Engl J Med 2018;378:1671-1680]

The current analysis was performed following the collection of additional data on vital status at week 52, representing 99.6 percent of the intention-to-treat population. [Am J Respir Crit Care Med 2020;doi:10.1164/rccm.201911-2207OC]

“Because the number of missing patients exceeded the numbers of deaths in the study we felt caution was warranted in the interpretation of the original published findings,” said lead author Dr David Lipson from the Perelman School of Medicine, University of Pennsylvania in Philadelphia, Pennsylvania, US. “These new repeat analyses demonstrate the robustness of the original finding.”

In the phase III, double-blind, multicentre IMPACT study, 10,355 patients (mean age 65.3 years, 66 percent male) with COPD were randomized to FF/UMEC/VI (100/62.5/25 μg), FF/VI (100/25 μg), or UMEC/VI (62.5/25 μg) in a 2:2:1 ratio.

Treatment with triple therapy led to significantly reduced risk of all-cause mortality at 52 weeks (hazard ratio [HR], 0.72; p=0.042) compared with dual therapy containing UMEC/VI. While death risk was also reduced with triple therapy when compared with the ICS/LABA FF/VI, the difference between groups was not statistically significant (HR, 0.89; p=0.387).

“We believe that the mortality finding with FF/UMEC/VI compared to UMEC/VI was primarily driven by the steroid component and its effect on reducing exacerbations, especially hospitalized exacerbations,” said Lipson.

“[As] frequently exacerbating patients are at higher risk of hospitalization and death, these are the patients who appear to achieve the greatest survival benefit with once-daily FF/UMEC/VI triple therapy,” he explained.

Independent adjudicated results revealed that the triple therapy arm also had lower rates of death due to cardiovascular or respiratory causes as well as COPD-related death.

According to the researchers, this is the first trial to demonstrate a survival benefit with a pharmacologic therapy in COPD patients. Thus far, only smoking cessation, lung volume reduction surgery, and oxygen therapy in select patients have been shown to improve survival in these patients.  

“The data from patients [originally on triple therapy when entering the trial; 40 percent] … suggest that maintenance on a triple therapy is associated with a trend towards lower risk of death than step down to either dual therapy,” noted Lipson and co-authors.

“This supports the benefit of both ICS and LAMA in this population, and is of importance as international treatment guidelines suggest consideration of step down of therapy in stable patients,” they added. “However, our findings suggest that physicians should use caution when considering step down in therapy in patients with characteristics that mirror those enrolled in IMPACT.”