Inhaled corticosteroids for chronic obstructive pulmonary disease: what is their role in therapy?

Figures & data

Table 1 Long-term studies of ICSs as monotherapy for patients with COPD

Study	Inclusion criteria/patients, n	Treatment	Primary efficacy outcome	Secondary efficacy outcomes	Safety
Wise et al^Citation7	Participants from LHS (smoking-cessation trial) who were current smokers or had quit within 2 years; 40–69 years of age; FEV1:FVC <0.7; FEV1 30%–90% predicted; N=1,116 (ICS n=559, Pbo n=557); baseline postbronchodilator FEV1% predicted, ICS 69%, Pbo 67%	Triamcinolone acetonide MDI 100 µg/inhalation; Pbo identical vehicle MDI; six inhalations BID; total daily ICS dose 1,200 µg	Rate of decline in FEV1 postbronchodilator NS; mean decline, ICS 44.2 mL/year, Pbo 47.0 mL/year (95% CI for difference −11.0 to 5.4)	Respiratory symptoms (ATS questionnaire) at 36 months, NS for cough, phlegm, wheezing; dyspnea, P=0.02 (no dyspnea, ICS 68.2%, Pbo 61.5%); new or worsening respiratory symptoms per 100 PY, ICS 21.1, Pbo 28.2 (P=0.005); respiratory hospitalizations per 100 PY, ICS 0.99, Pbo 2.1 (P=0.07); respiratory ED visits per 100 PY, ICS 1.3, Pbo 1.0 (P=0.36); respiratory outpatient visits, ICS 1.2, Pbo 2.1 (P=0.03); airway reactivity, P=0.02 at 9 and 33 months in favor of ICS; HRQoL (SF36), mental health subscale score (change from baseline to 36 months), ICS −2.3; Pbo −0.1 (P=0.03)	All-cause mortality, ICS n=15; Pbo n=19 (P=0.49); thrush, ICS n=5; Pbo n=2; moderate-severe throat irritation, ICS 2.3%, Pbo 1.1% (P=0.02); moderate-severe bruising, ICS 0.8%, Pbo 0.4%; cataracts, ICS n=122, Pbo n=114; BMD (% change from baseline to 36 months), lumbar spine – ICS -0.35, Pbo 0.98 (P=0.007); femoral neck – ICS −2, Pbo −0.22 (P<0.001)
Pauwels et al^Citation8	Current smokers ≥5 cigarettes/day or smoking history ≥10 years or ≥5 pack-years; FEV1:slow vital capacity <0.7; FEV1 50%–100% predicted, N=1,277 (ICS n=634, Pbo n=643); baseline prebronchodilator FEV1, ICS 77%, Pbo 77%	Budesonide DPI 400 µg; Pbo DPI; BID for 3 years	Change over time in FEV1: over the first 6 months, ICS improved FEV1 at rate of 17 mL/year vs Pbo decline of 81 mL/year (P<0.001) From 9 months to end of treatment, NS difference: ICS −57 mL/year, Pbo −69 mL/year >3 years in study completers: ICS −140 mL, Pbo −180 mL (P=0.05)	ICS had more beneficial effect in patients who smoked less; age, sex, baseline FEV1, presence or absence of serum IgE antibodies, and reversibility of airflow limitation had no effect on outcome	Skin bruising, ICS n=63 (10%), Pbo n=27 (4%) (P<0.001); oral candidiasis, ICS n=31, Pbo n=10 (P<0.001); BMD (measured in 194 patients), femoral trochanter decline – ICS 0.04%, Pbo 0.38% (P=0.02); cataracts, bone fractures, diabetes similarly distributed between groups
Vestbo et al^Citation9	30–70 years of age; FEV1:FVC <0.7; no self-reported asthma; N=290 (ICS n=145, Pbo n=145); baseline postbronchodilator FEV1, ICS 86%, Pbo 87%	Budesonide DPI; Pbo DPI; 800 µg in morning and 400 µg in evening for 6 months followed by 400 µg BID for 30 months	Rate of FEV1 decline: ICS 46.0 mL/year, Pbo 49.6 mL/year (P=0.70), with no effect of sex, smoking status, or baseline FEV1	Symptoms decreased in both treatment groups with no differences; exacerbations, ICS 155, Pbo 161; reversibility to β2-agonist from visit one to end of study, ICS 8.1% to 6.7%, Pbo 7.2% to 8.2%	Pneumonia: ICS n=16, Pbo n=24
Burge et al^Citation10	Current or former smokers; 40–75 years of age; nonasthmatic COPD; FEV1 postbronchodilator ≥0.8 L, but <85% predicted normal; FEV1:FVC <0.7; N=751 (ICS n=376, Pbo n=375); baseline postbronchodilator FEV1% predicted, ICS 50%, Pbo 50%	Fluticasone propionate MDI with spacer 500 µg; Pbo MDI with spacer; BID for 3 years	Decline in FEV1 postbronchodilator: ICS 50 mL/year, Pbo 59 mL/year (P=0.16), with no effect of smoking status, age, sex, or FEV1 response to oral corticosteroids At 3 and 36 months, predicted mean FEV1 76 and 100 mL higher with ICS vs Pbo, respectively (P<0.001)	Exacerbation rate (median), ICS 0.99/year, Pbo 1.32/year (P=0.026); SGRQ similar at baseline and 6 months, thereafter increased over time and worsened at a faster rate with Pbo (3.2 units/year) vs ICS (2.0 units/year) (P=0.004)	Hoarseness/dysphonia, ICS n=35, Pbo n=16; throat irritation, ICS n=43, Pbo n=27; oral candidiasis, ICS n=41, Pbo n=24; bruising, ICS n=27, Pbo n=15; fractures, ICS n=9, Pbo n=17; cataracts, ICS n=5, Pbo n=7

Abbreviations: ATS, American Thoracic Society; BID, bis in die (twice daily); BMD, bone-mineral density; DPI, dry-powder inhaler; ED, emergency department; ERS, European Respiratory Society; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; HRQoL, health-related quality of life; ICS, inhaled corticosteroid; LHS, lung health study; MDI, metered-dose inhaler; NS, not significant; Pbo, placebo; PY, person-years; SGRQ, St George’s Respiratory Questionnaire.

Figure 1 Effectiveness of ICS-LABA inhalers.

Notes: Pooled effect estimates of combined ICS-LABA inhalers vs (A) placebo and (B) LABA on moderate-severe exacerbations. Copyright ©2014. Dove Medical Press. Reproduced with permission from Oba Y and Lone NA. Comparative efficacy of inhaled corticosteroid and long-acting beta agonist combinations in preventing COPD exacerbations: a Bayesian network meta-analysis. Int J Chron Obstruct Pulmon Dis. 2014;9:469–479.³⁰
Abbreviations: BDP, beclomethasone dipropionate; BUD, budesonide; CrI, credibility interval; FF, fluticasone furoate; FM, formoterol; FP, fluticasone propionate; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; MF, mometasone furoate; SAL, salmeterol; VI, vilanterol.

Table 2 Distribution of pneumonia events and incidence rates by treatment in the UPLIFT study

Treatment	Events	Years in study	Incidence rate	Incidence-rate ratio (95% CI)	P-value
Any ICS vs no ICS
No ICS	383	6,885	0.056		Reference
ICS	738	10,836	0.068	1.22 (1.08–1.38)	0.012
FP vs other ICS and no ICS
FP	437	5,685	0.077	1.38 (1.20–1.58)	<0.001
Other ICS	301	5,151	0.058	1.05	0.52
No ICS	383	6,885	0.056		Reference
Effect of Tio on pneumonia rate, irrespective of ICS
FP/Pbo	230	2,720	0.081	1.45 (1.19–1.77)	<0.001
FP/Tio	217	2,964	0.073	1.31 (1.08–1.60)	0.006
Other ICS/Pbo	153	2,461	0.062	1.12 (0.90–1.38)	0.29
Other ICS/Tio	148	2,690	0.055	0.99 (0.79–1.23)	0.94
No ICS/Pbo	184	3,317	0.055		Reference
No ICS/Tio	199	3,567	0.056	1.00 (0.82–1.22)	0.95

Note: Reproduced with permission from Morjaria JB, Rigby A, Morice AH. Inhaled corticosteroid use and the risk of pneumonia and COPD exacerbations in the UPLIFT study. Lung. 2017;195(3):281–288. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/legalcode.⁷⁴

Abbreviations: FP, fluticasone propionate; ICS, inhaled corticosteroid; Pbo, placebo; Tio, tiotropium.

Figure 2 The role of ICS in patients with COPD.

Notes: Eosinophil thresholds for beneficial ICS effect are discussed in the text. Data regarding the effect of ICS on comorbidity presence or course are limited.
Abbreviations: ACO, asthma–COPD overlap; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; WBCs, white blood cells.

Figure 3 COPD exacerbations in the TRILOGY study.

Notes: Unadjusted annual rate of COPD exacerbations of differing severity in the intent-to-treat population for the TRILOGY study. Reprinted from The Lancet, 388(10048), Singh D, Papi A, Corradi M, et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial, Pages 963–973, Copyright 2016, with permission from Elsevier.⁸¹
Abbreviations: BDP, beclomethasone dipropionate; FF, fluticasone furoate; GB, glycopyrronium bromide.

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