Optimizing de-escalation of inhaled corticosteroids in COPD: a systematic review of real-world findings

Figures & data

Figure 1. PRISMA flow diagram for the identification of real-world or observational studies included in the systematic review concerning optimizing ICS therapy in COPD. COPD: chronic obstructive pulmonary disease; ICS: inhaled corticosteroid; LABA: long-acting β₂-adrenoceptor agonist; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Table 1. Definition of COPD exacerbations as reported by the studies included in the systematic review

Study and year	Reference	Definition of COPD exacerbation
Kaplan et al., 2019 (POWER study)	[33,36]	“A moderate COPD exacerbation was defined by requirement for the treatment with systemic corticosteroids and/or antibiotics”. “A severe COPD exacerbation was defined by hospitalization, including an ER visit of longer than 24 hours”.
Lee et al., 2019 (analysis of KOLD/KOCOSS cohorts)	[31]	“Exacerbation was defined as symptomatic deterioration requiring additional short-course treatment of antibiotics or systemic steroids with an unexpected visit to the clinic or ER, or hospitalization”. “Severe exacerbation was defined “as an exacerbation event resulting in admission or an ER visit”.
Oshagbemi et al., 2019	[24]	A moderate to severe exacerbation was defined “as recorded by validated read codes (H312200, H3y1.00) from clinical and referral files [19]”. Severe exacerbations were defined as “COPD-related hospitalizations/A&E visit evaluated using Read codes (8H2R.00, 66Yi.00) from both clinical and/or referral file in addition to validated Read codes (H312200, H3y1.00) for acute exacerbations of COPD from the referral file”.
Greulich et al., 2018 (CRYSTAL study post-hoc analysis)	[32,35]	“Moderate COPD exacerbation was defined as an exacerbation requiring treatment with either systemic corticosteroids and/or antibiotics”. “Severe exacerbation was defined as one that required hospitalization or an ER visit lasting longer than 24 hours”.
Vogelmeier et al., 2017 (DACCORD subgroup analysis)	[30]	An exacerbation was defined “based on the prescription of oral steroids and/or antibiotics or hospitalization”.
Worth et al., 2017 (DACCORD subgroup analysis)	[34]	An exacerbation was defined “based on prescription of oral steroids and/or antibiotics or hospitalization”.
Kunz et al., 2015 (GLUCOLD follow-up study)	[28,37]	NA
Suissa et al., 2015	[26]	NA
Rossi et al., 2014 (OPTIMO study)	[29]	A COPD exacerbation was defined as “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”.
Schermer et al., 2004 (analysis of the COOPT study washout phase)	[25]	“An exacerbation was defined as an episode with one or more subsequent unscheduled contacts with either a general practitioner or a chest physician due to worsening of respiratory symptoms”.
Jarad et al., 1999 (analysis of ISOLDE study run-in phase)	[27]	A COPD exacerbation was defined as “an episode of increased shortness of breath and/or sputum production requiring treatment with antibiotics and/or prednisolone”.

A&E: accident and emergency department; COPD: chronic obstructive pulmonary disease; ER: emergency room; NA: not available.

Table 2. Literature search terms used for OVID MEDLINE. The final search strategy applied to conduct this systematic review is reported at steps #29, #30, and #31

#	Search Strategy
1	ICS*.mp. [mp = title, abstract, full text, caption text]
2	corticosteroid*.mp. [mp = title, abstract, full text, caption text]
3	glucocorticoid*.mp. [mp = title, abstract, full text, caption text]
4	COPD*.mp. [mp = title, abstract, full text, caption text]
5	chronic*.mp. [mp = title, abstract, full text, caption text]
6	obstructive*.mp. [mp = title, abstract, full text, caption text]
7	pulmonary*.mp. [mp = title, abstract, full text, caption text]
8	disease*.mp. [mp = title, abstract, full text, caption text]
9	chronic obstructive*.mp. [mp = title, abstract, full text, caption text]
10	pulmonary disease*.mp. [mp = title, abstract, full text, caption text]
11	chronic obstructive pulmonary disease*.mp. [mp = title, abstract, full text, caption text]
12	withdrawal*.mp. [mp = title, abstract, full text, caption text]
13	de-escalation*.mp. [mp = title, abstract, full text, caption text]
14	optimization*.mp. [mp = title, abstract, full text, caption text]
15	switch*.mp. [mp = title, abstract, full text, caption text]
16	real-life*.mp. [mp = title, abstract, full text, caption text]
17	real-world*.mp. [mp = title, abstract, full text, caption text]
18	observational*.mp. [mp = title, abstract, full text, caption text]
19	clinical*.mp. [mp = title, abstract, full text, caption text]
20	practice*.mp. [mp = title, abstract, full text, caption text]
21	clinical practice*.mp. [mp = title, abstract, full text, caption text]
22	1 or 2 or 3
23	5 and 6 and 7 and 8
24	9 and 10
25	4 or 11 or 22 or 23
26	12 or 13 or 14 or 15
27	19 and 20
28	16 or 17 or 18 or 21 or 27
29	22 and 25 and 26 and 28
30	limit 29 to english language
31	limit 30 to full text

ICS: inhaled corticosteroid; COPD: chronic obstructive pulmonary disease.

Table 3. Characteristics of the studies included in the systematic review

Study’s lead author, year, and study’s name	Reference	Study ID	Study characteristics	Study duration	Number of analyzed patients	Treatment at baseline	Treatment during study period	Patients characteristics	Age (years)	Male (%)	Current smokers	Smoking history (pack-years)	Post- bronchodilator FEV1  predicted (%)	Duration of inhaled steroid use prior to entry into the study	Baseline number of exacerbations in year preceding the study	Investigated outcomes
Kaplan et al., 2019 (POWER study)	[33,36]	NCT02202616	Real-world, multicenter, post-approval, prospective, interventional, randomized, open-label, single-arm study	4 months	338	TIO (18 μg q.d. via DPI Handihaler®), FP/SAL (100/50 μg, 125/50 μg, 250/50 μg, or 500/50 μg, b.i.d. via DPI or pMDI)	All patients switched treatment at baseline to IND/GLY (110/50 μg q.d.)	Moderate to severe COPD (FEV1 ≥ 30% and <80% of predicted)	66.1	55.9	50.9	47.6	NA	NA	<2 in the  previous year and none in the 6 weeks prior to study entry	Lung function, dyspnea, health-related  QoL, and safety
Lee et al., 2019 (analysis of KOLD/KOCOSS cohorts)	[31]	NA	Non-interventional cohort study	4 years	478	ICS, ICS/LABA, ICS/LAMA, ICS/LABA/LAMA	ICS user treatment group: ICS, ICS/LABA, ICS/LAMA, ICS/LABA/LAMA; ICS nonuser treatment group: LABA, LAMA, LABA/LAMA	Persistent COPD (post-bronchodilator FEV1/FVC<70%)	68.2	91.8	30.8	42.5	55.9	NA	0.60	Drug utilization patterns, exacerbation frequency and rate
Oshagbemi et al., 2019 (NA)	[24]	NA	Real-world primary care population cohort study	9 years	48,157	ICS-containing treatment regimen	ICS user treatment group: patients receiving an ICS prescription for ≥3 months prior to study entry; past ICS user treatment group: patients who withdrew from ICS for ≥3 months prior to study entry	COPD	68.4	54.1	42.6	NA	NA	NA	None in the 6 weeks prior to study entry	Risk of moderate- to-severe and severe exacerbations and all-cause mortality
Greulich et al., 2018 (CRYSTAL study post-hoc analysis)	[32,35]	NCT01985334	Clinical-practice setting, prospective, multicenter, randomized, open-label study	3 months	1,080	LABA, LAMA, ICS/LABA free combination or FDC	Patients either switched treatment at baseline to IND/GLY (110/50 μg q.d.), or continued former treatment with LABA, LAMA, ICS/LABA free combination or FDC)	Moderate COPD (post-bronchodilator FEV1/FVC<70%; post-bronchodilator FEV1 ≥ 50% and <80% of predicted)	64.5	63.1	49.8	≥10	63.5	NA	≤1	CID, and prevention of decline in lung function, dyspnea, health-related QoL, and exacerbations
Vogelmeier et al., 2017 (DACCORD subgroup analysis)	[30]	EUPAS4207	Non-interventional, prospective study	2 years	1,258	ICS, ICS/LABA, ICS/LAMA, ICS/LABA/LAMA, PDE/4 inhibitor- or theophylline-containing regimen, or other	ICS user treatment group: ICS, ICS/LABA, ICS/LAMA, ICS/LABA/LAMA; withdrawal treatment group: LABA, LAMA, LABA/LAMA, PDE/4 inhibitor- or theophylline-containing regimen, or other	COPD (post-bronchodilator FEV1/FVC<70%; change in FEV1 post- bronchodilator, pre-bronchodilator <15% or 200 mL)	65.5	59.1	30.7	NA	63.6	NA	NA	Exacerbation rate and CAT score
Worth et al., 2017 (DACCORD subgroup analysis)	[34]	NA	Real-world, non-interventional study	1 year	2,724	No medication, LABA, LAMA, ICS/LABA, triple therapy	Patients either initiated treatment with IND/GLY or switched treatment at baseline to IND/GLY	COPD	66.7	58.1	39.6	NA	63.7	NA	0.28 in the previous 6 months prior to study entry	Exacerbation rate and CAT score
Kunz et al., 2015 (GLUCOLD follow-up study)	[28,37]	NCT00158847	Prospective, non-interventional study (follow-up study of the interventional GLUCOLD trial)	5 years	79	FP (500 μg b.i.d.), FP/SAL (500/50 μg b.i.d.), PCB (b.i.d.)	Patients either discontinued ICS or were treated with ICS-containing regimen from 0 to 50% of the time or from 50 to 100% of the time	COPD (post-bronchodilator FEV1/FVC<90%; post-bronchodilator FEV1 < 90% of predicted)	64.3	89.7	51.4	46.0	62.0	6 or 30 months of ICS treatment duration in FP or FP/SAL groups during the GLUCOLD study	NA	Lung function, health-related QoL, and AHR deterioration
Suissa et al., 2015 (NA)	[26]	NA	Observational, population based study	4.9 years	146,717	Patients treated with ICS-containing regimen (FP, BUD, or others) according to prescription registry	Discontinuation of ICS (FP, BUD, or others)	COPD	78.6	50.7	NA	NA	NA	NA	NA	Risk of serious pneumonia
Rossi et al., 2014 (OPTIMO study)	[29]	NA	Real-world, prospective, multicenter, study	6 months	816	FP/SAL (500/50 μg b.i.d.), BUD/FOR (400/12 μg b.i.d.), BDP/FOR (200/12 μg b.i.d.), other ICS/LABA from different inhalers	ICS user treatment group: ICS/LABA; ICS withdrawal treatment group: LABA, LAMA, or LABA/LAMA	Moderate COPD (post-bronchodilator FEV1/FVC<88% and<89% predicted for men and women, respectively; post-bronchodilator FEV1 > 50% of predicted)	72.4	71.6	23.0	NA	71.4	52  weeks	<2	Lung function, exacerbation rate, CAT score, and frequency of hospital admissions
Schermer et al., 2004 (analysis of COOPT study washout phase)	[25]	NA	Prospective, clinical-practice setting, open-label study	3 months	201	Patients treated with ICS-containing regimen (FP, BDP, or BUD)	Discontinuation of ICS (FP, BDP, or BUD)	COPD (post-bronchodilator FEV1/FVC<88% and<89% predicted for men and women, respectively; post-bronchodilator FEV1 < 90% of predicted)	60.6	84.1	49.0	NA	65.6	NA	0.33 in the previous 2 years and none in the 6 weeks prior to study entry	Risk of an adverse respiratory outcome
Jarad et al., 1999 (analysis of ISOLDE study run-in phase)	[27]	NA	Observational study	2 months	272	Patients treated with ICS-containing regimen	Discontinuation of ICS (BDP or BUD) in patients treated with ICS-containing regimen prior to study entry	Moderate to severe COPD (post-bronchodilator FEV1/FVC<75%; change in FEV1 post-bronchodilator <10%, post-bronchodilator FEV1 < 70% of predicted)	66.0	72.0	NA	44.0	42.8	52 weeks (for patients who discontinued ICS at study entry)	0.28	Risk of exacerbation

AHR: airway hyperresponsiveness; BDP: beclomethasone dipropionate; b.i.d.: bis in die, twice-daily; BUD: budesonide; CAT: COPD assessment test; CID: clinically important deterioration; COPD: chronic obstructive pulmonary disease; FDC: fixed-dose combination; FEV₁: forced expiratory volume in 1 second; FOR: formoterol; FP: fluticasone propionate; FVC: forced vital capacity; GLY: glycopyrronium; IND: indacaterol; ICS: inhaled corticosteroid; LABA: long-acting β₂-adrenoceptor agonist; LAMA: long-acting muscarinic antagonist; NA: not available; OCS: oral corticosteroid; PCB: placebo; PDE4: phosphodiesterase type 4; q.d.: quaque die, once daily; SABA: short-acting β₂-adrenoceptor agonist; SAL: salmeterol; SAMA: short-acting muscarinic antagonist; TIO: tiotropium bromide.

Table 4. Studies included in the systematic review in which ICS withdrawal was significantly superior ↑, similar ≈, or inferior ↓ to ICS continuation

From	To	Overall risk of exacerbation	Risk of moderate to severe exacerbation	Risk of severe exacerbation	FEV1	AHR deterioration	TDI	CAT score	SGRQ	CCQ score	MRC score	Risk of adverse respiratory outcome	Hospital admissions	Risk of serious pneumonia	Risk of all-cause mortality
ICS- containing  regimen	ICS discontinuation	↓ [30]; ≈ [31]; ↑ [27]	≈ in eosinophilic patietns [24]	≈ in eosinophilic patietns [24]; ↑ [31]	/	/	/	↓ [30]	/	/	/	↑ in women, elderly patients, smokers, subjects with high bronchodilator reversibility [25]	/	↓ [26]	≈ [24]
ICS/LABA/ LAMA	LABA/LAMA	≈ [34]	/	/	/	/	/	↓ [34]	/	/	/	/	/	/	/
ICS/LABA	LABA/LAMA	↓ [34]; ≈ [32,35]	/	/	↑ [32,33, 35,36]	/	↑ [32,33, 35,36]	↓ [33,34,36]	/	≈ [32,35]	/	/	/	/	/
ICS/LABA	LABA or LAMA or LABA/LAMA	≈ [29]	/	/	≈ [29]	/	/	≈ [29]	/	/	/	/	≈ [29]	/	/
ICS/LABA	ICS discontinuation or reduction of ICS use to 0–50% or 50–100% of the time	/	/	/	↓ [28,37]	↑ [28,37]	/	/	↑ [28,37]	↑ [28,37]	↑ [28,37]	/	/	/	/

Reference numbers are enclosed in the brackets. /: not available; AHR: airway hyperresponsiveness; CAT: COPD assessment test; CCQ: clinical COPD questionnaire; COPD: chronic obstructive pulmonary disease; FEV₁: forced expiratory volume in 1^st second; ICS: inhaled corticosteroid; LABA: long-acting β₂-adrenoceptor agonist; LAMA: long-acting muscarinic antagonist; MRC: medical resource council; TDI: transition dyspnea index.

Kaplan A, Chapman KR, Anees SM, et al. Real-life effectiveness of indacaterol-glycopyrronium after switching from tiotropium or salmeterol/fluticasone therapy in patients with symptomatic COPD: the POWER study. Int J Chron Obstruct Pulmon Dis. 2019;14:249–260.

 PubMed Web of Science ®Google Scholar

NCT02202616. Prospective cohort study for the real - life effectiveness evaluation of GlycOpyrronium with IndacatERol combination in the management of COPD in Canada (POWER Study) (POWER); 2014 [cited 2020 May 10]. Available from: https://clinicaltrials.gov/ct2/show/NCT02202616

 Google Scholar

Lee SH, Lee JH, Yoon HI, et al. Change in inhaled corticosteroid treatment and COPD exacerbations: an analysis of real-world data from the KOLD/KOCOSS cohorts. Respir Res. 2019;20(1):62. .

 PubMedGoogle Scholar

Oshagbemi OA, Franssen FME, van Kraaij S, et al. Blood eosinophil counts, withdrawal of inhaled corticosteroids and risk of COPD exacerbations and mortality in the clinical practice research datalink (CPRD). Copd. 2019;16(2):152–159.

 PubMedGoogle Scholar

Rothnie KJ, Mullerova H, Hurst JR, et al. Validation of the recording of acute exacerbations of COPD in UK primary care electronic healthcare records. PloS One. 2016;11(3):e0151357.

 PubMed Web of Science ®Google Scholar

Greulich T, Kostikas K, Gaga M, et al. Indacaterol/glycopyrronium reduces the risk of clinically important deterioration after direct switch from baseline therapies in patients with moderate COPD: a post hoc analysis of the CRYSTAL study. Int J Chron Obstruct Pulmon Dis. 2018;13:1229–1237.

 PubMed Web of Science ®Google Scholar

NCT01985334. Study to evaluate the efficacy and safety of glycopyrronium or indacaterol maleate and glycopyrronium bromide fixed-dose combination regarding symptoms and health status in patients with moderate COPD switching from treatment with any standard COPD regimen; 2013 [cited 2020 May 10]. Available from: https://clinicaltrials.gov/ct2/show/NCT01985334

 Google Scholar

Vogelmeier C, Worth H, Buhl R, et al. “Real-life” inhaled corticosteroid withdrawal in COPD: a subgroup analysis of DACCORD. Int J Chron Obstruct Pulmon Dis. 2017;12:487–494.

 PubMed Web of Science ®Google Scholar

Worth H, Buhl R, C-P C, et al. GOLD 2017 treatment pathways in ‘real life’: an analysis of the DACCORD observational study. Respir Med. 2017;131:77–84.

 PubMed Web of Science ®Google Scholar

Kunz LIZ, Postma DS, Klooster K, et al. Relapse in FEV1 decline after steroid withdrawal in COPD. Chest. 2015;148(2):389–396.

 PubMed Web of Science ®Google Scholar

NCT00158847. Modification of disease outcome in COPD; 2005 [cited 2020 May 10]. Available from: https://clinicaltrials.gov/ct2/show/NCT00158847

 Google Scholar

Suissa S, Coulombe J, Ernst P. Discontinuation of inhaled corticosteroids in COPD and the risk reduction of pneumonia. Chest. 2015;148(5):1177–1183. .

 PubMed Web of Science ®Google Scholar

Rossi A, Guerriero M, Corrado A. Withdrawal of inhaled corticosteroids can be safe in COPD patients at low risk of exacerbation: a real-life study on the appropriateness of treatment in moderate COPD patients (OPTIMO). Respir Res. 2014;15(1):77.

 PubMedGoogle Scholar

Schermer TR, Hendriks AJ, Chavannes NH, et al. Probability and determinants of relapse after discontinuation of inhaled corticosteroids in patients with COPD treated in general practice. Primary Care Respir J. 2004;13(1):48–55.

 PubMedGoogle Scholar

Jarad NA, Wedzicha JA, Burge PS, et al. An observational study of inhaled corticosteroid withdrawal in stable chronic obstructive pulmonary disease. ISOLDE study group. Respir Med. 1999;93(3):161–166.

 PubMed Web of Science ®Google Scholar