Triple Therapy for COPD: One Drug Too Many, Too Often?

SAN FRANCISCO — Patients with chronic obstructive pulmonary disease (COPD) who changed treatment from so-called triple therapy to a two-drug product omitting the inhaled corticosteroid (ICS) component tended to see improved symptom control, as well as fewer adverse effects, a researcher said here.

In a German registry study, it took about 14 months for half of patients who made the switch to develop a new COPD exacerbation, compared with 9.5 months for those who stayed on triple therapy, said Claus Vogelmeier, MD, of Philipps-University Marburg in Germany.

And more patients in the switch group obtained clinically relevant improvement in COPD Assessment Test (CAT) scores, he told attendees at the American Thoracic Society annual meeting.

Vogelmeier said these data had two implications: one, that switching to dual therapy doesn’t worsen patients’ COPD symptoms and may improve them; and two, that “physicians are capable” of identifying patients likely to benefit from treatment step-down.

In recent years, triple therapy has become a standard of care for COPD maintenance. It consists of a long-acting beta-agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an ICS.

But while ICS agents cause fewer side effects than systemic steroids, they still carry some risks. For patients achieving reasonable symptom control with triple therapy, researchers and clinicians have questioned whether the ICS needs to be continued indefinitely — and thus, whether a LABA/LAMA combination would be sufficient.

Vogelmeier said the strategy seems to have been validated in formal trials — one of the first was published in 2014, and another in 2018 — but it hasn’t been clear whether it also works in less carefully selected “real-world” patients. Hence, his group analyzed data from a longitudinal study of German COPD patients called DACCORD, focusing on a third cohort that began enrollment in 2017 and was followed through 2021.

This group (excluding those with no follow-up visits) comprised 340 patients who switched from triple therapy to a fixed-dose LABA/LAMA product and 784 who remained on triple therapy. There were some demographic differences between groups — those remaining on triple therapy were disproportionately male, had longer average duration of disease, and poorer lung function (58% of predicted forced expiratory volume in 1 second vs 67%).

Since this wasn’t a randomized trial, patients’ treatments were selected for certain reasons, which the investigators asked about. The most common reason cited for remaining on triple therapy was to maintain symptom control (35% of patients); for those switching, the most common was unspecified “patient’s wish” (26%). Relatively few patients switched expressly because triple therapy wasn’t working or had intolerable side effects.

The study’s primary outcome was time to first COPD exacerbation. Vogelmeier and colleagues calculated that the 1-year risk was exactly doubled among patients remaining on triple therapy (HR 2.00, 95% CI 1.60-2.51). By month 12, nearly 60% of the no-switch group had experienced an exacerbation, versus about 35% of those who did switch.

CAT scores at baseline averaged 21.0 in the switch group and 20.0 for non-switchers. At the 1-year evaluation, these means had declined by 2 points for switchers (reflecting improvement) and by 1 point in non-switchers. Some 58% of switchers had scores indicating clinically relevant improvement, compared with 49% of non-switchers (P<0.001).

Vogelmeier also reported exacerbation outcomes stratified by patients’ history of exacerbations during the year prior to baseline. Among those with two or more, more than 60% of patients who switched had no exacerbations during the year of follow-up, whereas fewer than half of this subgroup remaining on triple therapy had no exacerbations during follow-up.

Dual therapy also appeared safer during the follow-up year, both for all adverse events and those rated as serious. This appeared to be the case even when exacerbations were not counted as adverse events.

Mark Dransfield, MD, of the University of Alabama at Birmingham, who co-moderated the session where Vogelmeier spoke, asked whether these data indicate that ICS therapy is overtly harmful in COPD maintenance.

“It’s very hard to tell,” Vogelmeier replied. “What we do not know is how good the indication was for triple treatment to start with.”

Triple therapy is generally recommended as step-up treatment for patients who remain symptomatic with LABA/LAMA products, and as one review observed, “many patients start triple therapy inappropriately or continue triple therapy after they no longer need it.”