Download Chronic Obstructive Pulmonary Disease Vol 19 No 4 2013

National Medicines
Information Centre
VOLUME 19
NUMBER 4
2013
ST. JAMES’S HOSPITAL • DUBLIN 8
TEL 01-4730589 or 1850-727-727 • FAX 01-4730596 • www.nmic.ie
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death worldwide
The assessment of COPD should include the degree of airflow limitation, the severity of
symptoms and the risk of future exacerbations
Smoking cessation is the intervention which has the greatest capacity to influence the natural
progression of COPD
Pharmacological treatment should be individualised to the patient and regularly reviewed for
effectiveness and technique
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable condition, which is characterised by chronic
slowly progressive airway obstruction.1-3 COPD is now the preferred term for patients with airflow obstruction who were
previously diagnosed with chronic bronchitis or emphysema.4 It is a major cause of morbidity and the 4th leading cause
of death worldwide; it is expected to be the 3rd leading cause of death by 2020.1,5 It is considered that there is widespread
under-recognition and under-diagnosis of COPD.1,6 Studies in Europe estimate the prevalence of COPD to be approximately
10%, however it varies considerably between European countries.6 Ireland has the highest rate of admissions for exacerbations
of COPD in the Organisation for Economic Co-operation and Development (OECD) countries.7 COPD is more common in
older people; European studies in people aged >70 years showed a prevalence of COPD of 20% in men and 15% in women.6
COPD is associated with a significant economic burden in terms of the direct medical costs associated with it and the care
provided by family members to patients with COPD.1,5,6 The Global Initiative for Chronic Obstructive Lung Disease (GOLD),
which was established to increase the awareness of the burden of COPD and to improve prevention and management, published
updated guidelines for the management of COPD in 2013.1 Guidelines have also been published by other groups including the
National Institute for Health and Care Excellence (NICE).4 This bulletin will provide an update on the management of COPD.
PATHOPHYSIOLOGY
Inhaled cigarette smoke and other noxious particles cause an inflammatory response which induces parenchymal tissue destruction
and narrowing of the peripheral airways leading to progressive airflow obstruction.1,4 Significant airflow obstruction may be
present before the patient is aware of it.4 In affected individuals lung function deteriorates progressively over several years,
with increasing symptoms such as cough, sputum production and dyspnoea.8 Exacerbations of COPD, defined as increased
cough, dyspnoea or sputum production, are triggered by factors including infection (bacterial and/or viral) and environmental
pollutants. Frequent exacerbations are associated with a more rapid decline in lung function.8 Pulmonary hypertension
may develop late in the course of COPD due to hypoxic constriction of small pulmonary arteries; this may progress to right
ventricular hypertrophy and cor pulmonale. Many patients with COPD have co-morbidities that have a major impact on quality
of life and survival, such as ischaemic heart disease, heart failure, osteoporosis and depression.1,8
The prevalence of COPD is directly related to the prevalence of cigarette smoking and the result of cumulative exposure
over decades, however, not all people with the same smoking history will develop COPD.1 Other risk factors for COPD include
older age, occupational exposure to noxious particles, passive exposure to cigarette smoke, early childhood lung infections
and alpha-1 antitrypsin deficiency.
DIAGNOSIS and ASSESSMENT
Diagnosis: A clinical diagnosis of COPD should be considered in any patient > 35 years with risk factors for COPD, and
symptoms that include dyspnoea, chronic cough or sputum production.1,4 The diagnosis of COPD is based on a combination
of history and physical examination with confirmation of the diagnosis using spirometry.1,4 Spirometry measures the volume
of air forcibly exhaled from the point of maximal inspiration (FVC - forced vital capacity) and the volume of air exhaled
during the 1st second of this manoeuvre (FEV1 - forced expiratory volume in one second); the ratio of these two measurements
(FEV1/FVC) is calculated. The presence of a post-bronchodilator FEV1/FVC < 0.70 confirms the presence of persistent
airflow limitation of COPD.1,4 In addition to spirometry, patients require a chest x-ray to exclude other conditions such as
lung cancer and tuberculosis.4 Additional investigations may include serial peak flow measurements (to exclude asthma, which
is frequently indistinguishable from COPD), ECG and echocardiography (to assess cardiac status if there are clinical features
of cor pulmonale) and alpha-1 antitrypsin deficiency (if early onset, minimal smoking history or positive family history).4
Assessment of a patient with COPD is based on the severity of airflow limitation, the severity of symptoms and the patient’s risk
of future exacerbations.1,4,9 The patient’s risk of exacerbations is assessed by spirometry to determine the GOLD classification
of airflow limitation (table 1) and by assessing the number of exacerbations in the previous 12 months. The risk of exacerbation
increases in patients with a history of frequent exacerbations (≥2 per year) and worsening airflow limitation.1 There are several
validated questionnaires which are used to assess patients’ symptoms in COPD, including the COPD Assessment Test (CAT)
(range 0-40) available on http://catestonline.org and the modified Medical Research Council (mMRC) questionnaire (range
0-4).1,10 GOLD classifies patients with COPD into different groups (A-D) depending on their level of future exacerbation risk
and symptoms as shown in table 2. This classification guides the management of COPD (see later section).
Table 1: Classification of severity of airflow
Table 2: Assessment of patients with COPD1
limitation in COPD according to GOLD1
Patient
Exacerbations
Spirometric
GOLD 1
GOLD 2
GOLD 3
GOLD 4
In patients with FEV1/FVC < 0.70
Mild
FEV1 ≥80% predicted
Moderate 50% ≤ FEV1 < 80% predicted
Severe
30% ≤ FEV1 < 50% predicted
Very severe FEV1 < 30% predicted
GOLD - Global Initiative for Chronic Obstructive Lung
Disease, FEV1/FVC - forced expiratory volume in one second/
forced vital capacity
Category
A
B
C
D
Characteristics
Low Risk, Less Symptoms
Low Risk, More Symptoms
High Risk, Less Symptoms
High Risk, More Symptoms
Classification
GOLD 1-2
GOLD 1-2
GOLD 3-4
GOLD 3-4
GOLD - Global Initiative for Chronic Obstructive Lung Disease
≤1
≤1
≥2
≥2
per year
MANAGEMENT
The main goals in the management of COPD are to improve the patient’s health by: (1) reducing symptoms, (2) reducing the
rate of lung function decline, (3) preventing exacerbations and (4) reducing mortality.1,8 A multidisciplinary approach involving
non-pharmacological and pharmacological treatment is recommended for the optimal management of a patient with COPD.4
The National COPD programme is working towards establishing an improved national model of care with combined hospital
and community based initiatives such as COPD outreach and pulmonary rehabilitation programmes.2 Patients with COPD
frequently have other co-morbidities (such as cardiovascular disease, osteoporosis, depression and lung cancer) associated with
either smoking or ageing, which should also be managed.1
Non-pharmacological treatment
Smoking cessation is the intervention which has the greatest capacity to influence the natural history of COPD and is
the key intervention for people who continue to smoke.1,4,8,11 The delivery of smoking cessation messages and interventions
to stop smoking can result in 25% long-term quit rates; they should be offered to all smokers visiting a health care professional,
even if the visit is unrelated to COPD.1 Pharmacotherapeutic agents should be offered to aid smoking cessation – see below.
Patient education is an essential aspect of COPD management. Patients should have a self management plan with advice on
how to prevent exacerbations and actions in the event of one occurring.1,4 Physical activity is recommended for all patients with
COPD.1 The Irish Thoracic Society has a useful website for patients and healthcare professionals, “Living with COPD”
(http://www.livingwithcopd.ie/),12 which can also be accessed from the COPD Support Ireland website (www.COPD.ie).13
Pulmonary rehabilitation programmes have been shown to have a number of benefits in patients with COPD, including
reduced dyspnoea, improved exercise capacity, improved health related quality of life (HRQoL), reduced number and duration of
hospitalisations and improved survival.1,4,9,14,15 A number of pulmonary rehabilitation programmes have been set up nationally.2,16
Long-term administration of oxygen therapy (LTOT) (> 15 hours per day) in patients with chronic respiratory failure has been
shown to increase survival in patients with severe resting hypoxaemia.1,8 LTOT is indicated for patients who have a PaO2 ≤7.3
kPa or a PaO2 of 7.3-8.0 kPa with evidence of pulmonary hypertension, peripheral oedema with congestive cardiac failure or
polycythaemia, when assessed on two separate occasions.1,4,8 Patients commenced on LTOT should be reviewed at least yearly to
monitor compliance, education and prescription needs. Non-invasive positive pressure ventilation (NIV) is increasingly being
used in patients with stable very severe COPD, who may have required assisted ventilation during an exacerbation.1 It may be
useful in a subset of patients in combination with LTOT. It has been associated with improved survival but not improved HRQoL.1
Pharmacological Management
None of the existing pharmacological agents has been shown to modify the long-term decline in lung function associated with
COPD, however appropriate therapy can reduce COPD symptoms, reduce the frequency and severity of exacerbations and
improve health status and exercise tolerance.1 Tables 3 and 4 outline the most commonly used medicines in the management of
COPD. Inhaled therapy whenever possible is the preferred route in stable COPD.1
Table 3: Currently authorised inhaled medications for COPD
Inhaler device types and
dosage
(microgram)
Short-acting beta2 agonists (SABA)17-19
Salbutamol **, ***, **** MDI (100, 200)
DPI (100, 200)
Terbutaline
DPI (500)
2.73-2.96
4.15-8.24
5.83
4-6
Tachycardia, tremor, headache
4-6
Long-acting beta2 agonists (LABA)20-23
Formoterol
DPI (4.5 – 12)
Tachycardia, tremor, headache, palpitations, muscle
spasms, hypokalaemia
18.67-23.44
12
Salmeterol
DPI (50)
26.63
12
Indacaterol
DPI (150-300)
30.72-33.32
24
Short-acting muscarinic antagonists (SAMA)24
Ipratropium bromide *** MDI (20)
Caution in patients with cardiovascular disease. Risk of QT
prolongation. Palpitations, headache, tremor
Caution in patients with cardiovascular disease. Risk of
drug interaction with potent CYP3A4 inhibitors. Headache,
tremor, palpitations, muscle cramps
Caution in patients with cardiovascular disease. Upper
respiratory tract infection, nasopharyngitis, sinusitis,
headache, dizziness, cough, throat irritation, rhinorrhoea,
muscle spasm, chest pain, peripheral oedema
2.47
6-8
Long-acting muscarinic antagonist (LAMA)25-28
Tiotropium bromide
DPI (18)
SMI (5)
Glycopyrronium bromide▼ DPI (44)
Caution in patients with glaucoma or urinary retention.
Headache, dizziness, throat irritation, cough, dry mouth,
nausea, gastrointestinal motility disorder
38.57
38.57
34.50
24
Drug
Monthly costs in
Euros #
Duration
of action Undesirable Effects/Special precautions include*
(hours)
Aclidinium bromide▼
DPI (322)
Combination of LABA and LAMA29
Indacaterol/
DPI (85/43)
Glycopyrronium bromide▼
Inhaled corticosteroids (ICS)30-32
Budesonide
DPI (100,200,400)
Not marketed in Ireland 12
Caution in patients with glaucoma, urinary retention or
cardiovascular disease. Dry mouth
Caution in patients with glaucoma, urinary retention
or cardiovascular disease. Nasopharyngitis, insomnia,
headache, dry mouth, gastroenteritis, urinary tract infection
Sinusitis, nasopharyngitis, headache, cough, diarrhoea
Not marketed in Ireland 24
See individual drugs
13.91-16.83
Fluticasone
8.19-34.20
5.65-31.85
Caution in patients with tuberculosis. Oropharyngeal
candidiasis, cough, hoarseness, throat irritation
Risk of drug interaction with ritonavir. Oropharyngeal
candidiasis, pneumonia, hoarseness
46.40-45.49
See individual drugs
MDI (50-500)
DPI (50-500)
Combination of LABA and ICS33,34
Budesonide/formoterol
DPI (200/6, 400/12)
24
Salmeterol/fluticasone
DPI (50/100, 50/250, 50/500) 29.09-51.12
See individual drugs
# monthly costs according to MIMS Ireland October 2013, * - the Summary of Product Characteristics should be consulted for full prescribing information,
** - oral formulation also available, *** - nebule formulation also available, **** - intravenous formulation also available, MDI – metered dose inhaler; DPI –
dry powder inhaler; BD - twice daily, SMI – soft mist inhaler, ▼ - drug subject to additional monitoring
Table 4: Currently authorised oral formulations for COPD
Drug
Methylxanthines35-38
Aminophylline**
Theophylline
Monthly costs
in Euros #
Special Precautions /Undesirable Effects Include*
Caution in patients with cardiac disease. Drug interactions common.
Headache, nausea, vomiting, gastric irritation, anorexia
Therapeutic drug monitoring recommended
2.70
2.13-7.73
Phosphodiesterase-4 inhibitors39
Roflumilast▼
Not available
Associated with risk of psychiatric disorders; rare cases of suicidal
ideation reported. Weight loss, anorexia, insomnia, headache, diarrhoea,
nausea, abdominal pain
Systemic corticosteroids40
Methylprednisolone
Prednisolone
Variable
Hypothalamic-pituitary adrenal suppression, infection, congestive heart
failure, peptic ulcer
# monthly costs according to MIMS Ireland October 2013,, * - the Summary of Product Characteristics should be consulted for full prescribing information,
** - intravenous formulations also available, ▼ - drug subject to additional monitoring
Bronchodilators
Airway smooth muscle relaxation, leading to bronchodilatation is achieved mainly by beta2 agonists and muscarinic antagonists.41
Short-acting bronchodilators are used for rescue or as needed treatment and long-acting bronchodilators are used for maintenance
treatment.1,8,42 The choice of bronchodilator therapy (see table 3 and 4) depends on the individual patient’s response in terms
of symptom relief and tolerability.43
Beta2 agonists: Short-acting beta2 agonists (SABAs) improve bronchodilator function in patients with moderate to severe COPD
(see table 3).8 The long-acting beta2 agonists (LABAs) have been shown to significantly improve FEV1, patients’ symptoms and
exacerbation rate but they have no effect on mortality and rate of decline in lung function.1,44 There have been cardiovascular
safety concerns regarding the use of beta2 agonists, however studies have not found an association between their use and increased
mortality in COPD.1,8,45
Muscarinic antagonists: Ipratropium bromide is the only short-acting muscarinic antagonist (SAMA) currently available; its
effects are similar to the SABAs.46 There are several long-acting muscarinic antagonists (LAMAs) available (see table 3); they
show similar efficacy in terms of improved symptoms, reduced exacerbations and hospitalisation for COPD.1,8,43,47-50 A Cochrane
review which compared tiotropium to LABAs concluded that its effects were superior in terms of preventing exacerbations and
hospitalisations,51 however the results of an observational study of older adults with COPD suggested that patients prescribed
LABAs had a lower mortality than those prescribed LAMAs.52 Tiotropium has also been shown to have more benefits than
ipratropium bromide for people with moderate to severe COPD.53
There have been concerns regarding increased mortality in patients receiving tiotropium, in particular with use of the soft mist
inhaler device.1,48,50,54-56 A recent study, which excluded patients with recent myocardial infarction or unstable arrhythmia found
no difference in mortality between the soft mist and dry powder device.57,58 Post-authorisation safety studies on cardiovascular
outcomes have been requested for glycopyrronium bromide▼ and aclidinium bromide▼ (currently not marketed in Ireland).59
Methylxanthines are thought to act as non-selective phosphodiesterase inhibitors (see table 4).1 A methylxanthine should only be
used after a trial of short-acting and long-acting bronchodilators and in those unable to use inhaled therapy.1,4 If required, slow
release preparations are recommended. Theophylline, the most commonly used preparation, has a narrow therapeutic index and
drug monitoring is required. It is metabolised by cytochrome P450 and there is a significant risk of interaction with commonly
used medicines including digoxin, warfarin, macrolides and quinolones.1,8
Combination bronchodilator therapy increases the degree of bronchodilation with equivalent or fewer side-effects.1,60-62 The
combination of tiotropium and LABA resulted in a better HRQoL and lung function compared to using tiotropium alone, but
no difference in hospital admissions or mortality was noted.41,61 Combinations of indacaterol/tiotropium, and indacaterol/
glycopyrronium▼ have also been shown to be associated with significant improvement in symptoms.41,60,63
Other pharmacological agents
Inhaled corticosteroids: There are conflicting views on the benefits of inhaled corticosteroids (ICS) in COPD.1,8,64,65 Their use is
associated with a reduction in exacerbations and rate of decline of HRQoL, however they are associated with an increased risk
of pneumonia.8,65,66 Long-term monotherapy with ICS is not recommended.1 Guidelines recommend combinations of LABA and
ICS patients at high risk of exacerbations (not all preparations are licensed for COPD);1 which have been shown to improve
lung function and HRQoL and reduce exacerbations.1,8,67-70 The combination of ICS, LABA and tiotropium has also been shown
to improve lung function and HRQoL.1,41,71
Phosphodiesterase- 4 (PDE-4) inhibitors’ principal action is to reduce inflammation.1 Roflumilast▼, (not currently marketed
in Ireland), is a once daily oral preparation (see table 4). It improves FEV1 in patients treated with salmeterol or tiotropium and
has been shown to reduce moderate and severe exacerbations in patients with severe COPD treated with corticosteroids.1 PDE-4
inhibitors should always be used in combination with at least one long-acting bronchodilator.1 Roflumilast▼ is metabolised by
cytochrome P450 3A4 to an active metabolite, which itself is metabolised by CYP 3A4,5,39 therefore there is a potential risk of
drug-drug interactions. Roflumilast▼ should not be used in patients treated with theophylline.1
Systemic corticosteroids are used to treat exacerbations of COPD, but there is no evidence to support their long-term use in
stable COPD,1,73 and they are not normally recommended.4 Some patients with advanced COPD may require maintenance
corticosteroids; in these cases the dose of oral corticosteroids should be kept as low as possible.4
Adjunctive therapeutic agents
Vaccination: Patients with COPD should receive influenza and pneumococcal vaccines, which reduce serious illness and death
in patients with COPD.1 The use of continuous prophylactic antibiotics has shown inconsistent results,74,75 and is not currently
recommended for COPD.1 Controversy exists regarding the use of mucolytic agents such as carbocisteine and N-acetylcysteine,
however they may provide symptomatic relief in some patients.1,4
Pharmacotherapy for smoking cessation: Unless contraindicated, patients who are planning to stop smoking should be offered
nicotine replacement therapy, varenicline▼59 or bupropion as appropriate with a suitable support programme.1,4,8
Inhaler devices
The choice of inhaler device for an individual patient is an essential aspect to consider in COPD management.1,41 Each device has
different operating and maintenance instructions, and successful use of a given drug/device combination requires that patients
are continually instructed in its use.76 Poor inhaler technique is often a major cause of suboptimal COPD management.4,76
In most cases bronchodilators are best administered using a hand-held inhaler device.4 The devices currently available are
pressurised metered dose inhalers (pMDI), dry powder inhalers (DPIs) and a propellant soft mist inhaler (SMI) (see table 3).
Some patients may have coordination difficulties using the pMDIs; this can be improved by use of a spacer or with breath
activated devices. Patients may also find it difficult to use some DPIs, which may require loading by the patient, or there may
be low inspiratory flow rate with a severe exacerbation.41 Poor inhaler technique has been reported in 8-59% of patients using
pMDIs and 4-94% of patients using DPIs (depending on the type of device) resulting in little or no pulmonary drug deposition.76
Currently the only SMI in clinical use contains tiotropium.76 There are no substantial differences between the effects of drugs
delivered via a pMDI and a nebuliser to elderly patients.76 Guidelines recommend nebulisers for patients with stable COPD
only when other therapies do not provide symptomatic benefit; they have significant disadvantages particularly as they are
less portable and inhibit patient activity.1
PRACTICAL ASPECTS OF MANAGEMENT
Stable COPD: The GOLD guidelines recommend a stepwise approach for the management of stable COPD, based according
to an assessment of the individual’s disease severity, symptoms and exacerbations as outlined in table 5.
Table 5: Pharmacological therapies for stable COPD1
Patient Group
1st Choice
Alternative Choice
Other Possible
Treatments*
A: Gold 1-2
Low risk of exacerbations,
less symptoms
SAMA prn or SABA
prn
LAMA or LABA or SABA + SAMA
Theophylline
B: Gold 1-2
Low risk of exacerbation,
more symptoms
LAMA or LABA
LAMA + LABA
SABA and/or SAMA
Theophylline
C: GOLD 3-4
High risk of exacerbation, less
symptoms
ICS + LABA or
LAMA
LAMA + LABA or LAMA + PDE-4
inhibitor or LABA + PDE-4 inhibitor
SABA and/or SAMA
Theophylline
D: GOLD 3-4
High risk of exacerbations, more
symptoms
ICS + LABA and/or
LAMA
ICS + LABA + LAMA or ICS + LABA +
PDE-4 inhibitor or LAMA
+ LABA or LAMA + PDE-4 inhibitor
Carbocisteine
SABA and/or SAMA
Theophylline
* can be used alone or in combination with the recommended first and alternative choice options, SAMA – short-acting muscarinic antagonist, SABA –
short-acting β2- agonist, LAMA – long-acting muscarinic antagonist, LABA – long-acting β2- agonist, ICS – inhaled corticosteroid, PDE – phosphodiesterase
Management of exacerbations: Exacerbations of COPD can be precipitated by several factors including respiratory tract
infections (viral or bacterial). The diagnosis is made following assessment of the patient presenting with an acute change in
symptoms. It is estimated that up to 80% of patients can be managed on an outpatient basis with pharmacological therapies such
as bronchodilators, corticosteroids and antibiotics.1 Indications for hospital assessment or admission include marked increase
in intensity of symptoms (such as sudden onset resting dyspnoea), severe underlying COPD, onset of new physical signs
(such as cyanosis, peripheral oedema), failure to respond to initial medical management, frequent exacerbations, older
age and insufficient home support.1 SABAs, with or without SAMAs are usually the preferred bronchodilators for treatment
of an exacerbation.1 Evidence from in-patient settings has shown that use of systemic corticosteroids in COPD exacerbations
shortens recovery time, improves FEV1 and arterial hypoxaemia, reduces the risk of early relapse and treatment failure and
lessens duration of hospital stay.1 There is insufficient evidence on the optimal duration of treatment although most guidelines
recommend 30-40mg prednisolone for 7-14 days.1,4,77,78 A gradual withdrawal of corticosteroids may be required if they are used at
doses ≥40mg/day or for >3 weeks.79 A recent RCT supports the use of 5 days’ treatment with oral corticosteroids for exacerbation
of COPD.80,81 The choice of antibiotic therapy to use in COPD should be based on the local bacterial resistance pattern.1 Irish
guidelines recommend first line primary care treatment with amoxicillin or doxycycline or clarithromycin; combinations of
antibiotics are not required for COPD.82 In addition to pharmacological therapy, hospital management includes respiratory
support with oxygen therapy and ventilatory support.1 The use of NIV has increased significantly in patients hospitalised with
COPD and has been associated with improved mortality.1,4,83 COPD Outreach Services which allow selected patients with
COPD to be discharged early and cared for at home have been shown to be safe and effective and have been instituted in many
acute care hospitals around the country.2
Palliative care: At the end of life, patients with advanced COPD have a higher disease burden than those with lung cancer.84
Palliative care is an important aspect to consider in the management of a patient with advanced COPD, however patients with
COPD are less likely to receive such services than patients with lung cancer. The hospice foundation has details of recent research
on this topic (http://hospicefoundation.ie/what-we-do/palliative-care-for-all/advanced-respiratory-disease/).
SUMMARY
COPD is a preventable and treatable condition which is associated with high rates of morbidity and mortality; it is widely
under-diagnosed. Pharmacotherapy coupled with the active management of smoking, patient education and lifestyle (including
planned exercise) helps to reduce the number of exacerbations and hospitalisations.1 Pharmacological treatment should be
individualised to the patient and regularly reviewed for effectiveness and technique. The National COPD programme is
working towards establishing an improved national model of care with combined hospital and community based initiatives
such as COPD outreach and pulmonary rehabilitation programmes.
FOR PERSONAL USE ONLY. NOT TO BE REPRODUCED WITHOUT PERMISSION OF THE EDITOR
List of references available on request. Date of preparation: October 2013
Every effort has been made to ensure that this information is correct and is prepared from the best available resources at our disposal at the time of issue.
Prescribers are recommended to refer to the individual Summary of Product Characteristics (SmPC) for specific information on a drug.
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