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McMaster Textbook of Internal Medicine

Publications of the Week, July 13

2020-07-13

Triple vs dual therapy +/- glucocorticoids in moderate to very severe COPD

Rabe KF, Martinez FJ, Ferguson GT, et al; ETHOS Investigators. Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD. N Engl J Med. 2020 Jul 2;383(1):35-48. doi: 10.1056/NEJMoa1916046. Epub 2020 Jun 24. PMID: 32579807.

In patients with chronic obstructive pulmonary disease (COPD) a stepwise treatment approach is used to improve symptoms and minimize COPD exacerbations, starting with a long-acting muscarinic antagonist (LAMA) or a long-acting beta2-agonist (LABA) followed by their combination and adding a third agent, an inhaled glucocorticoid, if needed. Triple therapy reduces COPD exacerbations as well as improves lung function and health-related quality of life compared with dual therapy, and it is recommended if patients continue to have symptoms or exacerbations while receiving dual therapy with LAMA/LABA or inhaled glucocorticoid/LABA combinations. However, inhaled glucocorticoids may increase the risk for adverse events, including pneumonia, fractures, and cataracts. The ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial compared the efficacy and safety of 2 single-inhaler, triple fixed-dose combinations (ie, 2 different doses of budesonide + LAMA + LABA) with dual therapies (LAMA/LABA and inhaled glucocorticoid/LABA).

This 52-week randomized controlled study was done in symptomatic patients with moderate to very severe COPD who had ≥1 exacerbation in the preceding year. The trial assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy—comprising an inhaled glucocorticoid, a LAMA, and a LABA—or 1 of 2 dual therapies:

  • Triple therapy with 320 microg budesonide + LAMA + LABA: Budesonide 320 microg, glycopyrrolate 18 microg, formoterol 9.6 microg.
  • Triple therapy with 160 microg budesonide + LAMA + LABA: Budesonide 160 microg, glycopyrrolate 18 microg, formoterol 9.6 microg.
  • Dual therapy with glycopyrrolate + formoterol: Glycopyrrolate 18 microg, formoterol 9.6 microg.
  • Dual therapy with budesonide + formoterol: Budesonide 320 microg, formoterol 9.6 microg.

The primary endpoint was the annual rate of moderate or severe COPD exacerbations, analyzed in the modified intention-to-treat population with the use of on-treatment data only. Secondary endpoints included all-cause mortality.

There were 8509 patients studied across the 4 treatment groups. The annual rate of moderate or severe exacerbations was significantly lower with the higher-dose 320-microg budesonide triple therapy than with glycopyrrolate/formoterol dual therapy (24% lower; rate ratio [RR], 0.76; 95% CI, 0.69-0.83) or with budesonide/formoterol dual therapy (13% lower; RR, 0.87; 95% CI, 0.79-0.95). Similarly, the rate was significantly lower with the lower-dose 160 microg budesonide triple therapy than with glycopyrrolate/formoterol dual therapy (25% lower; RR, 0.75; 95% CI, 0.69-0.83) or with budesonide/formoterol dual therapy (14% lower; RR, 0.86; 95% CI, 0.79-0.95). Mortality was significantly lower in patients receiving higher-dose budesonide triple therapy than in those receiving LAMA/LABA dual therapy (28 vs 49 deaths; hazard ratio [HR], 0.54; 95% CI, 0.34-0.87). The incidence of serious pneumonia was significantly higher in patients receiving a glucocorticoid, as part of either dual or triple therapy, than in those receiving LAMA/LABA dual therapy (2.4%-3.0% vs 1.3%).

In summary, for selected patients with moderate to very severe COPD, triple therapy consisting of twice-daily glucocorticoid (budesonide, 160 microg or 320 microg), a LAMA (glycopyrrolate), and a LABA (formoterol) resulted in lower rates of COPD exacerbations than dual therapy with LAMA/LABA or glucocorticoid/LABA combinations.

See also
  • How to prevent COPD exacerbations A lecture by Dr Jadwiga Wedzicha, from Imperial College London, UK, delivered at McMaster International Review Course in Internal Medicine (MIRCIM) in May 2019.
  • Publications of the Week, June 29 A digest of noteworthy publications curated by editors from McMaster University. This week’s focus: benefits of comprehensive disease-modifying pharmacologic therapies in patients with heart failure with reduced ejection fraction.
  • Publications of the Week, June 2
    First review of all available evidence         A digest of noteworthy publications curated by editors from McMaster University. This week’s focus: the first review of all available evidence looking at how physical distancing, facemasks, and eye protection affect the spread of COVID-19, SARS, and MERS.
  • Publications of the Week, May 27
    Reports on remdesivir         A digest of noteworthy publications curated by editors from McMaster University. This week’s focus: first RCT data on remdesivir use in COVID-19.
  • COPD exacerbations in the emergency department A lecture by Dr Jadwiga Wedzicha, from Imperial College London, UK, delivered at McMaster International Review Course in Internal Medicine in Kraków in May 2018.
  • Publications of the Week, November 23 A digest of noteworthy publications curated by editors from McMaster University. This week’s focus: major GI bleeding in elderly individuals taking aspirin.
  • Publications of the Week, October 26 A digest of noteworthy publications curated by editors from McMaster University. This week’s focus: criteria for the clinical diagnosis of brain death (part 1).
  • Publications of the Week, August 24 A digest of noteworthy publications curated by editors from McMaster University. This week’s focus: data on the association of estrogen plus progestin or estrogen alone with breast cancer incidence and mortality.
  • Publications of the Week, August 10 A digest of noteworthy publications curated by editors from McMaster University. This week’s focus: different types of P2Y12 inhibitors in acute coronary syndrome.
  • Publications of the Week, July 27 A digest of noteworthy publications curated by editors from McMaster University. This week’s focus: the HALT-IT trial, investigating the use of tranexamic acid in patients with gastrointestinal bleeding.

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