Medicines for chronic obstructive airway diseases
Type | Recommendation |
---|---|
When to deprescribe in COPD | |
CBR |
Given the risk of adverse effects associated with prolonged ICS treatment potentially outweighing the benefits in people at low risk of COPD exacerbation, we suggest deprescribing of inhaled corticosteroids (ICS) be offered to older people who have been using triple therapy (long-acting muscarinic antagonist + long-acting beta2-agonist + ICS) for stable chronic obstructive pulmonary disease (COPD) without a severe exacerbation requiring hospitalisation, or less than two moderate exacerbations in the past 12 months. |
Ongoing treatment in COPD | |
CBR | We suggest continuing maintenance therapy as appropriate with a long-acting bronchodilator(s) (e.g. long-acting muscarinic antagonist, long-acting beta2 agonist), either as monotherapy or in combination depending on symptomatic response. |
How to deprescribe in COPD | |
CBR |
We suggest individualised deprescribing based on the individual's preference. In general, we suggest discontinuing ICS without the need for tapering; however, some people may prefer a gradual stepwise reduction. |
GPS |
Healthcare providers should regularly check inhaler techniques and adherence, especially if symptoms remain persistent (ungraded good practice statement). |
GPS |
In severe disease, consideration should be given to which inhaler is used (i.e. insufficient airflow to utilise a dry powder Ellipta device vs. a jet Respimat device) (ungraded good practice statement). |
GPS |
Healthcare providers should consider and offer adequate education on lifestyle interventions (e.g. smoking cessation, nutrition, alcohol, physical activity) to individuals as appropriate (ungraded good practice statement). |
GPS |
Pulmonary rehabilitation should be offered to all people with COPD and may result in significant quality of life and symptom improvements to offset any anxiety around deprescribing (ungraded good practice statement). |
Monitoring in COPD | |
CBR |
We suggest monitoring lung function using a spirometry test three to six months after deprescribing, or sooner if clinical deterioration. |
CBR |
We suggest closely monitoring for changes in symptoms and quality of life every six weeks for the first six months after deprescribing, then monitoring for exacerbation frequency every six months thereafter, with cough and shortness of breath most likely for the first three months of withdrawal. |
CBR, consensus-based recommendation
Chronic Obstructive Pulmonary Disease (COPD)
ICS, in combination with a long-acting bronchodilator, are widely used in the treatment of COPD. ICS can reduce respiratory exacerbation frequency in patients with severe COPD or concomitant asthma and may improve quality of life in those with forced expiratory volume (FEV1) < 50% [177, 721]. Guidelines recommend adding ICS to long-acting bronchodilators (“triple therapy”) in patients with a severe exacerbation (requiring hospitalisation) or at least two moderate exacerbations in the previous 12 months, and significant symptoms despite LAMA+LABA therapy [177, 722, 723].
Asthma
This guideline does not include recommendations for deprescribing in the context of adult asthma management, as the evidence identified for deprescribing is limited to COPD and the therapy adjustment strategies for asthma management in adults (i.e. stepping up or stepping down therapy) is part of standard practice. Healthcare providers are encouraged to refer to existing clinical resources, including but not limited to the Australian Asthma Handbook, Therapeutic Guidelines, and the Global Initiative for Asthma (GINA) guidance, as appropriate [724-726].
Inhaled short-acting beta2 agonists (salbutamol, terbutaline) or budesonide with formoterol is used when required for acute symptomatic relief in asthma, whereas inhaled corticosteroids (ICS) form the cornerstone of preventive treatment. Most individuals with asthma require ICS as maintenance therapy, as they improve lung function and quality of life while reducing airway hyper-responsiveness, inflammation, exacerbation frequency and severity, and the risk of asthma-related death [177]. The role of theophyllines is limited in the management of obstructive pulmonary diseases due to the narrow therapeutic range and possible severe adverse effects including on the cardiovascular system [727].
Many patients remain on the same asthma medicines for years, often at higher-than-necessary doses for symptom control. Current evidence of the dose-response relationship of ICS in adult asthma showed that 80-90% of the maximum achievable efficacy of ICS are obtained in adult asthma with a standard daily dose (defined as 200-250 µg/day of fluticasone propionate or equivalent) across the spectrum of severity [728]. Higher ICS doses result in an increased risk of systemic adverse effects with limited additional benefits [728]. A cohort study found that many individuals were prescribed medium to high doses of ICS, either alone or in combination with add-on therapies such as long-acting β-agonists (LABAs), leukotriene receptor antagonists, theophylline, or long-acting muscarinic antagonists [729]. Notably, half of these patients had neither a reliever prescription nor an exacerbation in the preceding year.
The management of asthma is introduced in a stepwise manner and the stepping-down approach is standard practice [724-726, 730]. Current guidelines recommend stepping down to the minimum effective dose or discontinuing ICS therapy once good asthma control has been achieved for two to three months in adults [177, 730]. In people with severe asthma (defined as asthma that remains uncontrolled despite adherence to optimised treatment and management of contributing factors, or that worsens when high-dose therapy is reduced [731]), any dose reduction should ideally be undertaken in consultation with a respiratory specialist [730].
Overlap of asthma and COPD
People with overlapping of asthma and COPD typically have more rapid disease progression, high symptom burden, worse quality of life, and more frequent and severe exacerbations than those with either condition alone [723]. Specialist input is required for managing asthma-COPD overlap due to limited evidence and varying management approaches.
Refer to the narrative evidence summary, the GRADE Summary of Findings table in the guidelines, and the Technical Report for a complete presentation of the deprescribing evidence based on the GRADE framework (including other factors considered in developing the recommendations).
ICS are often overprescribed in COPD and are not recommended for people with mild disease or those at low risk of exacerbations. Guidelines recommend adding ICS to long-acting bronchodilators (“triple therapy”) in patients with a severe exacerbation (requiring hospitalisation) or at least two moderate exacerbations in the previous 12 months, and significant symptoms despite LAMA+LABA therapy [177, 722, 723]. The use of ICS is associated with an increased risk of pneumonia, cataracts, osteoporosis, oral candidiasis, and potentially impaired glucose tolerance [177, 721]. At high doses (e.g. beclomethasone dipropionate 1000-2250 mcg/day), older people may also be at risk of skin thinning and bruising [177]. The decision to use ICS must be carefully balanced against the potential risks, with the risk increases with prolonged use. If there is no clear indication or demonstrated benefit, deprescribing ICS may be safe, provided long-acting bronchodilator therapy, such as a LABA, a long-acting muscarinic antagonist (LAMA), or both, is maintained [721].
We identified seven studies (two double-blind RCTs, one cross-over RCT, two before-and-after studies, and two prospective cohort studies) related to the deprescribing of ICS or tiotropium in people with COPD from the systematic review and meta-analysis [732-738].
Overall, the evidence supporting deprescribing is of low and very low certainty, and only for people with COPD who were either current or ex-smokers. No evidence was found for other medicines used in the management of asthma. One cohort study reported an increased risk of exacerbation in people who discontinued ICS compared with those who had never been treated with ICS; however, this finding had very low certainty due to methodological limitations. Most studies indicated that deprescribing ICS in patients with stable COPD, who had not experienced a recent exacerbation (e.g. within the last 12 months), was safe and did not lead to COPD exacerbations. However, there is a lack of quality evidence to inform evidence-based recommendations. If ICS discontinuation is considered appropriate, close, periodic monitoring of lung function (e.g. spirometry), as well as monitoring changes in symptoms and quality of life, is necessary. Monitoring could be undertaken every six weeks for the first six months after deprescribing, followed by monitoring exacerbation frequency every six months thereafter. It may be helpful to provide examples of common symptoms when encouraging individuals to self-monitor and report symptoms to their healthcare providers. As some symptoms are non-specific, many people may not recognise that they could be indicative of a disease exacerbation.
Key study characteristics and results
A narrative summary of each study is provided below, highlighting key characteristics and main findings.
O'Brien 2001 conducted a double-blind cross-over RCT that randomised 24 men using inhaled beclomethasone dipropionate with stable but severe irreversible airflow obstruction to deprescribing (placebo inhaler) or continued therapy with a six-week follow-up [736]. All 24 participants were either current or ex-smokers. There was no significant difference in the mean percentage change in the forced vital capacity (FVC) between the baseline and the placebo period (-3.60%, 95% CI -8.87, 1.67) and between baseline and the treatment period (3.23%, 95% CI -3.08, 9.55). There was a significant reduction in the mean percentage change in FEV1 between the baseline and the placebo period (-6.28%, 95% CI -12.04, -0.52) but no significant difference between the baseline and the treatment period (5.03%, 95% CI -3.89, 13.95). Comparing placebo and treatment periods, there were also no significant differences in COPD exacerbations, exercise-induced dyspnea measured using the T Borg scale assessment of dyspnoea, distance walked during the 6-minute walk test, fatigue, emotional function and mastery measured using the Chronic Respiratory Disease Questionnaire.
Choudhury 2007 randomised 260 primary care patients with COPD to either a placebo group (n=132) or an active group, 500mcg fluticasone propionate twice daily (n=128), in a double-blind RCT [734]. To be eligible, participants must have a history of smoking and have been using an ICS regularly (> three days a week) for at least six months. Those with a chronic active lung disease or lung cancer were excluded. There was no significant difference in the frequency of exacerbations in the placebo group compared to the active group receiving ICS (MD 0.21, 95% CI -0.47 to 0.89). Three COPD-related deaths occurred in the active group (OR 0.14, 95% CI 0.01 to 2.65). At 12 months, there were no significant differences in adverse drug effects associated with ICS (sore throat, oral thrush, hoarseness of voice, skin bruising, skin thinning) and quality of life (measured using EuroQol 5-D total and visual analogue scale) between the two groups.
Borrill 2009 randomised 14 participants with moderate COPD without a recent history of exacerbation to the continuation of ICS/LABA combination therapy (n = 5) or placebo inhaler (n=9) [733]. Participants were included if their postbronchodilator FEV1 was between 50 to 80% of the predicted value, FEV1/FVC ratio was < 70%, they were using a stable dose of 500 to 1,000 mcg fluticasone propionate per day, salmeterol 100 mcg per day, and are current or ex-smokers. Participants were excluded if they had a history of more than one COPD exacerbation in the 12 months prior that requiring oral corticosteroids or a history of COPD exacerbation requiring ICU admission or intubation. At six weeks, there was an increase in airway neutrophils (16.5%, p = 0.03) indicating increased airway inflammation and a significant decrease in FEV1 (0.35 L, p = 0.017) in the placebo group. However, there was no significant difference in the frequency of exacerbations (4/5 intervention vs 0/9 control; OR 9.00, 95% CI 0.38, 210.39) between the two groups.
Jarad 1999 conducted an open-label prospective cohort study that compared COPD who withdrew regular ICS (n=160) with COPD patients who were naïve to ICS (n=112) [735]. Participants were included if they were clinically stable for at least 3 months before study entry. Participants in the regular ICS group were using a median daily dose of 800 mcg (range 50-2400) as either beclomethasone dipropionate or budesonide). Their ICS were withdrawn over one week. In the following seven weeks, exacerbations appeared to be more common among participants who had withdrawn ICS (38%) compared to those who had never been treated (6%), although there were multiple potential confounding factors.
Patel 2022 conducted a cohort study that included 11,093 patients with COPD who were using ICS for 12 months or more and withdrew at least once during the study period [737]. During the period without ICS, exacerbations, COPD-related hospitalisation, pneumonia or pneumonia episodes were 31%, 11%, 13%, and 7% respectively. Among patients who were prescribed long-acting bronchodilator maintenance therapy during the ICS withdrawal period, 2965/3849 (77%) received a long-acting muscarinic antagonist (LAMA) monotherapy. In comparison to patients receiving monotherapy of either LAMA or LABA, those who were receiving fixed doses of dual LAMA/LABA therapy on average were able to remain without ICS for longer.
Steeves 2024 conducted a retrospective cohort study involving 75 patients with COPD who had been prescribed a stable dose of ICS for at least one year that was subsequently discontinued during the study observation period [738]. The majority of patients were using budesonide/formoterol as their ICS inhaler, with one patient receiving mometasone monotherapy. Most participants (57/75, 75%) were on a medium ICS dose, defined as 400-800 mcg of budesonide or 440 mcg of mometasone, while the remaining patients were on a low dose (200-400 mcg of budesonide or 110-220 mcg of mometasone). Patients were excluded if they had concurrent asthma, used multiple ICS inhalers or nebulisers, or had significant oral steroid use (≥ 5 mg prednisone per day or equivalent for > six weeks) within 12 months of ICS discontinuation. Those with a congestive heart failure exacerbation in the two years prior to ICS discontinuation, a COVID-19 infection up to one year before or six months after ICS discontinuation, or a severe COPD exacerbation requiring hospitalisation within two years prior to ICS discontinuation were also excluded. The study found that within 12 months of ICS discontinuation, five patients (7%) experienced a COPD exacerbation requiring an emergency department visit or hospitalisation, with a mean time to event of approximately six months.
In addition to ICS deprescribing, we identified one study related to tiotropium deprescribing. Adams 2009 conducted a 3-week post-hoc evaluation that included 713 participants previously involved in an RCT [732]. All participants had clinically stable COPD, smoking history, FEV1 of at least 65% of predicted normal values, and at least 70% FVC. Participants were excluded if their total blood eosinophil count was >600 cells/mm3, needed daytime supplemental oxygen regularly, or were taking the equivalent of 10 mg prednisone or more daily in the last month. In this post-hoc study, participants either had their tiotropium discontinued (n=445) or placebo discontinued (n=268). After three weeks, there were no significant differences between the two groups in Transition Dyspnea Index Focal score, peak expiratory flow rate, and quality of life.
Different methods were used for deprescribing in the included studies and there was no direct evidence that any particular method was associated with the greatest benefits and harms. Either method is likely to be acceptable to patients. Given the relatively low rates of COPD exacerbations requiring an emergency department visit or hospitalisation following ICS discontinuation, abrupt discontinuation may be a suitable option for most patients who are unlikely to benefit from continued use. However, individual preferences and factors should be considered as part of the shared decision-making.
ICS were abruptly ceased in one RCT (n= 260, low certainty) [734], withdrawn over one week based on the participant's own discretion in another RCT (n=272, very low certainty) [735], and the method was not described in the other four studies (n=12052) [731-733, 736]. In Steeves 2024, the majority of patients (66/75, 88%) discontinued ICS abruptly, while nine (12%) underwent a gradual taper using various tapering regimens [738]. All five COPD exacerbations requiring an emergency department visit or hospitalisation following ICS discontinuation occurred in patients who discontinued abruptly. However, due to the low event rate and small sample size, statistical significance could not be determined.