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What is the role of triple inhaled therapy in COPD?

Petite, Sarah E. PharmD, BCPS

Journal of the American Academy of PAs: October 2019 - Volume 32 - Issue 10 - p 44–45
doi: 10.1097/01.JAA.0000580568.79593.55
Pharmacology Consult

ABSTRACT Triple inhaled therapy for maintenance of chronic obstructive pulmonary disease (COPD) consists of an inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting 2-agonist">beta2-agonist. Recent clinical studies evaluating triple therapy found a reduction in COPD exacerbations compared with other combination therapies. This article discusses the role of triple therapy in treating patients with COPD.

Sarah E. Petite is an assistant professor of pharmacy practice at the University of Toledo (Ohio) College of Pharmacy and Pharmaceutical Sciences. The author has disclosed no potential conflicts of interest, financial or otherwise.

Mary Lou Brubaker, PharmD, PA-C, department editor



Chronic obstructive pulmonary disease (COPD) is a progressive airway disease and the third leading cause of death in the United States.1 COPD is associated with significant morbidity and mortality and accounts for an estimated $32 billion annually in direct costs.1,2 The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend treatment for patients with COPD.1

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A patient's GOLD group is established by symptom severity and number of exacerbations and determines the subsequent choice of inhaled therapy.1

  • Group A—patients have one or fewer exacerbations not requiring hospitalization, and no severe symptoms. These patients should receive a short- or long-acting bronchodilator.
  • Group B—patients have one or fewer exacerbations not requiring hospitalization, but have severe symptoms. These patients should receive a long-acting bronchodilator, either a long-acting muscarinic antagonist (LAMA) or long-acting 2-agonist">beta2-agonist (LABA).
  • Group C—patients with two or more moderate exacerbations or one or more leading to hospitalization, but no severe symptoms. First-line therapy is a LAMA.
  • Group D—patients with two or more moderate exacerbations or one or more leading to hospitalization, and severe symptoms. First-line therapy is a LAMA, unless the patient has very severe symptoms, such as a COPD Assessment Test Score greater than or equal to 20. For these patients, a LAMA/LABA combination is recommended. The decision to initiate an inhaled corticosteroid is determined by two separate eosinophil levels. Use of a LABA/inhaled corticosteroid is recommended first-line in group D patients with elevated eosinophils, defined as 300 or more cells/mcL, or a history of asthma. Triple therapy (LAMA/LABA/inhaled corticosteroid) is not a recommended first-line therapy and is reserved for patients on LAMA/LABA therapy with further exacerbations and elevated eosinophils, defined as 100 or more cells/mcL.
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The introduction of the first single inhaler triple therapy (combination fluticasone, umeclidinium, and vilanterol) has raised interest in triple therapy in clinical trials. Lipson and colleagues conducted the phase III trial, supported by GlaxoSmithKline, which led to FDA approval.3 This study compared the triple therapy with budesonide/formoterol. At the time of the study, LABA and an inhaled corticosteroid were a recommended first-line option in the GOLD guidelines.4 Included patients were in GOLD group B or D and the primary endpoints were change from baseline in trough FEV1 and evaluation of symptoms with the St. George's Respiratory Questionnaire (SGRQ). A significant difference in trough FEV1 was observed with triple therapy (142 mL versus -29 mL; P < .001) and SGRQ scores (-6.6 versus -4.3; P < .001); however, the difference in SGRQ scores was not determined to be clinically significant. The rate of moderate-severe exacerbations was also reduced with triple therapy (0.22 versus 0.34; P = .002). This study demonstrated the potential efficacy of triple therapy compared with LABA/inhaled corticosteroid. Before this study's publication, a comparison of LAMA/LABA to LABA/inhaled corticosteroid demonstrated a significant reduction in COPD exacerbations with LAMA/LABA.5 This study led to the guideline removal of LABA/inhaled corticosteroid as first-line therapy in 2017.1 Therefore, the clinical implications of a comparison of LABA/inhaled corticosteroid to triple therapy are limited.

The comparison of LAMA/LABA to LAMA/LABA/inhaled corticosteroid was evaluated in a randomized, double-blind trial, supported by GlaxoSmithKline.6 This study compared the same triple therapy as the previous study with umeclidinium/vilanterol and fluticasone/vilanterol. Inclusion criteria were similar to the previous trial. The primary endpoint was the rate of moderate-severe COPD exacerbations over 1 year. A significant reduction in the rate of COPD exacerbations was observed with triple therapy compared with LAMA/LABA (0.91 versus 1.21; P < .001). However, more than 70% of patients were on an inhaled corticosteroid at randomization and for those randomized to LAMA/LABA, the inhaled corticosteroid was abruptly discontinued. In order to minimize the risk of exacerbations caused by inhaled corticosteroid withdrawal, therapy must be slowly tapered.7 Therefore, abrupt withdrawal of the inhaled corticosteroid may have led to the increased rate of exacerbations observed for patients randomized to LAMA/LABA.

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The potential benefit of an inhaled corticosteroid in a maintenance regimen for a patient with COPD must be balanced with the risk of pneumonia.8 The previously mentioned studies demonstrated a significant increase in pneumonia incidence (2% to 8% per year) with inhaled corticosteroid-containing regimens.5,6 This risk should be considered when choosing initial therapy.1 When initiating maintenance therapy, avoid inhaled corticosteroids unless the patient has elevated eosinophils or a history of asthma.1 Consider withdrawing inhaled corticosteroids if the patient is stable on a regimen containing an inhaled corticosteroid.

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Potential benefits to triple inhaled therapy include a reduction in COPD exacerbations, but for most patients, this benefit is outweighed by the risk of pneumonia. The use of triple therapy for patients with COPD should be reserved for patients with elevated eosinophils or a history of asthma.1

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1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of COPD. Accessed July 17, 2019.
2. Centers for Disease Control and Prevention. National Center for Health Statistics. Chronic obstructive pulmonary disease (COPD) includes: chronic bronchitis and emphysema. Accessed July 17, 2019.
3. Lipson DA, Barnacle H, Birk R, et al FULFIL trial: once-daily triple therapy for patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;196(4):438–446.
4. Vestbo J, Hurd SS, Agustí AG, et al Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4):347–365.
5. Wedzicha JA, Banerji D, Chapman KR, et al Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med. 2016;374(23):2222–2234.
6. Lipson DA, Barnhart F, Brealey N, et al Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med. 2018;378(18):1671–1680.
7. Magnussen H, Disse B, Rodriguez-Roisin R, et al Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285–1294.
8. Iannella H, Luna C, Waterer G. Inhaled corticosteroids and the increased risk of pneumonia: what's new? A 2015 updated review. Ther Adv Respir Dis. 2016;10(3):235–255.

triple inhaled therapy; chronic obstructive pulmonary disease; corticosteroid; muscarinic antagonist; 2-agonist">beta2-agonist; pulmonary

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