Withdrawal of Inhaled Corticosteroids from Patients with COPD; Effect on Exacerbation Frequency and Lung Function: A Systematic Review

Figures & data

Table 1 PICO Framework

Population	Intervention	Comparison	Outcome
COPD patients on ICS therapy	Withdrawal of ICS therapy	Patients who withdraw ICS vs patients who continue ICS	Rate of moderate or severe exacerbations Change in lung function Resumption of ICS therapy

Figure 1 Withdrawal of inhaled corticosteroids from patients with COPD: effect on exacerbation frequency of withdrawal and proportion who resumes treatment.

Table 2 Outcomes of RCTs

Author/Year	Change in Moderate/Severe Exacerbation Frequency (Risk of Experiencing an Exacerbation)	Change in Lung Function (Post-Bronchodilatation FEV1)	Resumption of ICS
O’Brien 2001^Citation23 (ICS vs placebo)	No significant difference in rate of exacerbations between trial arms at 6 weeks. 17% in placebo vs 0 in steroid arm (p = 0.23).	Greater decrease in mean FEV1 in placebo vs steroid arm at 6 weeks. Difference in mean decrease in FEV1 of 0.1L (95% CI 0.002 to 0.195) between placebo vs steroid arm.
Van Der Valk 2002^Citation25 (ICS vs placebo)	Risk of first exacerbation in placebo vs steroid arm HR: 1.5 (95% CI 1.05 to 2.1) at 6 months. Proportion experiencing rapid recurrent exacerbations 26 (21.5%) patients in placebo vs 6 (4.9%) patients in steroid arm. RR: 4.4 (95% CI: 1.9 to 10.30)	No significant difference in decrease in mean FEV1 between trial arms at 6 months. Difference in mean decrease in FEV1 of 0.38L (−0.79 to 0.016) between placebo vs steroid arm.
Choudhury 2007^Citation24 (ICS vs placebo)	Intention to treat analysis: exacerbation risk in placebo vs steroid arm RR: 1.11 (95% CI 0.91 to 1.36) at 1 year. Per protocol analysis: exacerbation risk in placebo vs steroid arm HR: 1.48 (95% CI 1.17 to 1.86) at 1 year	No significant difference in decrease in mean FEV1 between trial arms at 1 year. Difference in mean decrease in FEV1 of 0.023L (p = 0.44) between placebo vs steroid arm.	46% patients in placebo arm resumed usual inhalers due to exacerbation or self-reported symptom worsening.
Wouters 2005^Citation30 (ICS/LABA vs LABA)	No significant difference in rate of exacerbations between trial arms at 1 year. Annual exacerbation rate of 1.6 per patient year in withdrawal vs 1.3 per patient year in steroid arm. RR: 1.2 (95% CI 0.9 to 1.5).	Greater decrease in mean FEV1 in ICS withdrawal vs continuation arm at 1 year. Adjusted difference in mean decrease in FEV1 of 0.05L (95% CI: 0.01 to 0.1) between withdrawal vs steroid arm.
Rossi 2014^Citation29 (ICS/LABA vs LABA)	No significant difference in rate of exacerbations between the trial arms at 6 months. Annual exacerbation rate of 0.57 per patient year in withdrawal vs 0.67 per patient year in steroid arm. RR: 0.86 (95% CI 0.62 to 1.20)	No significant difference in decrease in mean FEV1 between trial arms at 6 months. Difference in mean decrease in FEV1 of 0.014L (95% CI −0.046 to 0.019) between withdrawal vs steroid arm.
Vogelmeier 2017^Citation31 (ICS/LABA vs LABA/LAMA)	Not reported.	Improvement in mean FEV1 in ICS withdrawal vs continuation arm at 3 months. Difference in mean increase in FEV1 of 0.071L (95% CI 0.036 to 0.107, p<0.0001) between in withdrawal vs steroid arm.
Frith 2018^Citation27 (ICS/LABA vs LABA/LAMA)	No significant difference in rate of exacerbations between the trial arms at 3 months. Reported exacerbations: 10.1% withdrawal vs 13.2% patients in steroid arm.	Improvement in mean FEV1 in ICS withdrawal vs continuation arm at 3 months. Difference in mean increase in FEV1 of 0.045L (95% CI 0.005 to 0.084) between withdrawal vs steroid arm.
Magnussen 2014^Citation28 (ICS/LABA/LAMA vs LABA/LAMA)	No significant difference in rate of exacerbations between the trial arms at 1 year. Adjusted exacerbation event rate 0.95 per patient year (95% CI 0.87 to 1.04) in withdrawal vs 0.91 per patient year (95% CI 0.83 to 0.99) in steroid arm (p>0.05).	Greater decrease in mean FEV1 in ICS withdrawal vs continuation arm at 1 year. Difference in mean decrease in FEV1 of 0.043L (p = 0.001) between withdrawal vs steroid arm.
Chapman 2018^Citation26 (ICS/LABA/LAMA vs LABA/LAMA)	No significant difference in rate of exacerbations between trial arms at 6 months. Exacerbation rate 0.52 per patent year in withdrawal vs 0.48 per patient year in steroid arm. HR: 1.08 (95% CI: 0.83 to 1.40).	No significant difference in decrease in mean FEV1 between trial arms at 6 months. Difference in mean decrease in FEV1 of 0.026L (95% CI −0.053 to 0.001) between withdrawal vs steroid arm.
Harries 2022^Citation11 (ICS/LABA/LAMA vs LABA/LAMA)	No significant difference in rate of exacerbations between trial arms. Exacerbation rate 0.15 (± 0.37) per patent year in withdrawal vs 0.05 (± 0.22) per patient year in steroid arm (p=0.30).	No significant difference in mean FEV1% pred between trial arms at 6 months. FEV1% pred 72.00 (±16.59) withdrawal arm vs 71.63 (±12.63) steroid arm.	21% patients in the ICS withdrawal arm resumed ICS therapy at 3-month review on medical advice due to their symptom deterioration and decline in FEV1.

Abbreviations: bd, twice daily; qds, four times per day; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; FEV₁, Post-bronchodilatation Forced Expiratory Volume in 1 second.

Table 3 Characteristics of the RCTs

Author/Year	Study Design	Treatment Arms	Characteristics	Disease Severity FEV1 Mean (SD)	Exacerbation History Prior Year (mean (SD) Exacerbations Per Patient Year)	Run in Period	Length of Time of use of ICS prior to Study	Exacerbation Description (Moderate/Severe)
O’Brien 2001^Citation23	RCT, cross over. Withdrawal vs continuation. 6-week follow up	Beclomethasone dipropionate 336µg/day vs Placebo. (ICS vs placebo)	24 patients randomised. Age: 66.9 ± 1.9.	FEV1 1.61 ± 0.1L (47% pred)	Details not provided	None	Details not provided	Details not provided
Van Der Valk 2002^Citation25	COPE RCT, parallel arms. Withdrawal vs continuation. Double blind 6-month follow up	Fluticasone propionate 500µg bd + ipratropium 50µg qds vs Placebo (ICS vs placebo)	244 patients randomised Age: 64.0 ± 7.2	Withdrawal arm: FEV1: 1.69 ± 0.53L (56.1% ± 14.8% pred) Steroid arm: FEV1: 1.78 ± 0.53L (57.5% ± 14.1% pred)	Withdrawal arm: 1.36 ± 1.66 Steroid arm: 1.31 ± 1.50	4 months use of fluticasone propionate 500µg bd + ipratropium 50µg qds	83% patients had used for at least 6 months	Worsening of respiratory symptoms requiring treatment with a short course of oral corticosteroids or antibiotics as judged by the study physician.
Choudhury 2007^Citation24	WISP RCT, parallel arms. Withdrawal vs continuation. Double blind 1-year follow-up	Fluticasone propionate 500µg bd vs Placebo (ICS vs placebo)	260 patients randomised Age: 67.6 vs 67.3, steroid vs withdrawal.	Withdrawal arm: 1.40 ± 0.56L (55.0% ± 17.1% pred) Steroid arm: 1.31 ± 0.55L (53.2% ± 18.2% pred)	Withdrawal arm: 1.48 ± 1.77 Steroid arm: 1.59 ± 1.71	2 weeks on patient usual medication	Minimum 6 months. Mean 8 years	Moderate: treated with a course of antibiotics or oral steroids. Severe: treated with a course of antibiotics or oral steroids and resulting in hospital admission.
Wouters 2005^Citation30	COSMIC RCT, parallel arms. Withdrawal vs continuation. Double blind 1-year follow-up.	Fluticasone propionate 500µg bd + Salmeterol 50µg bd vs Salmeterol 50µg bd (ICS/LABA vs LABA)	373 patients randomised. Age (mean) - 64 vs 63 (withdrawal vs continuation).	Withdrawal arm: 1.44 ± 0.42L (49% ± 11.6% pred) Steroid arm: 1.43 ± 0.49L (48.1% ± 11.6% pred)	Not specified but ≥2 documented exacerbations.	3-month use of fluticasone propionate 500µg bd + salmeterol 50µg bd	Details not provided	Moderate: course of oral corticosteroids indicated based on a clinician’s judgment. Severe: admission to hospital.
Rossi 2014^Citation29	INSTEAD RCT. parallel arms. Withdrawal vs continuation. Double blind 6-month follow-up	Fluticasone propionate 500µg bd + Salmeterol 50µg bd vs Indacaterol 50µg/day (ICS/LABA vs LABA)	581 patients randomised.	FEV1 (L) – 1.54 ± 0.40	Included patients with no exacerbations in the previous year.	2-week use of fluticasone propionate 500µg bd + salmeterol 50µg bd	≥3 months	Moderate: managed with course of antibiotics and/or oral corticosteroid. Severe: requiring hospitalisation.
Vogelmeier 2017^Citation31	CRYSTAL RCT. Open-label trial. 3-month follow-up.	Patients were randomised to either remain on baseline LABA/ICS (unspecified) vs Indacaterol/Glycopyrronium 110/50µg/day (ICS/LABA vs LABA/LAMA)	4389 patients randomised. 1080 patients compared (269 LABA/ICS, 811 LABA/LAMA) Age – patients aged ≥40 years included.	Withdrawal arm: 1.80 ± 0.50L (63.70% ± 8.07% pred) Steroid arm: 1.76 ± 0.50L (63.30% ± 8.30% pred)	≤1 Withdrawal arm: 72.4% had no exacerbations, 27.1% had ≥ 1. Steroid arm: 71.8% had no exacerbations, 26.8% had ≥ 1.	None	≥3 months	Moderate: requiring systemic corticosteroids and/or antibiotics Severe: requiring hospitalisation
Frith 2018^Citation27	FLASH RCT. parallel arms. Withdrawal vs continuation. Double blind 3-month follow-up	Fluticasone propionate 500µg bd + Salmeterol 50µg bd vs Indacaterol/Glycopyrronium 110/50µg/day (ICS/LABA vs LABA/LAMA)	502 patients randomised. Age – 65.0±9.14 vs 65.1±8.44, IND/GLY vs SFC.	Withdrawal arm: 51.3% ± 12.77% pred Steroid arm: 51.7% ± 12.73% pred	Withdrawal arm: 61.3% had no exacerbations, 38.7% had ≥ 1. Steroid arm: 59.2% had no exacerbations, 40.8% had ≥ 1.	None	≥3 months	Requiring treatment with antibiotics and/or systemic corticosteroids and/or hospitalization.
Magnussen 2014^Citation28	WISDOM RCT. parallel arms. Withdrawal vs continuation. Double blind 1-year follow-up	Fluticasone propionate 500µg bd + Salmeterol 50µg bd + Tiotropium 18µg/day vs Salmeterol 50µg bd + Tiotropium 18µg/day (ICS/LABA/LAMA vs LABA/LAMA)	2485 patients randomised. Age – 63.8±8.5	Withdrawal arm: 0.98 ± 0.36L (34.3% ± 10.8% pred) Steroid arm: 0.97 ± 0.36L (34.2% ± 11.2% pred)	Not specified but ≥1 documented exacerbation	6 weeks on SFC 50/500µg bd + tiotropium 18µg/day	Details not provided. 69.4% of withdrawal arm and 70.5% of steroid arm using ICS prior to run in period	Moderate: increase in lower respiratory tract symptoms related to COPD or new onset of two or more such symptoms, with at least one symptom lasting ≥3 days, for which treating physician prescribed antibiotics, systemic glucocorticoids, or both. Severe: requiring hospitalization in an urgent care unit
Chapman 2018^Citation26	SUNSET RCT. Parallel arms. Withdrawal vs continuation. Double blind 6-month follow-up	Fluticasone propionate 500µg bd + Salmeterol 50µg bd + Tiotropium 18µg/day vs Indacaterol/Glycopyrronium 110/50µg/day (ICS/LABA/LAMA vs LABA/LAMA)	1053 patients randomised. Age – 65.3±7.80.	Withdrawal arm: 1.60 ± 0.44L (56.2% ± 9.66% pred) Steroid arm: 1.60 ± 0.46L (57.0% ± 10.30% pred)	Withdrawal arm: 63.4% had no exacerbations, 36.6% had ≥ 1. Steroid arm: 68.4% had no exacerbations, 31.6% had ≥ 1.	4 weeks on SFC 50/500µg bd + tiotropium 18µg/day	≥6 months triple therapy	Moderate: treated with systemic corticosteroids and/or antibiotics. Severe: requiring hospitalisation in addition to treatment with systemic corticosteroids and/or antibiotics.
Harries 2022^Citation11	Feasibility RCT. Withdrawal vs continuation. Open label 6-month follow-up	Unspecified: ICS therapy (>400µg/day beclomethasone dipropionate or equivalent) + LABA +LAMA vs LABA+LAMA (ICS/LABA/LAMA vs LABA/LAMA)	40 patients randomised. Age (years) – 70.10±9.22	Withdrawal arm: 1.77 ± 0.47L (73.53% ± 14.12% pred) Steroid arm: 1.87 ± 0.61L (72.79 ± 13.70% pred)	Withdrawal arm: 0.50 ± 0.51 Steroid arm: 0.45 ± 0.51	None	≥6 months triple therapy	Moderate: requiring treatment with antibiotics and/or oral corticosteroids in the community. Severe: requiring admission to hospital

Abbreviations: bd, twice daily; qds, four times per day; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; FEV₁, Post-bronchodilatation Forced Expiratory Volume in 1 second.

Figure 2 Risk of bias (ROB) summary of randomised controlled trials I for outcome measure change in exacerbation frequency.

Table 4 Characteristics of the Observational Studies

Author/Year	Study Design	Treatment arms	Characteristics	Disease Severity FEV1/FEV1% pred Mean (SD)	Exacerbation History Prior Year (Mean (SD) Exacerbations Per Patient Year)	Length of Time of Use of ICS Prior to Study	Exacerbation Description (Moderate/Severe)
Rossi 2014^Citation32	Non-randomised, prospective study of ICS withdrawal. 6-month follow-up	LABA/ICS vs LABA. At baseline: 56% using fluticasone/salmeterol 500/50 mcg bd 18% using budesonide/formoterol 400/12 mcg bd 12% using beclometasone/formoterol 200/12mcg bd 14% using ICS and LABA from different inhalers	914 patients non-randomly allocated to either arm Age – 72.1±9.2 vs 73.0±8.9, withdrawal vs continue.	Withdrawal arm: FEV1% pred 71.7% ± 10.4% Steroid arm: 70.8% ± 11.3%	Withdrawal arm: 36.7% had no exacerbations, 63.3% had ≥ 1. Steroid arm: 37.7% had no exacerbations, 62.3% had ≥ 1.	Regular treatment with ICS (frequency not specified)	A change in symptoms leading to a brief course of antibiotics or systemic corticosteroids or both, depending on what the treating physicians deemed fit, and which was reported on the patient’s individual record
Vogelmeier 2017^Citation33	DACCORD. Retrospective observational study. 2-year follow-up	Baseline medication combinations included ICS monotherapy, LABA/ICS, ICS/LAMA, LABA/ICS/LAMA.	1365 patients entered the study, 236 patients in withdrawal arm vs 1022 patients in steroid arm. Age (mean) – 65.4 (10.9) vs 66.5 (9.7), ICS withdrawn vs steroid arm	Withdrawal arm: 1.80 ± 0.80L (67.40% ± 31.20% pred) Steroid arm: 1.60 ± 0.60L (59.80% ± 23.30% pred)	Prior 6 months: Withdrawal arm: 74.2% had no exacerbations, 25.4% had ≥ 1. Steroid arm: 29.0% had no exacerbations, 70.7% had ≥ 1.	Details not provided	Prescription of oral steroids and/or antibiotics or hospitalisation.
Magnussen 2021^Citation34	Retrospective observational study using the OPCRD database. 1 year follow-up.	LABA/ICS/LAMA vs LABA/LAMA.	5230 patients. Age – 70.7±10.2 vs 71.0±8.8, steroid vs withdrawal.	Withdrawal arm: FEV1% pred 58.2% ± 20.9% Steroid arm: 53.9% ± 22.5%	Withdrawal arm: 1.1 ± 1.4 Steroid arm: 1.1 ± 1.4	≥2 fixed dose ICS/LABA and separate LAMA prescriptions, or ≥2 fixed dose ICS/LABA/LAMA prescriptions, in the prior year	Unscheduled hospital admission or A&E attendance for COPD/respiratory condition or generic hospitalisation code on same day as a lower respiratory coded consultation, course of oral steroids and/or antibiotics prescribed with lower respiratory consultation.
Neches Garcia 2022^Citation15	Retrospective observational study using records from the BIG-PAC administrative database. 1 year follow-up.	LABA/ICS/LAMA vs LABA/LAMA.	6541 patients. Age (mean) – 70.5±10.8.	Withdrawal arm: FEV1% pred 55.8% ± 14.1% Steroid arm: 52.2% ± 14.0%	Withdrawal arm: 0.4 ± 0.7 Steroid arm: 0.6 ± 0.9	Details not provided	Moderate: requiring treatment with antibiotics and/or oral corticosteroids. Severe: requiring hospitalisation.
Suissa 2022^Citation35	Retrospective observational study using CPRD data. 1 year follow-up.	LABA/ICS/LAMA vs LABA/LAMA.	85,334 patients. Age (mean) – 72.1±9.5 vs 71.9±9.3, withdrawl vs steroid.	Withdrawal arm: FEV1% pred 53.7% ± 18.6% Steroid arm: 53.3% ± 18.5%	Withdrawal arm: 42.8% no exacerbations, 57.2% had ≥ 1. Steroid arm: 42.1% had no exacerbations, 57.9% had ≥ 1.	≥1 month	Moderate: prescriptions of prednisolone Severe: hospitalisations for COPD
Whittaker 2022^Citation16	Retrospective observational study using CPRD data.	LABA/ICS/LAMA vs LABA/LAMA.	60,645 General cohort of COPD patients Age (mean) – 69.5±9.5 vs 67.8±10.2 withdrawl vs steroid	Not specified Withdrawal arm: 6.2% had FEV1% pred <30%. 27.2% had FEV1% pred 30–49%. Steroid arm: 6.5% had FEV1% pred <30%. 29.8% had FEV1% pred 30–49%	Withdrawal arm: 39.7% had no exacerbations, 60.3% had ≥ 1. Steroid arm: 32.6% had no exacerbations, 67.4% had ≥ 1.	≥4 months triple therapy	Moderate: events recorded in primary care. Severe: events requiring hospitalisation

Abbreviations: bd, twice daily; qds, four times per day; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; FEV₁, Post-bronchodilatation Forced Expiratory Volume in 1 second.

Table 5 Outcomes of Observational Studies

Author/Year	Change in moderate/severe exacerbation frequency (risk of experiencing an exacerbation)	Change in lung function (post-bronchodilatation FEV1)	Resumption of ICS
Rossi 2014^Citation32 LABA/ICS vs LABA.	No significant difference in rate of exacerbations between the trial arms. Exacerbations per patient per 6 months: 0.34 withdrawal arm vs 0.37 steroid arm. RR: 0.88 (95% CI: 0.68 to 1.14)	Change in mean FEV1 between trial arms not reported. No significant difference in FEV1% pred between trial arms at 6 months: 72.46% withdrawal vs 72.14% steroid arm (p=0.75)
Vogelmeier 2017^Citation33	Fewer exacerbations in withdrawal vs steroid arm at 2 years. Annualised mean exacerbation rate: Year 1: 0.414 withdrawal vs 0.433 steroid arm (p>0.05) Year 2: 0.237 withdrawal vs 0.402 steroid arm (p<0.05)	Not reported.	45.3% patients in withdrawal arm.
Magnussen 2021^Citation34 LABA/ICS/LAMA vs LABA/LAMA.	No significant difference in rate of exacerbations between the trial arms at 1 year. Annual exacerbation rate (mean (SD)): 1.01 (±1.46) per patient year in withdrawal vs 0.94 (±1.41) per patient year in steroid arm (p>0.05)	No significant difference in annualised change in FEV1 (mean (SD)) between trial arms: -0.049L (±0.23) withdrawal vs −0.019L (±0.25) steroid arm (p>0.05)	61.9% in withdrawal arm.
Neches Garcia 2022^Citation15 LABA/ICS/LAMA vs LABA/LAMA.	Increased exacerbations in withdrawal vs steroid arm. Annual exacerbation rate (mean (SD)): 0.50 (±0.80) per patient year in withdrawal vs 0.4 (±0.70) per patient year in steroid arm (p=0.018).	Not reported.
Suissa 2022^Citation35 LABA/ICS/LAMA vs LABA/LAMA.	Rate of total exacerbations between the trial arms not reported.	Not reported.	74% of withdrawal arm resumed ICS use
Whittaker 2022^Citation16 LABA/ICS/LAMA vs LABA/LAMA.	Not reported.	No significant difference in decrease in mean FEV1 between trial arms. Mean adjusted rate of FEV1 decline withdrawal vs steroid arm: -0.008L (95% CI: −0.012 to 0.0041) vs −0.015L (95% CI: −0.019 to 0.012) (difference, p = 0.264)

Abbreviations: bd, twice daily; qds, four times per day; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; FEV₁, Post-bronchodilatation Forced Expiratory Volume in 1 second.

Figure 3 Risk of bias (ROB) summary of randomised controlled trials II for outcome measure change in lung function.

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Data Sharing Statement

All data generated or analysed during this study are included in this published article [and its Supplementary Information Files].