Triple therapy tops dual therapy in COPD in ETHOS study

There is more evidence for the benefit of triple therapy in patients with moderate to severe COPD.

The ETHOS trial, published in the NEJM, comprised 8,509 patients with COPD from 26 countries including Australia. Patients with a diagnosis of active asthma within the past five to 10 years were excluded.

Patients were randomised to one of four arms – twice daily triple therapy of budesonide-glycopyrrolate-formoterol (either 80 µ)g or 160 µg doses of the glucocorticoid), or dual therapy with glycopyrrolate-formoterol or budesonide-formoterol.

In the primary outcome, annual rates of moderate to severe exacerbations were 1.08 with 160 µg ICS-LABA-LAMA, 1.07 with 320 µg ICS-LABA-LAMA, 1.42 with the LABA-LAMA and 1.24 with the ICS-LABA combination.

The exacerbation rate was 24% lower with 320 µg budesonide triple therapy than with glycopyrrolate-formoterol dual therapy and 13% lower than budesonide-formoterol.

“Similarly, the annual rate of moderate to severe exacerbation was significantly lower with 160 µg budesonide triple therapy than with glycopyrrolate-formoterol (25% lower; rate ratio, 0.75; 95% CI, 0.69 to 0.83; p<0.001) or glycopyrrolate-formoterol (14% lower; rate ratio, 0.86; 95% CI, 0.79 to 0.95; p=0.002),” the study authors wrote.

There was no difference between the two different triple therapy groups.

In secondary outcomes, both triple therapies also increased the time to the first moderate to severe exacerbation.

And the risk of death from any cause in the 320 µg budesonide triple therapy was 46% lower than in the glycopyrrolate-formoterol group and 22% lower than in the budesonide-formoterol group.

The risk of death from any cause with the 160 µg budesonide triple therapy was lower than with glycopyrrolate-formoterol but higher than with budesonide-formoterol.

“The triple therapy regimens showed a benefit over the dual therapy regimens with respect to the annual rate of moderate or severe exacerbations in both eosinophil subgroups (<150 and ≥150 cells per cubic millimetre) and regardless of whether the patients were using inhaled glucocorticoids or had bronchodilator reversibility at the time of screening.”

Rates of serious adverse events were similar in all treatment groups while the rates of pneumonia were higher in the three groups receiving budesonide than the glycopyrrolate-formoterol group.

The investigators, led by Professor Klaus Rabe from the University of Kiel and the German Center for Lung Research, said their findings of the superiority of triple therapy over dual therapy were consistent with those from other studies.

“It has been proposed that the benefits of triple therapy over LAMA–LABA therapy in previous studies may have resulted from a short-term increase in the rates of exacerbations in the LAMA–LABA groups due to the discontinuation of inhaled glucocorticoids in patients who had been using inhaled glucocorticoids before trial entry.”

“However, in the ETHOS trial, the benefits of both triple-therapy regimens over the LAMA–LABA regimen were similar among the patients who were using inhaled glucocorticoids at the time of screening and those who were not; this finding indicates that the results were not driven by the immediate discontinuation of inhaled glucocorticoids.”

While current guidelines still recommend patients with exacerbations on a single agent step up to dual therapy, they said their findings call this strategy into question.

However Dr Simon Bowler, one of the Australian trialists, told the limbic the study was an important one but the jury was still out.

“In patients with COPD having inhaled steroids reduced exacerbations at the price of a small increase in the amount of pneumonia, which is all on a par with what we understand.”

“It takes us forward a bit further showing that the benefit was present for people with both low eosinophils and modest eosinophils,” he said.

Dr Bowler, from Brisbane’s Mater Hospital, said the ETHOS findings were similar to those from the 2018 IMPACT study which was however criticised for not excluding people with asthma.

“There has been this big argument in respiratory medicine about whether people with COPD should or should not have inhaled steroids because they have got side effects. You get lower respiratory tract infections, sometimes pneumonia, there are theoretical issues with osteoporosis, theoretical issues with cataracts, and this is a population who often, particularly with severe COPD, are at risk of those things.”

“I think we’ve also got to be good custodians of the healthcare dollar,” Dr Bowler said.

PBS and local guidance dictate that triple therapy should be limited to patients with the most severe COPD, symptoms that cannot be adequately managed with dual therapy, and a history of repeated exacerbations.

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