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 number of randomised controlled trials of inhaled corticosteroids have been published and these have been combined in a systematic review (Yang 2012) [evidence level I], mainly involving patients without bronchodilator reversibility or bronchial hyper-responsiveness.

A meta-analysis of 38 studies (including 29 randomised controlled trials and nine observational studies) of inhaled corticosteroid use in COPD reported by Festic et al (Festic 2016), demonstrated similar increases in pneumonia risk, without associated increases in pneumonia-associated mortality or overall mortality; however ideally, further prospective studies which would systematically assess and monitor pneumonia as a pre-specified outcome are required.  A post-hoc meta-analysis of data from a GSK trials registry (Pavord 2016) gave a small signal suggesting that patients with eosinophil counts <2% were at marginally increased risk of pneumonia events whether or not they were receiving inhaled corticosteroids. This may be the group who also derive least benefit from inhaled corticosteroids. Further prospective studies are awaited.

Inhaled corticosteroids, given as a single agent, decrease the exacerbation rate compared to placebo in studies longer than a year, with weighted mean difference of  -0.26 exacerbations per participant, per year (95% CI -0.37 to -0.14, 2,586 participants). They also slow the rate of decline in quality of life, with the weighted mean difference in rate of change for the St George’s Respiratory Questionnaire (SGRQ) being -1.22 units/year (95% CI  -1.83 to -0.60, 2,507 participants).

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 2007Yang 2012).

Any potential benefits of inhaled corticosteroids should be weighed against the potential risks of local oropharyngeal adverse effects and pneumonia. Local adverse effects include increased risk of oral candidiasis (OR 2.65, 95% CI 2.03 to 3.46, 5586 participants) and hoarseness or dysphonia (OR 1.95, 95% CI 1.41 to 2.70, 3267 participants) (Yang 2012). A meta-analysis of 43 COPD studies (26 fluticasone studies, n =21,247; 17 budesonide studies, n = 10,150) has demonstrated an increased risk of pneumonia with use of inhaled corticosteroids, when given as monocomponents or in combination inhalers (Kew 2014b). Non-fatal serious adverse pneumonia events (i.e. requiring hospital admission) were increased with fluticasone (OR 1.78, 95%CI 1.50 to 2.12) and budesonide (OR 1.62, 95% CI 1.00 to 2.62). There were no significant differences in serious adverse events or mortality when budesonide and fluticasone were compared indirectly. The risk of any pneumonia event was found to be higher with fluticasone than budesonide (OR 1.86, 95%CI 1.04 to 3.34), but this should be interpreted with caution due to differences in definitions of pneumonia in the trials. The authors recommended that safety concerns regarding increased pneumonia should be balanced against the benefits of reduced exacerbations and improved quality of life (Kew 2014b).

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].

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).