Applying the wisdom of stepping down inhaled corticosteroids in patients with COPD: a proposed algorithm for clinical practice

Figures & data

Figure 1 GOLD recommendations for the pharmacologic management of stable COPD according to the four GOLD groups of COPD, which are based on a combined assessment of symptoms and exacerbation risk.

Note: Adapted by the author from the Global Strategy for Diagnosis, Management and Prevention of COPD 2015, © Global Initiative for Chronic Obstructive Lung Disease (GOLD), all rights reserved. Available from http://www.goldcopd.org.²
Abbreviations: CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council Dyspnea Scale; PDE-4i, phosphodiesterase-4 inhibitor; prn, as needed; SABA, short-acting β₂-agonist; SAMA, short-acting muscarinic antagonist.

Table 1 History of evidence for the use of ICS-containing treatment regimens in COPD

Timeline	Intervention	Evidence
1980s	N/A	• ICS were adopted in the management of COPD based on the fact that they were highly effective in asthma rather than scientific evidence^Citation11 asthma rather than scientific evidence^Citation11
Late 1990s	ICS alone	• Early RCTs in patients with mild COPD (ie, FEV1 near 80% predicted) found no improvement in the decline of lung function over time and no reduction in the exacerbation rate with various ICS compared with placebo^Citation11,Citation15,Citation17,Citation18
2000	ICS alone	• ISOLDE was the first trial to demonstrate the beneficial effects of ICS (ie, fluticasone propionate) on exacerbation rate in patients with moderate-to-severe COPD (ie, FEV1 ≤50% predicted); albeit, there was no effect on the rate of decline in lung function^Citation19
		• The Lung Health Study, which also included patients with lower FEV1 (mean 56% predicted), found that patients treated with an ICS (ie, triamcinolone) reported fewer visits to a physician for respiratory illness^Citation73
2001	ICS alone	• In a large population-based cohort study of 22,620 patients with COPD who were previously hospitalized, it was found that patients who received ICS within 90 days postdischarge had 24% fewer rehospitalizations and a 29% risk reduction for mortality during a 1-year follow-up^Citation20
2002	ICS alone	• A meta-analysis of early RCTs reported a significant 30% overall reduction in exacerbations with ICS^Citation74
	ICS + LABA	• RCTs began evaluating ICS in combination with a LABA (ie, either budesonide/formoterol or fluticasone propionate/salmeterol)^Citation11,Citation21,Citation22
2007	ICS + LABAa	• In the landmark TORCH trial, a 3-year, randomized, double-blind trial comparing salmeterol plus fluticasone propionate vs placebo, salmeterol alone, or fluticasone propionate alone in patients with COPD (FEV1 <60% of predicted), it was found that:^Citation22
		○ There was no significant benefit of ICS + LABA on all-cause mortality (primary end point); however, the statistical significance was borderline when compared with placebo (17.5% reduction; P=0.052)
		○ ICS + LABA significantly reduced the rate of exacerbations vs placebo (by 25%, P<0.001) and LABA or ICS alone (12%, P=0.002 and 9%, P=0.024, respectively)
		○ ICS + LABA had a much slower rate of decline in lung function compared with placebo (P≤0.003) and LABA or ICS alone (P<0.001, respectively)
		○ ICS + LABA significantly improved health status vs placebo, LABA, or ICS alone (P<0.001 for all)
	Adding ICS + LABA to LAMAb	• The Canadian Optimal trial was a 1-year, randomized, double-blind, placebo-controlled study that evaluated the addition of ICS + LABA (fluticasone propionate/salmeterol), LABA, or placebo in 449 patients with moderate-to-severe COPD who were receiving LAMA (tiotropium)^Citation75
		○ The findings of this trial were conflicting in that the addition of ICS + LABA to LAMA did not statistically influence rates of COPD exacerbation, but did improve lung function, quality of life, and hospitalization rates
2008	ICS + LABA vs LAMAa	• The INSPIRE trial, a 2-year, randomized, double-blind, double-dummy parallel study, directly compared ICS + LABA (fluticasone propionate/salmeterol) and LAMA (tiotropium) in a total of 1,323 patients with severe COPD, and was the first to show that there was no difference in exacerbation rate between ICS + LABA and LAMA^Citation24
2009	ICS + LABA + LAMAb	• In the CLIMB trial, a 12-week, randomized, double-blind, parallel-group, multicenter study, the efficacy and tolerability of adding a LAMA (tiotropium) to ICS + LABA (budesonide/formoterol) vs placebo was assessed in 660 patients with COPD after a 2-week run-in period^Citation76
		○ The addition of ICS + LABA to a LAMA vs LAMA alone reduced severe exacerbations (by 62%; P<0.001), as well as provided a rapid and sustained improvement in lung function (P<0.001), health status, and symptoms
2015	ICS + LABA	• In the SUMMIT trial, a placebo-controlled, double-blind, randomized, parallel group, multicenter study, mortality risk on ICS + LABA (fluticasone furoate/vilanterol) was evaluated in 16,485 patients from 43 countries who had COPD with moderate airflow limitation (FEV1 50%–70% predicted) and either a history or risk of cardiovascular disease^Citation26
		○ Risk of mortality was found to be 12.2% lower with ICS + LABA compared with placebo; albeit, this difference was not statistically significant (P=0.137)

Notes:

a Used as evidence to support recommendations for GOLD Group C.

b Used as evidence to support recommendations for GOLD Group D despite concerns about conflicting findings and/or short-term duration of trials.

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; INSPIRE, Investigating New Standards for Prophylaxis in Reduction of Exacerbations; ISOLDE, Inhaled Steroids in Obstructive Lung Disease in Europe; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; N/A, not applicable; RCT, randomized controlled trial; SUMMIT, Study to Understand Mortality and MorbidITy in COPD; TORCH, TOwards a Revolution in COPD Health.

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
Jaradetal^Citation39(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 al^Citation41 (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 al^Citation47 (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 al^Citation40 (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 al^Citation42 (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)
Wouters^Citation43 (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 al^Citation44 (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 al^Citation48 (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 al^Citation46 (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.

Table 3 LABA + LAMA combinations currently available or in development

LABA + LAMA combinationsa	Company
Available
Aclidinium/formoterol	AstraZeneca (London, UK)
Glycopyrronium/indacaterol	Novartis (Basel, Switzerland)
Tiotropium/olodaterol	Boehringer Ingelheim (Ingelheim, Germany)
Umeclidinium/vilanterol	GlaxoSmithKline (London, UK)
In development
Glycopyrronium/formoterol	AstraZeneca (London, UK)

Note:

a In alphabetical order.

Abbreviations: LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist.

Figure 2 A proposed step-by-step algorithm for safely withdrawing ICS from patients with COPD in real-life clinical practice.

Abbreviations: ACOS, asthma–COPD overlap syndrome; CAT, COPD Assessment Test; CCQ9, Chronic COPD Questionnaire; COPD, chronic obstructive pulmonary disease; FeNO, fractional exhaled nitric oxide; GINA, Global Initiative for Asthma; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; LABA, long-acting β₂-agonist; LABD, long-acting bronchodilator; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council Dyspnea Scale; ppb, parts per billion.

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