Evidence-based approach to ICS use in COPD
Evolving therapies in COPD
The first Global Initiative for Chronic Obstructive Lung Disease (GOLD) report, issued nearly 20 years ago, recommended the addition of ICS to regular bronchodilator treatment for symptomatic patients with moderate and severe COPD. [Am J Respir Crit Care Med 2001;163:1256-1276] Since then, ICS use became widespread among COPD patients.
“Until 5 years ago, approximately half of newly diagnosed COPD patients were receiving an ICS-containing regimen as their first-line maintenance therapy,” noted Anzueto. [NPJ Prim Care Respir Med 2017;27:43]
“While we recognize that a subset of COPD patients who have had multiple exacerbations or hospitalizations or those with high eosinophil counts [≥300 cells/µL] derive benefit from ICS use, for many others, it is unnecessary and can increase the risk of pneumonia, osteoporosis, skin bruising, and tuberculosis,” he continued. [https://goldcopd.org/wp-content/uploads/2019/11/GOLD-2020-REPORT-ver1.0wms.pdf; Prim Care Respir Med 2019;29:38]
Early studies (eg, WISP, COPE, COSMIC) of ICS withdrawal in patients with COPD who were not receiving any other COPD medication revealed poor clinical outcomes, including increased exacerbation risk. A more recent and robust meta-analysis concluded that this was due to a lack of alternative COPD medications. [Respir Res 2017;18:198] In recent years, new fixed combinations of LAMA/LABA bronchodilators such as tiotropium/olodaterol have become available, and were proven to be more effective and safer than ICS/LABA for the majority of patients with COPD. [Cochrane Database Syst Rev 2017;2:CD012066]
“Treatment of COPD should be dynamic, and patients need to be continuously assessed and re-assessed so as to be given optimal bronchodilator therapy with minimum harmful effects,” advised Anzueto. “If dual therapy is sufficient, a fixed LAMA/LABA combination should be chosen over ICS/LABA for maximized bronchodilation and reduced risk of pneumonia.”
“However, for patients on LAMA/LABA who have exacerbations that require hospitalization, therapy can be escalated to ICS/LAMA/LABA triple combination to reduce future exacerbations. If there are no exacerbations for a year, the ICS can be withdrawn,” he noted.
Guideline recommendations for ICS withdrawal
Several international and regional clinical practice guidelines for COPD currently recommend the use of long-acting bronchodilators as first-line therapy, while encouraging withdrawal of ICS in patients without a clear indication for it.
The 2020 GOLD strategy recommends de-escalation from ICS/LAMA/LABA to LAMA/LABA or switching from ICS/LABA to LAMA/LABA in COPD patients with pneumonia or inappropriate original indication or lack of response to ICS. [https://goldcopd.org/wp-content/uploads/2019/11/GOLD-2020-REPORT-ver1.0wms.pdf]
The European Respiratory Society (ERS) guidelines recommend withdrawal of ICS in COPD patients without a history of frequent exacerbations and subsequent treatment with one or two long-acting bronchodilators following ICS withdrawal. Continued use of ICS is recommended in patients with blood eosinophil counts ≥300 cells/µL, since there is an established benefit in preventing moderate and severe exacerbations among these patients. (Figure 1) [Eur Respir J 2020;55:2000351]
“However, ICS has been shown to increase the risk of pneumonia in patients with eosinophil counts <100 cells/µL,” Anzueto cautioned. [Am J Respir Crit Care Med 2020;201:1078-1085]
The American Thoracic Society (ATS) practice guidelines recommend that in COPD patients receiving triple therapy (ICS/LAMA/LABA), the ICS component can be withdrawn and patients can be switched to dual therapy with LAMA/LABA in the absence of exacerbations in the past year. [Am J Respir Crit Care Med 2020;201:e56-e69]
Clinical evidence for reducing ICS use
Benefits of ICS withdrawal in COPD have been established through several randomized clinical trials and real-world studies.
The WISDOM study (n=2,485) showed that gradual withdrawal of ICS from a triple ICS/LAMA/LABA regimen did not increase the risk of exacerbations in patients with severe COPD (hazard ratio [HR], 1.06; 95 percent confidence interval [CI], 0.94 to 1.19). [N Engl J Med 2014;371:1285-1294]
Similarly, in the SUNSET trial (n=1,053), direct ICS withdrawal in patients on long-term ICS/LAMA/LABA therapy without a history of frequent exacerbations did not impact COPD exacerbation rates (rate ratio, 1.08; 95 percent CI, 0.83 to 1.40). [Am J Respir Crit Care Med 2018;198:329-339]
The FLAME trial (n=3,362) compared the efficacy of LAMA/LABA vs ICS/LABA in reducing COPD exacerbation risk in patients with a history of exacerbations in the previous year. The annual rate of moderate-to-severe exacerbation was significantly lower in the LAMA/LABA group (0.98 vs 1.19; p<0.001). [N Engl J Med 2016;374:2222-2234]
In the open-label CRYSTAL trial (n=4,389), a direct switch from previous treatment with ICS/LABA, LABA or LAMA to LAMA/LABA in symptomatic patients with moderate COPD resulted in improvements in lung function (forced expiratory volume in 1 second [FEV1] treatment difference [D], 71 mL vs ICS/LABA; p<0.0001) and dyspnoea (transition dyspnoea index [TDI] D, 1.09 units vs ICS/LABA; p<0.0001). [Respir Res 2017;18:140]
FLASH was another study (n=502) of a direct switch from ICS/LABA to LAMA/LABA in moderate-to-severe COPD patients with up to one exacerbation in the previous year. Patients switched to LAMA/LABA experienced a significant improvement in lung function (pre-dose FEV1 D, 45 mL; p=0.028; pre-dose forced vital capacity [FVC] D, 102 mL; p=0.002) without new safety signals. [Respirology 2018;23:1152-1159]
A retrospective observational study, conducted in 13,611 non-exacerbating COPD patients initiating dual therapy, reported a significantly higher rate of adherence to LAMA/LABA vs ICS/LABA (25 percent vs 15 percent; relative risk, 1.68: 95 percent CI, 1.57 to 1.81; p<0.001) and significantly reduced use of rescue medication in patients on LAMA/LABA vs ICS/LABA (mean difference, -0.37; 95 percent CI, -0.50 to -0.24; p<0.001). [Int J Chron Obstruct Pulmon Dis 2020;15:2207-2215]
The use of LAMA/LABA instead of ICS/LABA can also reduce the risk of adverse events, particularly pneumonia, as demonstrated in a real-world clinical practice setting of COPD treatment (n=3,954). Fewer cases of severe pneumonia were reported among patients receiving LAMA/LABA vs ICS/LABA. (Figure 2) [Chest 2019;155:1158-1165]
Dual bronchodilation using LAMA/LABA is the preferred first maintenance therapy for symptomatic COPD patients with low risk of exacerbations. In patients already established on ICS/LABA, direct withdrawal of ICS and switch to LAMA/LABA can be undertaken. Addition of ICS, in the form of triple therapy (ICS/LAMA/LABA), should be reserved for patients with recurrent exacerbations, hospitalizations or eosinophil counts ≥300 cells/µL.