A re-evaluation of the role of inhaled corticosteroids in the management of patients with chronic obstructive pulmonary disease

Figures & data

Table 1. Summary of studies comparing fixed-dose combinations of LAMA/LABAs and ICS/LABAs.

Study/(Year)	Duration	N randomized	FEV1 % predicted (GOLD stage)	Entry criteria	Treatment (randomization)	Exacerbation RR for LAMA/LABA versus FSC	Treatment difference for LAMA/LABA versus FSC
							Lung function	Other outcomes	Pneumonia incidence
ILLUMINATE Vogelmeier et al. (2013) [60,61]	26 weeks	523	51 (II/III)	Symptomatic; no moderate/severe exacerbation in the previous year	QVA149 110/50 μg q.d. FSC 500/50 μg b.i.d. (1:1)	All exacerbations: RR 0.69 (95% CI 0.44, 1.07); p = 0.098 Moderate/severe exacerbations: RR 0.80 (95% CI 0.41, 1.56); p = 0.512	FEV1 AUC0–12h 0.138 l (95% CI 0.100, 0.176); p < 0.0001; primary end point at 26 weeks Trough FEV1 0.103 l (95% CI 0.065, 0.141); p < 0.0001	TDI total score 0.76 (95% CI 0.26, 1.26); p = 0.0031 SGRQ total score −1.24 (95% CI −3.33, 0.85); NS (clinically significant improvement from baseline with both treatments) Rescue medication use −0.39 (95% CI −0.71, −0.06) puffs/day; p = 0.019	0 versus 1.5%
LANTERN Zhong et al. (2015) [66]	26 weeks	744	52 (II/III)	Symptomatic; no more than 1 moderate/severe exacerbation in the previous year (21% had one in the previous year)	QVA149 110/50 μg q.d. FSC 500/50 μg b.i.d. (1:1)	Moderate/severe exacerbations: RR 0.69 (95% CI 0.48, 1.00); p < 0.05	Trough FEV1 0.075 l (95% CI 0.044, 0.107); p < 0.001; primary endpoint at 26 weeks	TDI total score 0.13 (95% CI −0.2, 0.47); NS SGRQ total score -0.69 (95% CI −2.38, 1.00); NS Rescue medication use −0.03 puffs/day (95% CI −0.26, 0.21); NS	0.8 versus 2.7%
Donohue et al. (2015) [65,106]	12 weeks	717	FEV1 ≥ 30 and ≤ 70%	Symptomatic; no moderate/severe exacerbation in prior year	UMEC/VI 62.5/25 μg q.d. FSC 500/50 μg b.i.d. (1:1)	–	Change from baseline in 24-h weighted-mean serial FEV1 0.080 l (95% CI 0.046, 0.113); p < 0.001; primary endpoint at 12 weeks Change from baseline in trough FEV1 0.151 ± 0.0126 versus 0.062 ± 0.0125 l	With both treatments, changes in TDI total score (> 1 point) and change from baseline in SGRQ total score (> 4 units) clinically meaningful over 12 weeks	NR (no serious events)
NCT01817764 Donohue et al. (2014) (abstract) [62]	12 weeks	707	FEV1 ≥ 30 and ≤ 70%	Symptomatic; no moderate/severe exacerbation in prior year	UMEC/VI 62.5/25 μg q.d. FSC 250/50 μg b.i.d. (1:1)	–	Change from baseline in 24-h weighted-mean serial FEV1 0.074 l (95% CI 0.038, 0.110); p < 0.001; primary end point at 12 weeks Change from baseline in trough FEV1 0.154 ± 0.0133 versus 0.072 ± 0.0134 l	With both treatments, changes in TDI total score (> 1 point) and change from baseline in SGRQ total score (> 4 units) clinically meaningful over 12 weeks in both studies; no treatment differences between UMEC/VI and FSC	Overall NR Pneumonia as SAE: 0 versus 0.85%
NCT01879410 Donohue et al. (2014) (abstract) [62]	12 weeks	700	FEV1 ≥ 30 and ≤ 70%	Symptomatic; no moderate/severe exacerbation in prior year	UMEC/VI 62.5/25 μg q.d. FSC 250/50 μg b.i.d. (1:1)	–	Change from baseline in 24-h weighted-mean serial FEV1 0.101 l (95% CI 0.063, 0.139); p < 0.001; primary end point at 12 weeks Change from baseline in trough FEV1 0.185 ± 0.0138 versus 0.087 ± 0.0140 l	With both treatments, changes in TDI total score (> 1 point) and change from baseline in SGRQ total score (> 4 units) clinically meaningful over 12 weeks in both studies; no treatment differences between UMEC/VI and FSC	Overall NR Pneumonia as SAE: 0.29 versus 1.15%

b.i.d.: Twice daily; CI: Confidence interval; FEV₁: Forced expiratory volume in 1 second; FSC: Fluticasone–salmeterol combination; GOLD: Global initiative for chronic Obstructive Lung Disease; HR: Hazard ratio; ICS: Inhaled corticosteroids; LABA: Long-acting β₂-agonist; LAMA: Long-acting muscarinic antagonist; NR: Not reported; NS: Not significant; q.d.: Once daily; RR: Rate ratio; SAE: Serious adverse event; SGRQ: St George’s respiratory questionnaire; TDI: Transition dyspnea index; UMEC/VI: Umeclidinium/vilanterol.

Figure 1. Clinical phenotypes of COPD proposed by the Spanish guideline for COPD (Guía Española de la EPOC; GesEPOC).

Table 2. Approved COPD indications in the EU and US for some LABA/ICS combinations.

Drug	Daily dose	Indication
		EU	US
Fluticasone propionate/salmeterol	500/50 µg × 2	Symptomatic treatment of patients with COPD, with a FEV1 < 60% predicted normal (pre-bronchodilator) and a history of repeated exacerbations, who have significant symptoms despite regular bronchodilator therapy	Not approved
Fluticasone propionate/salmeterol	250/50 µg × 2	Not approved	Twice-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema Also indicated to reduce exacerbations of COPD in patients with a history of exacerbations
Budesonide/formoterol	400/12 µg × 2	Symptomatic treatment of patients with severe COPD (FEV1 < 50% predicted normal) and a history of repeated exacerbations, who have significant symptoms despite regular therapy with long-acting bronchodilators	Not approved
Budesonide/formoterol	200/6 µg × 2	Not approved	Maintenance treatment of airflow obstruction in patients with COPD including chronic bronchitis and emphysema
Fluticasone furoate/vilanterol	100/25 µg	Symptomatic treatment of adults with COPD with a FEV1 < 70% predicted normal (post-bronchodilator) with an exacerbation history despite regular bronchodilator therapy	Long-term, once-daily, maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema Also indicated to reduce exacerbations of COPD in patients with a history of exacerbations

COPD: Chronic obstructive pulmonary disease; FEV₁: Forced expiratory volume in 1 second; LABA: Long-acting β₂-agonist; LAMA: Long-acting muscarinic antagonist; ICS: Inhaled corticosteroids.

Figure 2. Prevalence of GOLD group C and D subtypes, defined by FEV₁ < 50% predicted only (C1 and D1), exacerbation history only (C2 and D2) or both (C3 and D3), in the large COPD gene [107], Copenhagen [108] and ECLIPSE [109] trials. In each study, most patients were categorized as high risk on the basis of low FEV₁ alone.

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