Deciphering guiding principles for dual and triple therapy in COPD

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that is not well understood. Therapy for COPD is often started late, while triple therapy or inhaled corticosteroid (ICS)-containing regimens are used inappropriately in some patients.

“While some patients have frequent exacerbations that require hospital admissions, others have fewer exacerbations but may be troubled by disabling dyspnea; multiple COPD phenotypes require different approaches,” said Professor Jadwiga Wedzicha of the National Heart and Lung Institute, Imperial College in London, UK.

According to the Global Strategy for the Diagnosis, Management and Prevention of COPD (GOLD) 2020 report, dual bronchodilators improve outcomes vs single bronchodilators and should be used as first-line therapy in COPD. [https://goldcopd.org/gold-reports/]

“Dual bronchodilators comprising a long-acting β₂-agonist [LABA] and a long-acting antimuscarinic antagonist [LAMA] in a single inhaler are the cornerstone of COPD therapy and should be started as soon as possible once patients develop significant dyspnoea [Modified Medical Research Council grade ≥2],” advised Wedzicha. [Lancet Respir Med 2013;1:199-209] A lower dose, twice-daily LABA/LAMA regimen has been shown to improve symptoms and health status in COPD patients. [Am J Respir Crit Care Med 2015;192:1068-1079] Notably, these findings have been shown across different ethnic groups (Asian as well as European). [Int J Chron Obstruct Pulmon Dis 2017;12:3329-3339]

“Dual bronchodilators reduce exacerbations, while reduction of hyperinflation has important benefits for the cardiovascular system,” highlighted Wedzicha. [Respir Res 2011;12:150; Int J Chron Obstruct Pulmon Dis 2017;12:3469-3485] In studies where patient-reported outcomes (PROs) were the primary endpoint or included in pooled analyses, combination bronchodilators have demonstrated a greater impact on PROs compared with monotherapies. [Prim Care Respir J 2012;21:101-108; Eur Respir J 2014;43:1599-1609; Respir Med 2015;109:1312-1319; Respir Res 2015;16:92]

“ICS reduce exacerbations in COPD and should be added to the treatment regimen if patients are still experiencing exacerbations or requiring hospitalizations in spite of dual bronchodilator use,” said Wedzicha. According to the GOLD 2020 report, category A evidence (ie, the highest level of evidence) indicates that triple inhaled therapy with ICS/LAMA/LABA improves lung function, symptoms and health status and reduces exacerbations compared with dual therapy with ICS/LABA or LABA/LAMA or LAMA monotherapy. [Am J Respir Crit Care Med 2009;180:741-750; Thorax 2008;63:592-598; Respir Med 2012;106:382-389; Respir Med 2012;106:91-101]

“However, ICS should be used only in GOLD patient group D and at the lowest effective dose, as long-term ICS use is associated with adverse effects, including pneumonia,” noted Wedzicha. [Ann Am Thorac Soc 2015;12:27-34; BMJ 2017;357:j1415] “In addition, ICS should not be used in patients with blood eosinophil levels <100 cell/μL, as data modelling indicates that ICS-containing regimens have little or no effect below this level. Furthermore, ICS should not be used in the absence of exacerbations even if blood eosinophil level is raised.” [Lancet Respir Med 2018;6:117-126]

“Despite the recommendations, a substantial number of patients outside GOLD group D are still receiving ICS,” said Wedzicha. [Ann Am Thorac Soc 2019;16:200-208] “Both COPD guidelines and the GOLD strategy document recommend ICS withdrawal in cases of infrequent exacerbations, based on the SUNSET and WISDOM trials. However, recent data from ICS withdrawal studies indicate that ICS should not be withdrawn if blood eosinophil levels are ≥300 cell/μL. This has been incorporated into the American Thoracic and European Respiratory Societies’ COPD treatment guidelines.” [Am J Respir Crit Care Med 2020;201:e56-e69; Eur Respir J 2020;55:2000351]