Triple inhaler therapy cuts COPD flare-ups more than two-drug inhalers
Two large trials, ETHOS and IMPACT, found adding an inhaled steroid to a two-bronchodilator inhaler lowered exacerbation rates in COPD — at the cost of more pneumonia.
| Group | Value (value) |
|---|---|
| Budesonide 320 µg triple | 1.08 |
| Budesonide 160 µg triple | 1.07 |
| Glycopyrrolate–formoterol | 1.42 |
| Budesonide–formoterol | 1.24 |
For people with chronic obstructive pulmonary disease who keep having flare-ups, adding an inhaled steroid to a two-bronchodilator inhaler — so-called triple therapy — lowers the rate of moderate or severe exacerbations compared with either bronchodilator combination alone [s1][s2]. The benefit is real but bounded, and it comes with a higher risk of pneumonia [s2].
That is the consistent message of two of the largest COPD trials run, ETHOS and IMPACT, both published in the New England Journal of Medicine [s1][s2]. The clinical question they answer is not whether to treat COPD but which inhaler combination to give a patient who is still exacerbating despite two drugs.
What the inhalers contain
Modern COPD inhalers combine up to three ingredients: an inhaled corticosteroid, a long-acting muscarinic antagonist (LAMA) and a long-acting beta-2 agonist (LABA) [s1]. Dual therapy uses two of these; triple therapy uses all three. The trials tested whether the third component earns its place.
ETHOS: two steroid doses against two dual therapies
ETHOS was a 52-week phase 3 trial in patients with moderate-to-very-severe COPD who had had at least one exacerbation in the previous year [s1]. It assigned 8,509 patients (in the modified intention-to-treat population) in a 1:1:1:1 ratio to twice-daily triple therapy at one of two steroid doses — budesonide 320 µg or 160 µg, with glycopyrrolate 18 µg and formoterol 9.6 µg — or to one of two dual therapies: glycopyrrolate–formoterol, or budesonide–formoterol [s1].
The annual rate of moderate or severe exacerbations was 1.08 with 320-µg-budesonide triple therapy, 1.07 with the 160-µg triple, 1.42 with glycopyrrolate–formoterol, and 1.24 with budesonide–formoterol [s1]. Against the LAMA–LABA combination, the 320-µg triple was 24% lower (rate ratio 0.76; 95% CI 0.69 to 0.83; P<0.001) and the 160-µg triple 25% lower (rate ratio 0.75; 95% CI 0.69 to 0.83; P<0.001) [s1]. Against the steroid–LABA combination, the reductions were smaller — 13% (rate ratio 0.87; 95% CI 0.79 to 0.95; P=0.003) and 14% (rate ratio 0.86; 95% CI 0.79 to 0.95; P=0.002) [s1].
The size of the gap matters. Triple therapy clearly beat the LAMA–LABA inhaler, but the margin over the steroid-containing dual inhaler was modest — a reminder that most of the extra protection comes from having a steroid in the mix at all, not from the third ingredient specifically.
IMPACT: an independent trial, the same direction
IMPACT tested a once-daily single-inhaler triple therapy — fluticasone furoate 100 µg, umeclidinium 62.5 µg and vilanterol 25 µg — against two dual therapies in 10,355 patients over 52 weeks [s2]. The rate of moderate or severe exacerbations was 0.91 per year on triple therapy, against 1.07 on fluticasone furoate–vilanterol (rate ratio 0.85; 95% CI 0.80 to 0.90; a 15% difference; P<0.001) and 1.21 on umeclidinium–vilanterol (rate ratio 0.75; 95% CI 0.70 to 0.81; a 25% difference; P<0.001) [s2].
Severe exacerbations resulting in hospitalisation were also lower: 0.13 per year on triple therapy versus 0.19 on umeclidinium–vilanterol (rate ratio 0.66; 95% CI 0.56 to 0.78; a 34% difference; P<0.001) [s2]. Two separate trials, run by different manufacturers with different drug molecules, pointing the same way is the kind of replication that turns a single result into a treatment principle.
The pneumonia trade-off
The steroid is not free. In ETHOS, confirmed pneumonia ranged from 3.5% to 4.5% in the groups that contained an inhaled glucocorticoid, against 2.3% in the glycopyrrolate–formoterol group [s1]. In IMPACT, the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium–vilanterol (hazard ratio 1.53; 95% CI 1.22 to 1.92; P<0.001) [s2]. This is why triple therapy is not a default for every patient: the balance of fewer exacerbations against more pneumonia tips differently depending on how often someone is flaring.
What it means
The evidence supports stepping up to triple therapy in patients who continue to exacerbate on a dual combination — not as a starting point for everyone. Both trials were manufacturer-funded, ETHOS by AstraZeneca and IMPACT by GlaxoSmithKline [s1][s2], and both measured exacerbation rates rather than survival, so the case for triple therapy rests on preventing flare-ups, not on extending life.
This article describes trial results. It is not advice about any medicine, and nothing here should be used to start, stop or change treatment.
Sources
- Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD, New England Journal of Medicine, 24 June 2020
- Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD, New England Journal of Medicine, 18 April 2018
Sources
- Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD — New England Journal of Medicine , June 24, 2020
- Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD — New England Journal of Medicine , April 18, 2018
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