Inhaled corticosteroids for chronic obstructive pulmonary diseaseBMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e6843 (Published 25 October 2012) Cite this as: BMJ 2012;345:e6843
- Hye Yun Park, visiting research fellow,
- S F Paul Man, professor of medicine,
- Don D Sin, professor of medicine
- 1Institute of Heart and Lung Health (UBC James Hogg Research Center), St Paul’s Hospital, Vancouver, BC, Canada
- 2Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Seoul, South Korea
- 3Department of Medicine (Respiratory Division), University of British Columbia, Vancouver, BC, Canada
- Correspondence to: D D Sin, St Paul’s Hospital, 1081 Burrard Street, Vancouver, BC, Canada, V6Z 1Y6
A 65 year old female former smoker presents to your practice with gradually worsening shortness of breath while walking up a flight of stairs and a daily cough, productive of small amounts of white phlegm. She has a smoking history of 20 cigarettes a day for 20 years and chronic obstructive pulmonary disease (COPD). Her breathlessness had gradually worsened since an influenza-like illness six months ago, which was treated with a two week course of oral prednisolone and antibiotics. Since the illness she has used inhaled tiotropium 18 µg once daily and inhaled salbutamol as needed. Spirometry at the general practice shows a forced expiratory volume in one second (FEV1) of 63% predicted and a ratio of FEV1 to forced vital capacity of 0.65 after use of a bronchodilator. These values have not changed significantly over the previous year. As she is still symptomatic, her general practitioner recommends stopping tiotropium and starting a combination inhaler of a corticosteroid and a long acting β2 agonist.
What are inhaled corticosteroids?
Inhaled corticosteroids are glucocorticoids that bind to the glucocorticoid receptors in the airways and cause a reduction in lung inflammation.1 They are taken via metered dose inhalers or dry powder inhalers. The most commonly used inhaled corticosteroids in COPD are fluticasone propionate, budesonide, and beclometasone dipropionate (table 1⇓).
How well do inhaled corticosteroids work in COPD?
The role of inhaled corticosteroids in COPD is controversial. However, on the basis of current evidence, using them as monotherapy cannot be recommended for most patients with this condition. The effect of such monotherapy in relieving dyspnoea and improving lung function is modest and weaker than that of long acting bronchodilators.2 Inhaled corticosteroids also reduce the risk of exacerbations without affecting mortality or the rate of decline in lung function, and with significant adverse effects (see below). In the largest and longest trial to date, monotherapy with inhaled corticosteroids in patients with moderate to severe COPD was associated with an 18% relative reduction in the risk of exacerbations (requiring systemic corticosteroids or antibiotics) compared with placebo (table 2⇓).3
Clinical guidelines suggest the use of inhaled corticosteroids as an add-on therapy to long acting bronchodilators in symptomatic patients with severe airflow limitation (defined as an FEV1 of <50% predicted) or with two or more exacerbations a year irrespective of the FEV1 value (table 2⇑).8 9 This recommendation is based on a large body of high quality randomised clinical trials, which have shown that inhaled corticosteroids reduce the risk of exacerbations by 10-20% beyond that achieved by inhaled long acting β2 agonists.2 3 4 5 7 Overall, the number needed to treat to prevent one exacerbation with inhaled corticosteroids as add-on therapy for one year is about 6.10 Inhaled corticosteroids have also been shown to improve breathlessness and health related quality of life, as measured by the St George’s Respiratory Questionnaire (SGRQ), beyond that achieved with a long acting β2 agonist.3 Whether combinations of long acting β2 agonists plus inhaled corticosteroids slow the rate of decline in lung function is controversial, and any improvement in this outcome is unlikely to be clinically significant. The benefits of such combination treatment on total and COPD mortality are uncertain (table 1⇑ summarises the currently available treatment combinations for COPD).
COPD is now recognised as a heterogeneous disease, with multiple phenotypes. Some COPD phenotypes may be more responsive to inhaled corticosteroid treatment than others. For example, COPD patients presenting with features of asthma such as bronchial hyper-responsiveness,11 sputum eosinophilia, or peripheral eosinophilia have larger (short term) clinical responses to oral12 13 and inhaled corticosteroid treatments14 than patients without these features. However, the long term effects of inhaled corticosteroids in the “asthmatic” phenotype of COPD are not well known.
How safe are inhaled corticosteroids?
The use of inhaled corticosteroids is associated with increased risk of hoarseness (2% increase for each year of use), oral candidiasis (9%), and cough (4%).15 The risks of these adverse effects can be attenuated with proper inhaler techniques and use of a spacer (for metered dose inhalers) (see below).
Systemic adverse effects
Observational studies have suggested that long term use of inhaled corticosteroids is associated with increased risk of bone demineralisation, osteoporosis, and fracture. However, randomised controlled trials have shown mixed results in COPD. The use of inhaled triamcinolone for 40 months in the Lung Health Study resulted in accelerated bone demineralisation compared with placebo, with patients in the inhaled triamcinolone arm experiencing an additional decline of 0.59% a year in bone mineral density in the femoral neck and an additional decline of 0.44% a year in bone mineral density in the lumbar spine.16 In contrast, accelerated bone demineralisation was not noted with the use of fluticasone proprionate (via a dry powder inhaler, Diskus) over three years in the TORCH (Towards a Revolution in COPD Health) study17 or with the use of budesonide (via a dry powder inhaler, Turbuhaler) in another three year study.18 The discordance in data may reflect differences in the drugs, delivery devices (metered dose inhaler versus dry power inhalers), and the severity of airflow limitation of the study participants. Other potential systemic adverse effects of inhaled corticosteroids include skin bruising (1% increase for each year of use), and cataracts (<1%).
Pneumonia deserves special consideration because in 2009 the US Food and Drug Administration issued a “black box” pneumonia warning for all inhaled corticosteroid products used in COPD, on the basis of findings from several randomised clinical trials (table 3⇓). The warning requires all manufacturers of these drugs to add a box label indicating that the drug has a significant risk of serious or even life threatening adverse effects. Although some researchers remain doubtful that pneumonia is a true adverse effect—as pneumonia can be easily confused with COPD exacerbations—many clinical trials have shown an increased risk of pneumonia (even those confirmed with a chest radiograph) related to fluticasone Diskus treatment (including trials using 250 µg twice daily or trials using 500 µg twice daily), with an increase in relative risk of about 50%.25 26 The number needed to harm for serious pneumonia related to inhaled corticosteroids taken for a year is estimated to be 47.25 However, for unknown reasons, fluticasone delivered via metered dose inhaler6 or budesonide via dry powder inhaler has not been consistently associated with an increased risk of pneumonia.27
What are the precautions?
There are no absolute contraindications to the use of inhaled corticosteroids. However, they should be used cautiously in patients with pre-existing osteopaenia or osteoporosis and in those who have had pneumonia. Inhaled corticosteroids are largely metabolised in the liver via the cytochrome p450 (CYP) system (CYP3A4). Thus inhaled corticosteroids should be used cautiously or even avoided in patients who are using medications that interfere with the CYP3A4 enzyme, such as ritonavir or itraconazole, because such patients can develop adrenal suppression or Cushing’s syndrome.28
How cost effective are the combination treatments?
In one study, the incremental cost effectiveness of fluticasone propionate plus salmeterol versus salmeterol alone was €679.50 (£550; $880) per exacerbation avoided and €3.30 per symptom-free day.29 In another study involving 42 countries across five world regions, the cost effectiveness of combinations of inhaled corticosteroids plus long acting β2 agonists was $43 600 and $26 500 per quality adjusted life years gained compared with placebo or salmeterol respectively.30
How are inhaled corticosteroids taken and monitored?
Whether using metered dose or dry powder inhalers, proper inhaler techniques (figure⇓) are needed to optimise drug delivery to all airways and especially to the small airways (which are the predominant site of disease in COPD) and to reduce the risk of local and systemic adverse effects. With good inhaler techniques, 10-20% of the drugs in metered dose inhalers (and 15-30% from dry powder inhalers) reach the lungs of patients, with the rest deposited in the posterior pharynx or swallowed.1
Ingested drugs are absorbed in the gastrointestinal tract and undergo “first pass” metabolism in the liver, becoming inactivated. Fluticasone propionate is nearly fully metabolised through this process, whereas 80-90% of budesonide and beclometasone dipropionate undergoes first pass metabolism.1 Improper inhaler techniques, however, can lead to inadequate deposition in the lungs and increased deposition in the oropharynx, causing local irritation (resulting in cough, sore throat, hoarseness) and greater gastrointestinal absorption (and thus more systemic adverse effects).
Spacer devices, which are used with metered dose inhalers, are helpful in maximising drug delivery of inhaled corticosteroids and reducing local and systemic adverse effects especially for older and more frail patients, who have trouble with coordination.15 Patients should be advised to rinse their mouth and discard the rinse solution after using inhaled corticosteroids, to minimise throat irritation and prevent oral candidiasis.
At every follow-up visit, monitor the patient for proper inhaler technique, adherence to medications, and any signs of adverse effects.9 This monitoring includes careful clinical examination of the oropharynx for candidiasis (for example, for creamy yellow or yellow plaques or fiery red patches) and skin for bruises at every visit. For those who present with cough or fever, arrange plain (frontal) chest radiography to check for pneumonic opacities; for those with diabetes, obtain fasting serum glucose concentrations (or haemoglobin A1C concentrations) once or twice a year; and for those with a previous history of fracture, osteopenia, or osteoporosis, arrange bone densitometry measurements periodically (such as every two years). Because inhaled corticosteroids are a “controller” medication (their aim is to reduce exacerbations), patients may not report any noticeable improvements in symptoms or show changes in lung function at follow-up. Therefore assess effectiveness by determining the frequency and severity of exacerbations before and after treatment with inhaled corticosteroids. As exacerbations can vary from one season to another (for example, worse in winter) and from year to year, several years of observation may be necessary to assess adequately the effectiveness of inhaled corticosteroids. In patients who experience repeated exacerbations (that is, two or more exacerbations a year) but who develop pneumonia while taking inhaled corticosteroids, consider alternative drug treatments (such as a combination of long acting β-2 agonists and long acting antimuscarinics.8
How do the combination treatments compare with other drugs?
The combination treatment of long acting β2 agonists plus inhaled corticosteroids has also been compared against monotherapy with tiotropium, which is an inhaled long acting muscarinic antagonist. The largest trial to date indicates that treatment with long acting β2 agonists plus inhaled corticosteroids does not reduce the exacerbation rate beyond that achieved by tiotropium.24 In this study, total mortality was lower, although rates of pneumonia were higher, in the group taking long acting β2 agonists plus inhaled corticosteroids than in the tiotropium group.24 A large prospective trial powered on these endpoints is needed to determine the significance of these events.
A randomised controlled trial evaluating the addition of fluticasone propionate plus salmeterol to tiotropium over one year found that the exacerbation rates were similar among those assigned to tiotropium plus fluticasone propionate and salmeterol (sometimes referred to as “triple” therapy) and those assigned to tiotropium alone.23 However, rates of hospital admission for COPD and of quality of life improved with the addition of long acting β2 agonists plus inhaled corticosteroids. Other studies have shown superior bronchodilation and lower exacerbation rates with triple therapy than with tiotropium.31 32 A larger clinical trial is needed to clarify the role of long acting β2 agonists plus inhaled corticosteroids combined with long acting muscarinic antagonists on clinical endpoints such as exacerbation and quality of life. Until then, triple therapy cannot be recommended for patients, except for those with severe airflow limitation (FEV1 <50% of predicted) who have had a recent hospital admission for COPD.
Returning to the case scenario, the current evidence suggests that there is no significant therapeutic advantage in replacing inhaled tiotropium with a combination inhaler of a corticosteroid and a long acting β2 agonist, because the patient has had only one exacerbation or flare-up over the previous year and so is unlikely to benefit from an inhaled corticosteroid. The primary concern in this patient is worsening dyspnoea, which can be treated by adding an inhaled long acting β2 agonist to the tiotropium treatment and by exercise training through a well established pulmonary rehabilitation programme.8
Tips for patients
Inhaled corticosteroids are anti-inflammatory drugs that can be used in people with chronic obstructive pulmonary disease (COPD) who have repeated chest infections or “exacerbations” (sometimes also called “lung attacks”)
These drugs work best when combined with another drug (called long acting β2 agonists) to reduce the risk of exacerbations. Inhaled corticosteroids are rarely used by themselves for people with COPD
Because inhaled corticosteroids are delivered to the lungs through an inhaler, you must learn the correct inhaler techniques. Poor inhaler technique can increase the risk of bad side effects, such as hoarseness, sore throat, and oral thrush
It is very important to always rinse and gargle with water or mouthwash (“swish and spit”) after using your corticosteroid inhaler, to reduce the bad side effects
You can refer to a checklist on how to use an inhaler device correctly—see the figure⇑ in this article or go to www.nationalasthma.org.au/uploads/content/237-Inhaler_technique_in_adults_with_asthma_or_COPD.pdf)
Inhaled corticosteroids can also increase the risk of pneumonia, so if you develop a fever or productive cough, with coloured (usually green) phlegm, report these symptoms immediately to your doctor
Inhaled corticosteroids can also cause skin bruising and fragile, thin skin. If you see these signs, report them to your doctor
Cite this as: BMJ 2012;345:e6843
This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Albert Ferro, professor of cardiovascular clinical pharmacology, King’s College London. To suggest a topic for this series, please email us at.
DDS is a Canada Research Chair in chronic obstructive pulmonary disease.
Contributors: All authors contributed to the planning, drafting, revising, and final approval of the manuscript. DDS is the guarantor.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work. DDS has served on advisory boards of Merck, Takeda, and Novartis; has received honorariums for speaking engagements for GlaxoSmithKline, AstraZeneca, and Pfizer; and his institution has received research funding from AstraZeneca for an investigator initiated grant to evaluate novel blood biomarkers in COPD. The authors have no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient consent not required (patient anonymised, dead, or hypothetical).