COPD Triple Therapy: Balancing Benefits and Harms

As another so-called triple therapy for chronic obstructive pulmonary disease (COPD) hits the market, pulmonologists and primary care physicians are beginning to consider which patients are most appropriate for these treatments, and how much added benefit these products offer relative to more conventional -- and better understood -- two-drug combinations.

The FDA approved AstraZeneca's fixed-dose, triple therapy budesonide/glycopyrrolate/formoterol fumarate (Breztri Aerosphere) a week ago for maintenance treatment of COPD, based on the phase III ETHOS clinical trial findings, which showed a decrease in exacerbations among symptomatic patients who had experienced exacerbations within the past year.

The treatment joins the GlaxoSmithKline drug fluticasone furoate, umeclidinium, and vilanterol (Trelegy Ellipta) to become the second fixed-dose inhaled combination of an inhaled corticosteroid (ICS), long-acting muscarinic antagonist (LAMA) and long-acting beta agonist (LABA) approved for use in COPD patients in the U.S.

The goal of adding an ICS to maintenance COPD therapy was to reduce exacerbations and hospitalizations and improve mortality.

While randomized trials have clearly shown triple therapy to reduce exacerbations in select patients with COPD, the jury is still out on whether adding ICS to monotherapy or dual LABA/LAMA therapy helps patients live longer.

It is also now clear that the benefits of inhaled corticosteroids in the setting of COPD need to be weighed against an increased risk for pneumonia.

"There remains uncertainty about the benefits versus risks of triple therapy -- versus dual LABA/LAMA treatment or a LABA or LAMA alone -- in patients with stable COPD," Manoj Mammen, MD, a pulmonary disease researcher at the University at Buffalo in New York, told MedPage Today.

There is also uncertainty about the benefits versus the risks of triple therapy in patients with less advanced disease who do not have a high risk for frequent exacerbations.

"There are some signals that not necessarily triple therapy, but more intensive therapy in general, may benefit patients with COPD earlier in the course of their disease," said MeiLan K. Han, MD, a pulmonary specialist at Michigan Medical in Ann Arbor.

AstraZeneca's KRONOS trial of its triple therapy enrolled patients with a low risk for exacerbations, and found the fixed combination treatment to be beneficial and well tolerated in this group.

"I know there are some pharma companies doing some early intervention studies with triple therapy," Han told MedPage Today. "The question is, if I have a 40-year-old with mild disease (FEV₁ ≥ 80), but severe symptoms, would that patient be in a better place in 20 years if we treat with more intensive therapy? We really don't have an answer to that question yet."

She added that now that there are two fixed-dose inhaled triple therapies on the market in the U.S., there is some concern that clinicians who are not familiar with treatment guidelines will prescribe these treatments to patients who may not benefit and might be harmed.

What the Guidelines Say

The 2020 COPD management and treatment guideline update of the Global Initiative for COPD (GOLD) strongly recommends adding an inhaled steroid to treatment with one or two bronchodilators for patients with a history of COPD hospitalizations, two or more moderate exacerbations of their disease in the past year, a history of concomitant asthma, or blood eosinophil counts greater than 300 μL.

Use of triple therapy or an ICS with a monotherapy bronchodilator are strongly discouraged in patients with blood eosinophil counts of less than 100 μg, and those with a history of repeated pneumonia, the guideline states.

Randomized trials have repeatedly shown an increase in pneumonia events in patients treated with an ICS plus LAMA/LABA compared with dual therapy with a LAMA/LABA alone, although some studies have not shown this association.

In a 2018 meta-analysis involving 21 trials, pneumonia risk was significantly higher with triple therapy than with dual therapy without an ICS (relative risk 1.53, 95% CI 1.25-1.87).

And in a 2012 Cochrane review of 55 primary studies, long-term use of ICS (more than 6 months) was associated with an increased risk of pneumonia compared with placebo in studies that reported pneumonia as an adverse event (odds ratio 1.56, 95% CI 1.30-1.86, in 6,235 total participants).

In a new meta-analysis in Annals of the American Thoracic Society, Mammen and colleagues concluded that balancing the reduction in COPD exacerbation frequency risk against the increased pneumonia with the addition of ICS to dual therapy or monotherapy "favored the use of triple therapy only in the subgroup with a higher baseline risk of COPD exacerbation risk, specifically individuals with one or more exacerbation(s) in the past year requiring antibiotics and/or oral steroids or hospitalization."

Mammen told MedPage Today that the findings support the 2020 GOLD recommendations regarding the use of triple therapy. "Based on the evidence, there is a clear reduction of harm with the use of triple therapy over dual therapy for patients who are on dual therapy and still having exacerbations," he said.

Survival Signal Gets Stronger

Han noted that while mortality has not been a primary endpoint in the clinical trials evaluating triple therapy in COPD, several studies have suggested that adding an ICS to a LABA/LAMA may help patients live longer.

In a recently published post-hoc analysis of GlaxoSmithKline's IMPACT trial, which showed a reduction in COPD exacerbations with Trelegy Ellipta, researchers identified a signal of a reduced risk of all-cause mortality in patients treated with the triple therapy versus dual therapy.

Among patients on the triple fixed therapy, the hazard ratio for death was 0.72 (95% CI 0.53–0.99; P=0.042) versus umeclidinium/vilanterol and 0.89 (95% CI 0.67–1.16; P=0.387) versus fluticasone furoate/vilanterol.

Independent analysis confirmed a lower rate of cardiovascular and respiratory death among the patients treated with the triple therapy, as well as a lower risk of disease-specific death.

Results from AstraZeneca's newly reported ETHOS trial showed reduced mortality in patients treated with the budesonide, glycopyrrolate, formoterol triple therapy, but only for those who received higher doses of budesonide.

Two doses of the glucocorticoid -- 160 μg and 320 μg -- were evaluated in the trial, which compared twice-daily doses of the triple therapy with dual treatment with the LAMA glycopyrrolate and the LABA formoterol or formoterol and budesonide

Patients in the 320-μg budesonide triple-therapy group had a 46% lower death risk than patients in the glycopyrrolate-formoterol dual-therapy group.

In a press conference, the study's lead researcher, Klaus Rabe, MD, of the Airway Research Center North in Grosshansdorf, Germany, characterized the all-cause mortality reduction as "quite a sizable reduction given the [large] size of the trial." Each of the study's four treatment arms included roughly 2,100 patients.

"This is the first time we've seen a mortality signal for COPD, other than oxygen therapy," Han said. "We will see what the FDA does, but my guess is that both companies will be interested in a mortality reduction indication for these treatments."

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