O3.2 Inhaled corticosteroids (ICS)

Exacerbations have a detrimental effect on quality of life, and patients with severe disease and frequent exacerbations have an accelerated decline in their quality of life (Miravitlles 2004).

A Cochrane systematic review (Yang 2023a) of studies of long-term (more than 6 months) ICS monotherapy compared to placebo, in people with stable COPD has found that ICS monotherapy likely reduces the rate of clinically relevant COPD exacerbations (0.05 exacerbations per participant per year, 95% CI −0.07 to −0.02; vs 0.88 exacerbations per participant per year, 95% CI 0.82 to 0.94), and probably slows the rate of decline of lung function (FEV₁) (MD 6.31 mL/year benefit, 95% CI 1.76 to 10.85), although the magnitude of this change is of unclear clinical relevance. ICS as monotherapy likely results in a small improvement in health-related quality of life measures without meeting the threshold for a clinically important difference (MD −1.22 units/year, 95% CI −1.8 3 to −0.60) but there is probably no reduction in all-cause mortality (OR) 0.94, 95% CI 0.84 to 1.07). The potential benefits of ICS as monotherapy must be weighed against the potential adverse events such as a likely increase in the risk of pneumonia (OR 1.38, 95% CI 1.02 to 1.88), increased risk of oropharyngeal candidiasis (OR 2.66, 95% CI 1.91 to 3.68) and hoarseness (OR 1.98, 95% CI 1.44 to 2.74) [evidence level I].

A nested case-control analysis of a new-user database cohort of 103,386 patients treated with inhaled corticosteroids in Quebec during 1999-2005 found that cessation of inhaled corticosteroids was associated with a 36% decrease in the rate of severe pneumonia events defined as hospitalisation or death from pneumonia during the study period (Suissa 2015). 14,020 patients had a serious pneumonia episode during 4.9 years of follow-up (incidence rate 2.8/100/year). The decreasing rate of serious pneumonia occurred rapidly, going from 20% reduction in the first month to 50% reduction by the fourth month after discontinuation. The risk reduction was more marked with cessation of fluticasone than cessation with budesonide.

Inhaled corticosteroids alone do not improve mortality, with pooled results from nine studies involving 8,390 participants showing an odds ratio of death of 0.98 (95% CI 0.83 to 1.16). The effect of inhaled corticosteroids on the rate of decline in lung function is inconsistent. Pooled results from studies of six months duration or longer, show either no significant difference in the rate of decline in post-bronchodilator FEV₁ (generic inverse variance analysis: weighted mean difference of 5.8 ml/year (95% CI -0.28 to 11.88, 2,333 participants) or a small statistically significant difference (pooled means analysis: 6.88 ml/year, 95% CI 1.80 to 11.96, 4,823 participants, with the inclusion of the TORCH study (Calverley 2007, Yang 2023).

A comprehensive overview by Miravitlles et al (2021) of the risks associated with the use of ICS in patients with COPD found an increased risk of local disorders such as oral candidiasis and dysphonia and infectious adverse events such as pneumonia [evidence level I]. The pooled analysis of 16 RCTs with n=33,725 participants showed that exposure to ICSs almost tripled the risk of oral candidiasis (RR 2.89, 95% CI 2.36–3.55; p<0.00001). The pooled analysis of nine RCTs with 22 841 participants showed that exposure to ICS increased the risk of dysphonia by 277% (RR 3.77, 95% CI 2.81–5.05; p<0.00001; I²=0%). The pooled analysis of 19 RCTs with 66 485 participants showed that exposure to ICSs for ⩾1 year increased the risk of pneumonia by 41% (RR 1.41, 95% CI 1.23–1.61; p<0.00001; I²=55%). An interaction was found between the risk of pneumonia and the type of ICS used, with the highest risk being associated with fluticasone (10 studies with 45870 participants), whereas exposure to budesonide (six studies with 13 479 participants) was not associated with an increased risk of pneumonia (Miravitlles 2021). A dose–response relationship was observed, indicating that lower doses of ICS should be used in patients with COPD whenever possible. The risks of diabetes, osteoporosis, bone fractures and eye disorders are less clear.

In people with COPD and diabetes mellitus, particular care should be taken not to exceed the recommended dose of corticosteroids as there is some evidence of a direct relationship between corticosteroid dose and glucose levels in such patients (Slatore 2009) [evidence level III-2]. In a large, real-world, retrospective, Swedish cohort study, patients with COPD (n = 9651) were more susceptible to bone fractures and osteoporosis than those of the same age and sex without COPD (Janson 2021). The treatment of people with COPD, especially with high-dose ICS (⩾640 μg·day), was associated with a higher risk of bone fractures and osteoporosis-related events (risk ratio 1.52 (95% CI 1.24–1.62). Screening of patients with COPD for osteoporosis and identifying those at high risk of fracture (those with comorbidities such as asthma, cardiovascular disease and depression), may be beneficial. In some patients, reducing the dose or discontinuation of ICS might be warranted [evidence level III-2).

Withdrawal of inhaled corticosteroids was not associated with any statistically significant increase in exacerbation rate in a systematic review of 4 RCTs in 901 patients (Nadeem 2011) (OR 1.11, 95% CI 0.84 to 1.46) [evidence level I]. The 12 month Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM) trial, studied patients with severe COPD who were stable on triple therapy (tiotropium, fluticasone propionate and salmeterol). Staged withdrawal of fluticasone propionate over 12 weeks was compared to continuation of fluticasone propionate, plus salmeterol and tiotropium (Magnussen 2014). 2,495 COPD patients with FEV₁ <50% predicted and a history of at least one exacerbation in the last 12 months were studied.  The hazard ratio for the first COPD exacerbation that was moderate or severe was 1.06 with ICS withdrawal (95% CI 0.94 to 1.19) which was below the upper limit of the non-inferiority margin for the primary outcomes of exacerbation of 1.20 [evidence level II].  The mean reduction in FEV₁ was 43 ml greater in the ICS withdrawal group at 52 weeks, which was statistically signficant.  At 52 weeks there was no statistically different significance in a mMRC dyspnoea score, and there was a small difference in change in SGRQ score, favouring ICS continuation.  Although the authors concluded that in patients with severe COPD withdrawal of ICS in a tapered fashion was non-inferior to continuation of ICS, there were statistically significant reductions in FEV₁ and quality of life which may be clinically relevant to some patients.

In the 26 week SUNSET trial (Chapman 2018) abrupt withdrawal of ICS from long-term triple therapy (tiotropium AND fluticasone/salmeterol administered via separate inhalers) to a LABA/LAMA combination (indacaterol/glycopyrronium administered via Breezhaler) in COPD patients (mean FEV₁ 57%) with no more than one moderate or severe exacerbation in the previous year led to a small but significant decrease in trough FEV₁ (26 ml; (95% CI −53 to 1 mL) with no differences in the rates of COPD exacerbations (0.52 versus 0.48, rate ratio 1.08; 95% CI 0.83 to 1.40) or the time to first moderate or severe COPD exacerbation (hazard ratio 1.11; 95% CI 0.85 to 1.46). Patients with high blood eosinophils (≥ 300 cells/μL) at baseline showed greater differences in lung function (a mean decrease of 69 ml) and were at increased risk of exacerbations after ICS withdrawal (rate ratio 1.86; 95% CI 1.06 to 3.29). The incidence of adverse events was similar across both treatment arms.

In COPD patients without evidence of asthma and with infrequent exacerbations, ICS withdrawal could be considered.  Close follow-up is recommended following wihdrawal. Post hoc analysis suggests ICS withdrawal should be approached cautiously in patients with COPD and elevated eosinophil counts.

COPD patients with FEV₁ 50 to 80% predicted and no exacerbations in the past 12 months were able to be switched to indacaterol with no significant differences in FEV₁, dyspnoea score, SGRQ score or frequency of exacerbations over six months, providing reassurance that switching from salmeterol/fluticasone to indacaterol appeared to be safe in this group of milder COPD patients (Rossi 2014) [evidence level II].

In an RCT of 639 COPD patients, the commencement of fluticasone (250mcg bd) and salmeterol (50mcg bd) within 14 days of the index exacerbation, compared to salmeterol alone, was not associated with benefit in terms of incidence in moderate or severe exacerbations, over a 6 month follow-up, although a 100 ml FEV₁ benefit was demonstrated (Ohar 2014).

A systematic review of RCTs of ICS versus non-ICS therapy for COPD showed an increased risk of TB associated with ICS use (Peto OR, 2.29; 95% CI 1.04-5.03), and no excess risk of influenza with ICS use (Peto OR, 1.24; 95% CI 0.94-1.63) (Dong 2014) [evidence level I]. The risk for TB was higher in endemic areas (NNH 909), compared to non-endemic areas (NNH 1,667). Limitations of the systematic review included: these outcomes were not the primary outcomes; limited number of trials reporting TB events; lack of chest x-ray at recruitment; varying definitions for TB infection; and differential withdrawal rate between ICS and non-ICS groups; and the authors recommended further investigation (Dong 2014).