Table 2.
Summary of studies evaluating the withdrawal of ICS in patients with COPD
| Study | Study design | Study population (number of patients/COPD severity/exacerbation history) | Study comparisons | Main findings | |
|---|---|---|---|---|---|
| Observational | |||||
| Jaradetal39(1999) [ISOLDE] | Observational study of the 8-week run-in phase of the ISOLDE trial | • 272 • Moderate-to-severe COPD (mean FEV1 42.8% predicted; inclusion criteria: post-BD FEV1, <70% predicted; FEV1/FVC <75%; reversibility < 10%) • 28% of patients (n=76) had ≥ 1 exacerbation in the prior year |
Discontinuation of ICS (BDP or budesonide) vs untreated | Patients with COPD previously treated with ICS had an exacerbation rate of 38% compared with 6% of the chronically untreated group | |
| Schermer et al41 (2004) | Prospective, unblinded study of the 3-month ICS washout phase of the COOPT trial assessing the probability and determinants of adverse respiratory outcomes | • 201 (recruited from primary care) • Moderate COPD (mean FEV1, 65.6% predicted; inclusion criteria: post-BD FEV1, <90% predicted, excluded <35%; FEV1/FVC <88% for men, <89% for women) • Exacerbations in previous 2 years: 23.9%, 18.4%, and 57.7% had none, 1, and ≥2 exacerbations, respectively; no exacerbations for at least 6 weeks prior to ICS withdrawal |
Discontinuation of ICS (FP, BDP, or budesonide) | Probability of an adverse respiratory outcome following discontinuation of ICS was higher in women, elderly patients, smokers, and patients with higher bronchodilator reversibility while on ICS treatment | |
| Rossi et al47 (2014) [OPTIMO] | 6-month, multicenter, prospective, real-life study | • 914 • Mild-to-moderate COPD (mean FEV1 predicted 70.8% vs 71.7% for ICS + LABD vs LABD; all had FEV1/FVC <70%; inclusion criteria: post-BD FEV1/FVC <88% for men and <89% for women; FEV1, >50% predicted) • Low risk of exacerbation (<2 exacerbations/year) Symptomatic (average CAT > 10) |
ICS + LABD vs LABD (91 % on LABA ± LAMA) or other (9% on SABD ± theophylline) | Withdrawal of ICS in real-life practice was not associated with deterioration in exacerbation rates, lung function, and symptoms | |
| Randomized controlled trials | |||||
| O'Brien et al40 (2001) | 12-week, prospective, double-blind, randomized, placebo-controlled, crossover trial (6-week ICS withdrawal) | • 24 (male, elderly patients previously on ICS therapy [BDP]) • Severe, irreversible COPD • N/A |
ICS (BDP) vs placebo | Short-term withdrawal of ICS led to deterioration in lung function, and an increased frequency in exacerbations and exercise-induced dyspnea | |
| van der Valk et al42 (2002) [COPE] | 6-month, randomized, double-blind, placebo-controlled, single-center trial with a 4-month run-in period on ICS (FP) | • 244 • Moderate-to-very-severe COPD (mean FEV1, predicted: 57.5% vs 56.1% for ICS vs placebo; inclusion criteria: pre-BD FEV1, 25%–80% predicted) • Mean of 1.3 exacerbations per year |
ICS (FP) plus SAMA (IB) vs placebo plus SAMA (IB) | Discontinuation of ICS was associated with a rapid onset and higher recurrence risk of exacerbations, and a significant deterioration of health-related quality of life (SGRQ). There was a trend toward a decrease in lung function of 38 mL; however, statistical significance was not reached (P=0.056) | |
| Wouters43 (2005) [COSMIC] | 1-year, randomized, parallel-group, double-blind trial with a 3-month run-in period on ICS + LABA (FP/SLM) | • 373 • Moderate-to-severe COPD (mean FEV1 predicted: 48.1% vs 49% for ICS + LABA vs LABA; inclusion criteria: pre-BD FEV1 30%–70% predicted; FEV1/FVC <88% for men, <89% for women; reversibility <I0%) • High risk of exacerbations (≥2 exacerbations in the prior year) |
ICS + LABA (FP/SLM) vs LABA (SLM) | Withdrawal of ICS was associated with an acute and persistent deterioration of lung function and symptoms (ie, dyspnea and disturbed nights). Despite a significant increase in mild exacerbations, there was no difference in moderate-to-severe exacerbations in the withdrawal group. There were no significant differences in health status (SGRQ) between the treatment groups at 1 year | |
| Choudhury et al44 (2007) [WISP] | 1-year randomized, double-blind, placebo-controlled trial with a 2-week run-in period on patient's usual ICS | • 260 (recruited in primary care) • Moderate-to-severe COPD (mean FEV1, predicted: 53.2% vs 55% for ICS vs placebo; inclusion criteria: post-BD FEV1, <80% predicted; FEV1/FVC <70%; reversibility < 15% or > 15%, if <200 mL) • Exacerbation history: mean baseline exacerbations in the prior year of 1.86 for placebo and 1.93 for ICS |
ICS (FP) vs placebo | Risk of COPD exacerbation was increased in patients withdrawn from ICS. Withdrawal also led to earlier exacerbation, with a rapid deterioration in symptoms (ie, wheezing and increase in use of reliever inhaler in the first month). Patients that did not meet the guidelines for prescription of ICS (ie, 39.2% with an FEV1, <50% predicted) also had an increased risk of exacerbation after withdrawal. No significant differences were observed in lung function and health status (SGRQ) | |
| Rossi et al48 (2014) [INSTEAD] | 26-week, randomized, double-blind, double-dummy, parallel-group, Phase IV trial | • 581 • Moderate COPD (mean FEV1, 64.1% predicted; FEV1, 50%–79% predicted) • Low risk of exacerbations (no exacerbations in the prior year) |
ICS + LABA (FP/SLM) to LABA (IND) vs continuing ICS + LABA (FP/SLM) | No significant differences were observed in lung function, dyspnea (TDI), health status (SGRQ), use of rescue medication, and exacerbations, nor were there any serious adverse events between the two groups | |
| Magnussen et al46 (2014) [WISDOM] | 1-year, randomized, double-blind, parallel-group, active-controlled trial, with a 6-week run-in period on ICS + LABA + LAMA | • 2,485 • Severe-to-very-severe COPD (mean FEV1, 34.2% predicted; FEV1, <50% predicted • History of exacerbations (≥ 1 exacerbation in the prior year) |
ICS + LABA + LAMA (FP/SLM/TIO) vs stepwise withdrawal of ICS to LABA + LAMA (step 1: FP 1,000 to 500 μg/day for 6 weeks; step 2: FP 500 to 200 μg/day for 6 weeks; step 3: FP 200 μg/day to placebo for 40 weeks; maintenance of SLM/TIO throughout) | No difference in the occurrence of moderate or severe exacerbations was reported between the two groups (HR 1.06; P=0.35); however, there was a significantly greater decrease in lung function at weeks 18 and 52 (38 and 43 mL loss in FEV1,; P≤0.001, respectively); ie, when ICS was completely removed. There were no changes in dyspnea (mMRC) and minor changes in health status (SGRQ). No subgroups of patients that had an increased likelihood of an exacerbation after ICS withdrawal were identified | |
Abbreviations: BD, bronchodilator; BDP, beclomethasone dipropionate; CAT, COPD Assessment Test; COOPT, COPD on Primary Care Treatment; COPD, chronic obstructive pulmonary disease; COSMIC, COPD and Seretide: a Multicenter Intervention and Characterization; FEV1,, forced expiratory volume in 1 second; FP, fluticasone propionate; FVC, forced vital capacity; IB, ipratropium bromide; ICS, inhaled corticosteroids; IND, indacaterol; INSTEAD, Indacaterol: Switching Non-exacerbating Patients with Moderate COPD From Salmeterol/Fluticasone to Indacaterol; ISOLDE, Inhaled Steroids in Obstructive Lung Disease in Europe; LABA, long-acting β2-agonist; LABD, long-acting bronchodilator; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council Dyspnea Scale; N/A, not available; OPTIMO, Real-Life study On the aPpropriaTeness of treatment In Moderate COPD patients; SABD, short-acting bronchodilator; SAMA, short-acting muscarinic antagonist; SGRQ, St George's Respiratory Questionnaire; SLM, salmeterol; TDI, transition dyspnea index; TIO, tiotropium; WISDOM, Withdrawal of Inhaled Steroids During Optimized Bronchodilator Management.