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Over the past number of years many of us have struggled to keep pace with continuing changes in the guidelines produced by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) committee regarding the management of our patients with chronic obstructive pulmonary disease (COPD).
Most readers will be familiar with the block diagram as pictured in Figure 1.
For the purpose of this article I am going to refer to this as the COPD house. This house is made up of four rooms, each inhabited by patients with varying degrees of COPD.
Basically the inhabitants of the rooms downstairs, A and B, have better spirometry readings than those upstairs and the inhabitants of room B have more symptoms than those in room A.
When we analyse recent evidence regarding the management of those patients in rooms A and B we find that many are being prescribed inhaled steroids despite evidence that this may lead to increased occurrence of pneumonia in this group
There is very little evidence in Irish practice for changing patients from inhaled corticosteroids (ICS) to a more appropriate treatment.
Our practice, together with two other large group practices, is currently auditing a cohort of such patients and we intend on presenting our findings to the next meeting of the International Primary Care Respiratory Group.
A quick recap of correct current management of COPD would advise commencing patients in room A on short-acting beta agonists. For the purpose of this article I am deliberately not dealing with the other management essentials – smoking cessation, vaccines, etc.
The international Primary Care Respiratory Group have designed a desktop tool to assist those who wish to step-down steroids as follows:
In COPD, bronchodilation is recommended as first-line treatment for all patients classified as GOLD A or B.
GOLD B patients on monotherapy should step-up to a long-acting beta agonist (LABA) plus long-acting muscarinic antagonist (LAMA) if symptoms persist, and for patients with severe breathlessness, initial therapy with two bronchodilators may be considered.
In the FLAME study, LABA/LAMA combination indacaterol/glycopyrronium was significantly more effective than the LABA/ICS combination salmeterol/fluticasone at preventing COPD exacerbations in patients with a history of exacerbations in the previous year [Wedzicha 2016].
In the LANTERN study, the LABA/LAMA combination indacaterol/glycopyrronium demonstrated superiority over the LABA/ICS combination salmeterol/fluticasone in terms of lung function and significantly reduced the rate of moderate or severe exacerbations in patients with moderate-to-severe COPD and a history of ≥1 exacerbation in the previous year [Zhong 2015].
In the ILLUMINATE study, the LABA/LAMA combination indacaterol/glycopyrronium demonstrated significant improvements in terms of lung function and symptomatic benefit, compared with the LABA/ICS combination salmeterol/fluticasone [Vogelmeier 2013].
Up to 55.6 per cent of patients in primary care are treated with ICS and LABA [Driveness 2014].
Some 52 per cent of GOLD B patients and 39 per cent of GOLD A patients (using GOLD 2011 criteria) were receiving an ICS-containing regimen (US and five European countries) [Vestbo 2014].
About half, 49 per cent, of GOLD 2 patients with no exacerbations in the previous year and 50 per cent of GOLD 2 patients without concomitant asthma were prescribed ICS (UK) [Price 2014].
According to GOLD 2011 criteria, 32 per cent of patients were inappropriately receiving an ICS-containing therapy (France) [Burgel 2014].
ICS, alone or in combination with bronchodilators, was prescribed in 15.2 per cent and 66.8 per cent of patients respectively; ICS treatment was considered inappropriate in 62.1 per cent of patients, according to GOLD 2011 [Corrado 2012].
Among patients prescribed ICS alone or in combination with other therapies, 18.2 per cent were prescribed ICS inappropriately. Physical health status was significantly lower in patients inappropriately prescribed ICS compared with those appropriately prescribed ICS [de Miguel-Díez 2011].
Long-term ICS use is associated with a significant risk of pneumonia [Yawn 2013; Suissa 2013; Kew and Seniukovich 2014] and systemic effects [Price 2013].
ICS use was associated with a dose-related increase in the risk of pneumonia, with adjusted hazard ratios versus no use of 1.38 (low-dose), 1.69 (medium-dose) and 2.57 (high-dose; all p<0.01) [Yawn 2013].
Current use of ICS was associated with a 69 per cent increase in the rate of serious pneumonia (RR 1.69; 95 per cent CI 1.63,1.75). The risk was sustained with long-term use [Suissa 2013].
ICS use was associated with increased risk of serious adverse pneumonia events requiring hospital admission versus placebo (OR 1.78; 95 per cent CI 1.50, 2.12) [Kew and Seniukovich 2014].
The rate of pneumonia was significantly higher in patients receiving treatment with salmeterol/fluticasone compared with placebo (19.6 per cent versus 12.3 per cent respectively; p<0.001) [Calverley 2007].
Pneumonia was reported in 8 per cent and 4 per cent of 1,499 patients treated with salmeterol/fluticasone and tiotropium, respectively. The hazard ratio for time to reported pneumonia was 1.94 (95 per cent CI 1.19, 3.17; p=0.008) for salmeterol/fluticasone compared with tiotropium over two years [Wedzicha 2008].
A meta-analysis of 16 randomised controlled trials (17,513 participants) and seven observational studies (69,000 participants) demonstrated that long-term exposure to fluticasone and budesonide is associated with a significant increase in the risk of fractures [Loke 2011]. Over three years of treatment, each 500µg increase in beclomethasone daily dose equivalents was associated with a 9 per cent increased risk of fractures (95 per cent CI 1.06 to 1.12; p<0.001) [Loke 2011].
ICS use is associated with increases in the risk of diabetes onset and diabetes progression and is more pronounced at higher prescribed doses of ICS [Suissa 2010]. Patients with comorbid COPD and type 2 diabetes mellitus had significantly greater increases in HbA1c values when treated with ICS compared with those prescribed non-ICS therapies (higher HbA1c values are associated with a greater risk of the development of diabetes-related complications).
A reported lack of efficacy of ICS, an elevated risk of adverse effects (including pneumonia) and evidence showing no significant harm from withdrawal supports the recommendation that ICS therapy can be stopped [GOLD 2017].
Results from withdrawal studies provide equivocal evidence for ICS withdrawal: Some, but not all, have shown an increase in exacerbations and/or symptoms following withdrawal, while others have not; there has been evidence for a modest decrease in FEV1 [GOLD 2017]. The use of background long-acting bronchodilator medication may minimise any effect of ICS withdrawal [GOLD 2017]. Discontinuation of ICS was associated with a 37 per cent decrease in the rate of serious pneumonia (RR 0.63; 95 per cent CI 0.60 to 0.66). The risk reduction was rapidly evident, going from 20 per cent in the first month to 50 per cent by the fourth month after discontinuation [SuissaChest 2015].
Recent studies have indicated that ICS can be withdrawn in both low- and high-risk patients, provided adequate bronchodilator therapy is in place [Rossi 2014a; Rossi 2014b; Magnussen 2014].
In INSTEAD, in low-risk patients, there was no significant difference between maintaining treatment with LABA/ICS combination salmeterol/fluticasone propionate and switching to LABA (indacaterol) in terms of breathlessness, health status, rescue medication use, or COPD exacerbations [Rossi 2014a].
In OPTIMO, low-risk patients on ICS plus bronchodilator maintenance therapy experienced no deterioration of lung function symptoms and exacerbation rate upon ICS withdrawal compared with patients continuing ICS treatment [Rossi 2014b].
In WISDOM, in high-risk patients randomly assigned to continued triple therapy or withdraw fluticasone in three steps over a 12-week period, ICS withdrawal met the pre-specified non-inferiority criterion with respect to the first moderate or severe COPD exacerbation (HR 1.06; 95 per cent CI0.94 to 1.19) [Magnussen 2014].
In two post-hoc analyses, data from the WISDOM trial was used to assess whether patients with COPD with higher blood eosinophil counts would be more likely to have exacerbations if ICS treatment was withdrawn and if further stratification was possible when correlating eosinophil levels with exacerbation history. Withdrawal of ICS only increased exacerbation rates in patients with both raised eosinophils (≥400 cells/µL) and a history of frequent exacerbations (≥2) [Calverley 2016].
Based on the evidence presented above, we propose the following steps to identify the minority of patients who might benefit from ICS, and withdraw ICS in patients in whom it is not needed.
How to withdraw ICS in COPD patients who do not need it – key steps and processes
Optimise bronchodilation with dual bronchodilation (LABA plus LAMA). Initiate/continue LABA and LAMA treatment to optimise bronchodilation [Kaplan 2015; Magnussen 2014]. In lower-dose ICS patients, stop ICS and continue with LABA and LAMA alone [Kaplan 2015; Magnussen 2014].
Consultation with monitoring clinician 30 days after ICS step-down/discontinuation (including assessment of pulmonary function using spirometry). Patients should be encouraged to contact their physician should their condition worsen and/or an exacerbation occur within this time.
Follow-up with monitoring clinician after six months for full clinical review. See the patient twice yearly during the first year of ICS withdrawal. Patient should be encouraged to contact the physician earlier should their condition worsen and/or an exacerbation occur within this time [Kaplan 2015]. Follow with an annual review if the patient’s COPD is stable and exacerbation-free [Kaplan 2015].
Reassess potential for ICS use, if moderate or severe exacerbations occur, airflow limitation worsens or blood eosinophils become elevated COPD exacerbation following ICS withdrawal does not necessarily indicate a causal effect. 0.91; P<0.001) [Wedzicha 2016].
References on request